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Yang Z, Zheng Y, Gao Q. Lysine lactylation in the regulation of tumor biology. Trends Endocrinol Metab 2024; 35:720-731. [PMID: 38395657 DOI: 10.1016/j.tem.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024]
Abstract
Lysine lactylation (Kla), a newly discovered post-translational modification (PTM) of lysine residues, is progressively revealing its crucial role in tumor biology. A growing body of evidence supports its capacity of transcriptional regulation through histone modification and modulation of non-histone protein function. It intricately participates in a myriad of events in the tumor microenvironment (TME) by orchestrating the transitions of immune states and augmenting tumor malignancy. Its preferential modification of metabolic proteins underscores its specific regulatory influence on metabolism. This review focuses on the effect and the probable mechanisms of Kla-mediated regulation of tumor metabolism, the upstream factors that determine Kla intensity, and its potential implications for the clinical diagnosis and treatment of tumors.
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Affiliation(s)
- Zijian Yang
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yingqi Zheng
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
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Braga A, Chiacchiaretta M, Pellerin L, Kong D, Haydon PG. Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture. Nat Commun 2024; 15:5979. [PMID: 39013907 PMCID: PMC11252394 DOI: 10.1038/s41467-024-50166-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 06/17/2024] [Indexed: 07/18/2024] Open
Abstract
Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. Here we investigated the involvement of astrocytic lactate supply in maintaining consolidated wakefulness by downregulating, in a cell-specific manner, the expression of monocarboxylate transporters (MCTs) in the lateral hypothalamus of transgenic mice. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to wake-promoting orexin neurons, impairing wakefulness stability. Additionally, we show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexin neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability.
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Affiliation(s)
- Alice Braga
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA
| | - Martina Chiacchiaretta
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA.
| | - Luc Pellerin
- Inserm U1313, University and CHU of Poitiers, 86021, Poitiers, France
| | - Dong Kong
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA
- Division of Endocrinology, Department of Pediatrics, F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Philip G Haydon
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA.
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Xie J, Zhang Y, Li B, Xi W, Wang Y, Li L, Liu C, Shen L, Han B, Kong Y, Yao H, Zhang Z. Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke. J Transl Med 2024; 22:248. [PMID: 38454480 PMCID: PMC10921652 DOI: 10.1186/s12967-024-04993-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 02/12/2024] [Indexed: 03/09/2024] Open
Abstract
BACKGROUND Acute ischemic stroke is a common neurological disease with a significant financial burden but lacks effective drugs. Hypoxia-inducible factor (HIF) and prolyl hydroxylases (PHDs) participate in the pathophysiological process of ischemia. However, whether FG4592, the first clinically approved PHDs inhibitor, can alleviate ischemic brain injury remains unclear. METHODS The infarct volumes and behaviour tests were first analyzed in mice after ischemic stroke with systemic administration of FG4592. The knockdown of HIF-1α and pretreatments of HIF-1/2α inhibitors were then used to verify whether the neuroprotection of FG4592 is HIF-dependent. The targets predicting and molecular docking methods were applied to find other targets of FG4592. Molecular, cell biological and gene knockdown methods were finally conducted to explore the potential neuroprotective mechanisms of FG4592. RESULTS We found that the systemic administration of FG4592 decreased infarct volume and improved neurological defects of mice after transient or permanent ischemia. Meanwhile, FG4592 also activated autophagy and inhibited apoptosis in peri-infarct tissue of mice brains. However, in vitro and in vivo results suggested that the neuroprotection of FG4592 was not classical HIF-dependent. 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1 (OGFOD1) was found to be a novel target of FG4592 and regulated the Pro-62 hydroxylation in the small ribosomal protein s23 (Rps23) with the help of target predicting and molecular docking methods. Subsequently, the knockdown of OGFOD1 protected the cell against ischemia/reperfusion injury and activated unfolded protein response (UPR) and autophagy. Moreover, FG4592 was also found to activate UPR and autophagic flux in HIF-1α independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy effect and anti-apoptosis ability of FG4592. CONCLUSION This study demonstrated that FG4592 could be a candidate drug for treating ischemic stroke. The neuroprotection of FG4592 might be mediated by inhibiting alternative target OGFOD1, which activated the UPR and autophagy and inhibited apoptosis after ischemic injury. The inhibition of OGFOD1 is a novel therapy for ischemic stroke.
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Affiliation(s)
- Jian Xie
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yuan Zhang
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Bin Li
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Wen Xi
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yu Wang
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Lu Li
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Chenchen Liu
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Ling Shen
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Bing Han
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yan Kong
- Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China
| | - HongHong Yao
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
| | - Zhijun Zhang
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Institution of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, 210009, Jiangsu, China.
- The Brain Cognition and Brain Disease Institute of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, Guangdong, China.
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Chai YC, To SK, Simorgh S, Zaunz S, Zhu Y, Ahuja K, Lemaitre A, Ramezankhani R, van der Veer BK, Wierda K, Verhulst S, van Grunsven LA, Pasque V, Verfaillie C. Spatially Self-Organized Three-Dimensional Neural Concentroid as a Novel Reductionist Humanized Model to Study Neurovascular Development. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304421. [PMID: 38037510 PMCID: PMC10837345 DOI: 10.1002/advs.202304421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 10/15/2023] [Indexed: 12/02/2023]
Abstract
Although human pluripotent stem cell (PSC)-derived brain organoids have enabled researchers to gain insight into human brain development and disease, these organoids contain solely ectodermal cells and are not vascularized as occurs during brain development. Here it is created less complex and more homogenous large neural constructs starting from PSC-derived neuroprogenitor cells (NPC), by fusing small NPC spheroids into so-called concentroids. Such concentroids consisted of a pro-angiogenic core, containing neuronal and outer radial glia cells, surrounded by an astroglia-dense outer layer. Incorporating PSC-derived endothelial cells (EC) around and/or in the concentroids promoted vascularization, accompanied by differential outgrowth and differentiation of neuronal and astroglia cells, as well as the development of ectodermal-derived pericyte-like mural cells co-localizing with EC networks. Single nucleus transcriptomic analysis revealed an enhanced neural cell subtype maturation and diversity in EC-containing concentroids, which better resemble the fetal human brain compared to classical organoids or NPC-only concentroids. This PSC-derived "vascularized" concentroid brain model will facilitate the study of neurovascular/blood-brain barrier development, neural cell migration, and the development of effective in vitro vascularization strategies of brain mimics.
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Affiliation(s)
- Yoke Chin Chai
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - San Kit To
- Stem Cell Institute LeuvenDepartment of Development and RegenerationLeuven Institute for Single Cell Omics (LISCO)KU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Susan Simorgh
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Samantha Zaunz
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - YingLi Zhu
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Karan Ahuja
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Alix Lemaitre
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Roya Ramezankhani
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Bernard K. van der Veer
- Laboratory for Stem Cell and Developmental EpigeneticsDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Keimpe Wierda
- Electrophysiology Expert UnitVIB‐KU Leuven Center for Brain & Disease ResearchLeuven3000Belgium
| | - Stefaan Verhulst
- Liver Cell Biology Research GroupVrije Universiteit Brussel (VUB)Brussels1090Belgium
| | - Leo A. van Grunsven
- Liver Cell Biology Research GroupVrije Universiteit Brussel (VUB)Brussels1090Belgium
| | - Vincent Pasque
- Stem Cell Institute LeuvenDepartment of Development and RegenerationLeuven Institute for Single Cell Omics (LISCO)KU Leuven, O&N4, Herestraat 49Leuven3000Belgium
| | - Catherine Verfaillie
- Stem Cell Institute LeuvenDepartment of Development and RegenerationKU Leuven, O&N4, Herestraat 49Leuven3000Belgium
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Bosso M, Haddad D, Al Madhoun A, Al-Mulla F. Targeting the Metabolic Paradigms in Cancer and Diabetes. Biomedicines 2024; 12:211. [PMID: 38255314 PMCID: PMC10813379 DOI: 10.3390/biomedicines12010211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.
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Affiliation(s)
- Mira Bosso
- Department of Pathology, Faculty of Medicine, Health Science Center, Kuwait University, Safat 13110, Kuwait
| | - Dania Haddad
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
| | - Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
- Department of Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Department of Pathology, Faculty of Medicine, Health Science Center, Kuwait University, Safat 13110, Kuwait
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
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EL-Seedy A, Pellerin L, Page G, Ladeveze V. Identification of Intron Retention in the Slc16a3 Gene Transcript Encoding the Transporter MCT4 in the Brain of Aged and Alzheimer-Disease Model (APPswePS1dE9) Mice. Genes (Basel) 2023; 14:1949. [PMID: 37895298 PMCID: PMC10606527 DOI: 10.3390/genes14101949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/12/2023] [Accepted: 10/14/2023] [Indexed: 10/29/2023] Open
Abstract
The monocarboxylate transporter 4 (MCT4; Slc16a3) is expressed in the central nervous system, notably by astrocytes. It is implicated in lactate release and the regulation of glycolytic flux. Whether its expression varies during normal and/or pathological aging is unclear. As the presence of its mature transcript in the brain of young and old mice was determined, an unexpectedly longer RT-PCR fragment was detected in the mouse frontal cortex and hippocampus at 12 vs. 3 months of age. Cultured astrocytes expressed the expected 516 base pair (bp) fragment but treatment with IL-1β to mimic inflammation as can occur during aging led to the additional expression of a 928 bp fragment like that seen in aged mice. In contrast, cultured pericytes (a component of the blood-brain barrier) only exhibited the 516 bp fragment. Intriguingly, cultured endothelial cells constitutively expressed both fragments. When RT-PCR was performed on brain subregions of an Alzheimer mouse model (APPswePS1dE9), no fragment was detected at 3 months, while only the 928 bp fragment was present at 12 months. Sequencing of MCT4 RT-PCR products revealed the presence of a remaining intron between exon 2 and 3, giving rise to the longer fragment detected by RT-PCR. These results unravel the existence of intron retention for the MCT4 gene in the central nervous system. Such alternative splicing appears to increase with age in the brain and might be prominent in neurodegenerative diseases such as Alzheimer's disease. Hence, further studies in vitro and in vivo of intron 2 retention in the Slc16a3 gene transcript are required for adequate characterization concerning the biological roles of Slc16a3 isoforms in the context of aging and Alzheimer's disease pathology.
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Affiliation(s)
- Ayman EL-Seedy
- Laboratory of Cellular and Molecular Genetics, Department of Genetics, Alexandria University, Aflaton Street, El-Shatby, Alexandria 21545, Egypt;
- Neurovascular Unit and Cognitive Disorders (NEUVACOD), Faculty of Pharmacy (GP), Faculty of Fundamental and Applied Science (VL), University of Poitiers, Pôle Biologie Santé, 86073 Poitiers, France;
| | - Luc Pellerin
- IRMETIST, INSERM, Faculty of Medicine, University of Poitiers (U1313), CHU de Poitiers, 86021 Poitiers, France;
| | - Guylène Page
- Neurovascular Unit and Cognitive Disorders (NEUVACOD), Faculty of Pharmacy (GP), Faculty of Fundamental and Applied Science (VL), University of Poitiers, Pôle Biologie Santé, 86073 Poitiers, France;
| | - Veronique Ladeveze
- Neurovascular Unit and Cognitive Disorders (NEUVACOD), Faculty of Pharmacy (GP), Faculty of Fundamental and Applied Science (VL), University of Poitiers, Pôle Biologie Santé, 86073 Poitiers, France;
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Ueno M, Chiba Y, Murakami R, Miyai Y, Matsumoto K, Wakamatsu K, Takebayashi G, Uemura N, Yanase K. Distribution of Monocarboxylate Transporters in Brain and Choroid Plexus Epithelium. Pharmaceutics 2023; 15:2062. [PMID: 37631275 PMCID: PMC10458808 DOI: 10.3390/pharmaceutics15082062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
The choroid plexus (CP) plays central roles in regulating the microenvironment of the central nervous system by secreting the majority of cerebrospinal fluid (CSF) and controlling its composition. A monolayer of epithelial cells of CP plays a significant role in forming the blood-CSF barrier to restrict the movement of substances between the blood and ventricles. CP epithelial cells are equipped with transporters for glucose and lactate that are used as energy sources. There are many review papers on glucose transporters in CP epithelial cells. On the other hand, distribution of monocarboxylate transporters (MCTs) in CP epithelial cells has received less attention compared with glucose transporters. Some MCTs are known to transport lactate, pyruvate, and ketone bodies, whereas others transport thyroid hormones. Since CP epithelial cells have significant carrier functions as well as the barrier function, a decline in the expression and function of these transporters leads to a poor supply of thyroid hormones as well as lactate and can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases. In this review paper, recent findings regarding the distribution and significance of MCTs in the brain, especially in CP epithelial cells, are summarized.
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Affiliation(s)
- Masaki Ueno
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (Y.C.); (R.M.); (Y.M.); (K.M.); (K.W.)
| | - Yoichi Chiba
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (Y.C.); (R.M.); (Y.M.); (K.M.); (K.W.)
| | - Ryuta Murakami
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (Y.C.); (R.M.); (Y.M.); (K.M.); (K.W.)
| | - Yumi Miyai
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (Y.C.); (R.M.); (Y.M.); (K.M.); (K.W.)
| | - Koichi Matsumoto
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (Y.C.); (R.M.); (Y.M.); (K.M.); (K.W.)
| | - Keiji Wakamatsu
- Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (Y.C.); (R.M.); (Y.M.); (K.M.); (K.W.)
| | - Genta Takebayashi
- Department of Anesthesiology, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (G.T.); (N.U.); (K.Y.)
| | - Naoya Uemura
- Department of Anesthesiology, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (G.T.); (N.U.); (K.Y.)
| | - Ken Yanase
- Department of Anesthesiology, Faculty of Medicine, Kagawa University, Takamatsu 761-0793, Kagawa, Japan; (G.T.); (N.U.); (K.Y.)
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Monocarboxylate transporter 4 involves in energy metabolism and drug sensitivity in hypoxia. Sci Rep 2023; 13:1501. [PMID: 36707650 PMCID: PMC9883486 DOI: 10.1038/s41598-023-28558-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 01/20/2023] [Indexed: 01/29/2023] Open
Abstract
Metabolic reprogramming of cancer cells is a potential target for cancer therapy. It is also known that a hypoxic environment, one of the tumor microenvironments, can alter the energy metabolism from oxidative phosphorylation to glycolysis. However, the relationship between hypoxia and drug sensitivity, which targets energy metabolism, is not well known. In this study, A549 cells, a cell line derived from lung adenocarcinoma, were evaluated under normoxia and hypoxia for the sensitivity of reagents targeting oxidative phosphorylation (metformin) and glycolysis (α-cyano-4-hydroxycinnamic acid [CHC]). The results showed that a hypoxic environment increased the expression levels of monocarboxylate transporter (MCT) 4 and hypoxia-induced factor-1α (HIF-1α), whereas MCT1 and MCT2 expression did not vary between normoxia and hypoxia. Furthermore, the evaluation of the ATP production ratio indicated that glycolysis was enhanced under hypoxic conditions. It was then found that the sensitivity to metformin decreased while that to CHC increased under hypoxia. To elucidate this mechanism, MCT4 and HIF-1α were knocked down and the expression level of MCT4 was significantly decreased under both conditions. In contrast, the expression of HIF-1α was decreased by HIF-1α knockdown and increased by MCT4 knockdown. In addition, changes in metformin and CHC sensitivity under hypoxia were eliminated by the knockdown of MCT4 and HIF-1α, suggesting that MCT4 is involved in the phenomenon described above. In conclusion, it was shown that the sensitivity of reagents targeting energy metabolism is dependent on their microenvironment. As MCT4 is involved in some of these mechanisms, we hypothesized that MCT4 could be an important target molecule for cancer therapy.
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Tiwari AK, Adhikari A, Mishra LC, Srivastava A. Current Status of Our Understanding for Brain Integrated Functions and its Energetics. Neurochem Res 2022; 47:2499-2512. [PMID: 35689788 DOI: 10.1007/s11064-022-03633-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 10/18/2022]
Abstract
Human/animal brain is a unique organ with substantially high metabolism but it contains no energy reserve that is the reason it requires continuous supply of O2 and energy fluxes through CBF. The main source of energy remains glucose as the other biomolecules do not able to cross the blood-brain barrier. The speed of glucose metabolism is heterogeneous throughout the brain. One of the major flux consumption is Neuron-astrocyte cycling of glutamate and glutamine in glutamatergic neurons (approximately 80% of glucose metabolism in brain). The quantification of cellular glucose and other related substrate in resting, activated state can be analyzed through [18 F]FDG -positron-emission tomography (studying CMRglc) and [13 C/31P -MRS: for neuroenergetics & neurotransmitter cycling &31P-MRS: for energy induction & redox state). Merging basic in vitro studies with these techniques will help to develop new treatment paradigms for human brain diseased conditions.
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Affiliation(s)
- Anjani Kumar Tiwari
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), 226025, Lucknow, Uttar Pradesh, India.
| | - Anupriya Adhikari
- Department of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), 226025, Lucknow, Uttar Pradesh, India
| | - Lokesh Chandra Mishra
- Department of Zoology, Hansraj College, University of Delhi, North Campus, 110007, Delhi, India
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Yi O, Lin Y, Hu M, Hu S, Su Z, Liao J, Liu B, Liu L, Cai X. Lactate metabolism in rheumatoid arthritis: Pathogenic mechanisms and therapeutic intervention with natural compounds. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 100:154048. [PMID: 35316725 DOI: 10.1016/j.phymed.2022.154048] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/26/2022] [Accepted: 03/11/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a common chronic and systemic autoimmune disease characterized by persistent inflammation and hyperplasia of the synovial membrane, the degradation of cartilage, and the erosion of bones in diarthrodial joints. The inflamed joints of patients with RA have been recognized to be a site of hypoxic microenvironment which results in an imbalance of lactate metabolism and the accumulation of lactate. Lactate is no longer considered solely a metabolic waste product of glycolysis, but also a combustion aid in the progression of RA from the early stages of inflammation to the late stages of bone destruction. PURPOSE To review the pathogenic mechanisms of lactate metabolism in RA and investigate the potential of natural compounds for treating RA linked to the regulation of imbalance in lactate metabolism. METHODS Research advances in our understanding of lactate metabolism in the pathogenesis of RA and novel pharmacological approaches of natural compounds by targeting lactate metabolic signaling were comprehensively reviewed and deeply discussed. RESULTS Lactate produced by RA synovial fibroblasts (RASFs) acts on targeted cells such as T cells, macrophages, dendritic cells and osteoclasts, and affects their differentiation, activation and function to accelerate the development of RA. Many natural compounds show therapeutic potential for RA by regulating glycolytic rate-limiting enzymes to limit lactate production, and affecting monocarboxylate transporter and acetyl-CoA carboxylase to inhibit lactate transport and conversion. CONCLUSION Regulation of imbalance in lactate metabolism offers novel therapeutic approaches for RA, and natural compounds capable of targeting lactate metabolic signaling constitute potential candidates for development of drugs RA.
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Affiliation(s)
- Ouyang Yi
- Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Ye Lin
- Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Mingyue Hu
- Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Shengtao Hu
- Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Zhaoli Su
- Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Jin Liao
- Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Bin Liu
- College of Biology, Hunan University, Changsha, Hunan 410082, China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, 030027, China
| | - Xiong Cai
- Institute of Innovation and Applied Research in Chinese Medicine and Department of Rheumatology of The First Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
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11
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Zhang M, Wang Y, Bai Y, Dai L, Guo H. Monocarboxylate Transporter 1 May Benefit Cerebral Ischemia via Facilitating Lactate Transport From Glial Cells to Neurons. Front Neurol 2022; 13:781063. [PMID: 35547368 PMCID: PMC9081727 DOI: 10.3389/fneur.2022.781063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
Monocarboxylate transporter 1 (MCT1) is expressed in glial cells and some populations of neurons. MCT1 facilitates astrocytes or oligodendrocytes (OLs) in the energy supplement of neurons, which is crucial for maintaining the neuronal activity and axonal function. It is suggested that MCT1 upregulation in cerebral ischemia is protective to ischemia/reperfusion (I/R) injury. Otherwise, its underlying mechanism has not been clearly discussed. In this review, it provides a novel insight that MCT1 may protect brain from I/R injury via facilitating lactate transport from glial cells (such as, astrocytes and OLs) to neurons. It extensively discusses (1) the structure and localization of MCT1; (2) the regulation of MCT1 in lactate transport among astrocytes, OLs, and neurons; and (3) the regulation of MCT1 in the cellular response of lactate accumulation under ischemic attack. At last, this review concludes that MCT1, in cerebral ischemia, may improve lactate transport from glial cells to neurons, which subsequently alleviates cellular damage induced by lactate accumulation (mostly in glial cells), and meets the energy metabolism of neurons.
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Affiliation(s)
- Mao Zhang
- Department of Medical Genetics, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Yanyan Wang
- Department of Medical Genetics, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Yun Bai
- Department of Medical Genetics, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Limeng Dai
- Department of Medical Genetics, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Hong Guo
- Department of Medical Genetics, College of Basic Medical Sciences, Army Medical University, Chongqing, China
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12
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Gao X, Zeb S, He YY, Guo Y, Zhu YM, Zhou XY, Zhang HL. Valproic Acid Inhibits Glial Scar Formation after Ischemic Stroke. Pharmacology 2022; 107:263-280. [PMID: 35316816 DOI: 10.1159/000514951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Accepted: 02/02/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Cerebral ischemia induces reactive proliferation of astrocytes (astrogliosis) and glial scar formation. As a physical and biochemical barrier, the glial scar not only hinders spontaneous axonal regeneration and neuronal repair but also deteriorates the neuroinflammation in the recovery phase of ischemic stroke. OBJECTIVES Previous studies have shown the neuroprotective effects of the valproic acid (2-n-propylpentanoic acid, VPA) against ischemic stroke, but its effects on the ischemia-induced formation of astrogliosis and glial scar are still unknown. As targeting astrogliosis has become a therapeutic strategy for ischemic stroke, this study was designed to determine whether VPA can inhibit the ischemic stroke-induced glial scar formation and to explore its molecular mechanisms. METHODS Glial scar formation was induced by an ischemia-reperfusion (I/R) model in vivo and an oxygen and glucose deprivation (OGD)-reoxygenation (OGD/Re) model in vitro. Animals were treated with an intraperitoneal injection of VPA (250 mg/kg/day) for 28 days, and the ischemic stroke-related behaviors were assessed. RESULTS Four weeks of VPA treatment could markedly reduce the brain atrophy volume and improve the behavioral deficits in rats' I/R injury model. The results showed that VPA administrated upon reperfusion or 1 day post-reperfusion could also decrease the expression of the glial scar makers such as glial fibrillary acidic protein, neurocan, and phosphacan in the peri-infarct region after I/R. Consistent with the in vivo data, VPA treatment showed a protective effect against OGD/Re-induced astrocytic cell death in the in vitro model and also decreased the expression of GFAP, neurocan, and phosphacan. Further studies revealed that VPA significantly upregulated the expression of acetylated histone 3, acetylated histone 4, and heat-shock protein 70.1B in the OGD/Re-induced glial scar formation model. CONCLUSION VPA produces neuroprotective effects and inhibits the glial scar formation during the recovery period of ischemic stroke via inhibition of histone deacetylase and induction of Hsp70.1B.
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Affiliation(s)
- Xue Gao
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key, Soochow University, Suzhou, China
| | - Salman Zeb
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key, Soochow University, Suzhou, China
| | - Yuan-Yuan He
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key, Soochow University, Suzhou, China
| | - Yi Guo
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key, Soochow University, Suzhou, China
| | - Yong-Ming Zhu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key, Soochow University, Suzhou, China
| | - Xian-Yong Zhou
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key, Soochow University, Suzhou, China
| | - Hui-Ling Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key, Soochow University, Suzhou, China
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13
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Lactate Supply from Astrocytes to Neurons and its Role in Ischemic Stroke-induced Neurodegeneration. Neuroscience 2022; 481:219-231. [PMID: 34843897 DOI: 10.1016/j.neuroscience.2021.11.035] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/19/2021] [Accepted: 11/22/2021] [Indexed: 01/10/2023]
Abstract
Glucose transported to the brain is metabolized to lactate in astrocytes and supplied to neuronal cells via a monocarboxylic acid transporter (MCT). Lactate is used in neuronal cells for various functions, including learning and memory formation. Furthermore, lactate can block stroke-induced neurodegeneration. We aimed to clarify the effect of astrocyte-produced lactate on stroke-induced neurodegeneration. Previously published in vivo and in vitro animal and cell studies, respectively, were searched in PubMed, ScienceDirect, and Web of Science. Under physiological conditions, lactate production and release by astrocytes are regulated by changes in lactate dehydrogenase (LDH) and MCT expression. Moreover, considering stroke, lactate production and supply are regulated through hypoxia-inducible factor (HIF)-1α expression, especially with hypoxic stimulation, which may promote neuronal apoptosis; contrastingly, neuronal survival may be promoted via HIF-1α. Stroke stimulation could prevent neurodegeneration through the strong enhancement of lactate production, as well as upregulation of MCT4 expression to accelerate lactate supply. However, studies using astrocytes derived from animal stroke models revealed significantly reduced lactate production and MCT expression. These findings suggest that the lack of lactate supply may strongly contribute to hypoxia-induced neurodegeneration. Furthermore, diminished lactate supply from astrocytes could facilitate stroke-induced neurodegeneration. Therefore, astrocyte-derived lactate may contribute to stroke prevention.
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14
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Wei X, Hou Y, Long M, Jiang L, Du Y. Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis. Front Endocrinol (Lausanne) 2022; 13:927329. [PMID: 35957825 PMCID: PMC9357883 DOI: 10.3389/fendo.2022.927329] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/30/2022] [Indexed: 11/13/2022] Open
Abstract
Renal fibrosis is the result of renal tissue damage and repair response disorders. If fibrosis is not effectively blocked, it causes loss of renal function, leading to chronic renal failure. Metabolic reprogramming, which promotes cell proliferation by regulating cellular energy metabolism, is considered a unique tumor cell marker. The transition from oxidative phosphorylation to aerobic glycolysis is a major feature of renal fibrosis. Hypoxia-inducible factor-1 α (HIF-1α), a vital transcription factor, senses oxygen status, induces adaptive changes in cell metabolism, and plays an important role in renal fibrosis and glucose metabolism. This review focuses on the regulation of proteins related to aerobic glycolysis by HIF-1α and attempts to elucidate the possible regulatory mechanism underlying the effects of HIF-1α on glucose metabolism during renal fibrosis, aiming to provide new ideas for targeted metabolic pathway intervention in renal fibrosis.
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Affiliation(s)
- Xuejiao Wei
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Yue Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Mengtuan Long
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
| | - Lili Jiang
- Department of Physical Examination Center, The First Hospital of Jilin University, Changchun, China
| | - Yujun Du
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yujun Du,
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15
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Lundquist AJ, Llewellyn GN, Kishi SH, Jakowec NA, Cannon PM, Petzinger GM, Jakowec MW. Knockdown of Astrocytic Monocarboxylate Transporter 4 in the Motor Cortex Leads to Loss of Dendritic Spines and a Deficit in Motor Learning. Mol Neurobiol 2021; 59:1002-1017. [PMID: 34822124 DOI: 10.1007/s12035-021-02651-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/16/2021] [Indexed: 10/19/2022]
Abstract
Monocarboxylate transporters (MCTs) shuttle molecules, including L-lactate, involved in metabolism and cell signaling of the central nervous system. Astrocyte-specific MCT4 is a key component of the astrocyte-neuron lactate shuttle (ANLS) and is important for neuroplasticity and learning of the hippocampus. However, the importance of astrocyte-specific MCT4 in neuroplasticity of the M1 primary motor cortex remains unknown. In this study, we investigated astrocyte-specific MCT4 in motor learning and neuroplasticity of the M1 primary motor cortex using a cell-type specific shRNA knockdown of MCT4. Knockdown of astrocyte-specific MCT4 resulted in impaired motor performance and learning on the accelerating rotarod. In addition, MCT4 knockdown was associated with a reduction of neuronal dendritic spine density and spine width and decreased protein expression of PSD95, Arc, and cFos. Using near-infrared-conjugated 2-deoxyglucose uptake as a surrogate marker for neuronal activity, MCT4 knockdown was also associated with decreased neuronal activity in the M1 primary motor cortex and associated motor regions including the dorsal striatum and ventral thalamus. Our study supports a potential role for astrocyte-specific MCT4 and the ANLS in the neuroplasticity of the M1 primary motor cortex. Targeting MCT4 may serve to enhance neuroplasticity and motor repair in several neurological disorders, including Parkinson's disease and stroke.
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Affiliation(s)
- Adam J Lundquist
- Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, 90033, USA. .,Department of Neurology, University of Southern California, 1333 San Pablo St, MCA-241, Los Angeles, CA, 90033, USA.
| | - George N Llewellyn
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Susan H Kishi
- Department of Neurology, University of Southern California, 1333 San Pablo St, MCA-241, Los Angeles, CA, 90033, USA
| | - Nicolaus A Jakowec
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.,Molecular and Cellular Biology Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90033, USA
| | - Paula M Cannon
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Giselle M Petzinger
- Department of Neurology, University of Southern California, 1333 San Pablo St, MCA-241, Los Angeles, CA, 90033, USA
| | - Michael W Jakowec
- Department of Neurology, University of Southern California, 1333 San Pablo St, MCA-241, Los Angeles, CA, 90033, USA
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16
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Zhou J, Guo P, Guo Z, Sun X, Chen Y, Feng H. Fluid metabolic pathways after subarachnoid hemorrhage. J Neurochem 2021; 160:13-33. [PMID: 34160835 DOI: 10.1111/jnc.15458] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/12/2021] [Accepted: 06/20/2021] [Indexed: 01/05/2023]
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular disease with high mortality and morbidity. In recent years, a large number of studies have focused on the mechanism of early brain injury (EBI) and delayed cerebral ischemia (DCI), including vasospasm, neurotoxicity of hematoma and neuroinflammatory storm, after aSAH. Despite considerable efforts, no novel drugs have significantly improved the prognosis of patients in phase III clinical trials, indicating the need to further re-examine the multifactorial pathophysiological process that occurs after aSAH. The complex pathogenesis is reflected by the destruction of the dynamic balance of the energy metabolism in the nervous system after aSAH, which prevents the maintenance of normal neural function. This review focuses on the fluid metabolic pathways of the central nervous system (CNS), starting with ruptured aneurysms, and discusses the dysfunction of blood circulation, cerebrospinal fluid (CSF) circulation and the glymphatic system during disease progression. It also proposes a hypothesis on the metabolic disorder mechanism and potential therapeutic targets for aSAH patients.
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Affiliation(s)
- Jiru Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Peiwen Guo
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zongduo Guo
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaochuan Sun
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yujie Chen
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Hua Feng
- Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.,Chongqing Key Laboratory of Precision Neuromedicine and Neuroregeneration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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17
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Roumes H, Dumont U, Sanchez S, Mazuel L, Blanc J, Raffard G, Chateil JF, Pellerin L, Bouzier-Sore AK. Neuroprotective role of lactate in rat neonatal hypoxia-ischemia. J Cereb Blood Flow Metab 2021; 41:342-358. [PMID: 32208801 PMCID: PMC7812521 DOI: 10.1177/0271678x20908355] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hypoxic-ischemic (HI) encephalopathy remains a major cause of perinatal mortality and chronic disability in newborns worldwide (1-6 for 1000 births). The only current clinical treatment is hypothermia, which is efficient for less than 60% of babies. Mainly considered as a waste product in the past, lactate, in addition to glucose, is increasingly admitted as a supplementary fuel for neurons and, more recently, as a signaling molecule in the brain. Our aim was to investigate the neuroprotective effect of lactate in a neonatal (seven day old) rat model of hypoxia-ischemia. Pups received intra-peritoneal injection(s) of lactate (40 μmol). Size and apparent diffusion coefficients of brain lesions were assessed by magnetic resonance diffusion-weighted imaging. Oxiblot analyses and long-term behavioral studies were also conducted. A single lactate injection induced a 30% reduction in brain lesion volume, indicating a rapid and efficient neuroprotective effect. When oxamate, a lactate dehydrogenase inhibitor, was co-injected with lactate, the neuroprotection was completely abolished, highlighting the role of lactate metabolism in this protection. After three lactate injections (one per day), pups presented the smallest brain lesion volume and a complete recovery of neurological reflexes, sensorimotor capacities and long-term memory, demonstrating that lactate administration is a promising therapy for neonatal HI insult.
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Affiliation(s)
- Hélène Roumes
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
| | - Ursule Dumont
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
| | - Stéphane Sanchez
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
| | - Leslie Mazuel
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
| | - Jordy Blanc
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
| | - Gérard Raffard
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
| | - Jean-François Chateil
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
| | - Luc Pellerin
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France.,Département de Physiologie, Université de Lausanne, Lausanne, Switzerland
| | - Anne-Karine Bouzier-Sore
- Centre de Résonance Magnétique des Systèmes Biologiques, UMR5536, CNRS/Université de Bordeaux, Bordeaux Cedex, France
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18
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Immunoreactivity of receptor and transporters for lactate located in astrocytes and epithelial cells of choroid plexus of human brain. Neurosci Lett 2020; 741:135479. [PMID: 33212210 DOI: 10.1016/j.neulet.2020.135479] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/19/2020] [Accepted: 10/30/2020] [Indexed: 11/20/2022]
Abstract
Glucose metabolism produces lactate and hydrogen ions in an anaerobic environment. Cerebral ischemia or hypoxia is believed to become progressively lactacidemic. Monocarboxylate transporters (MCTs) in endothelial cells are essential for the transport of lactate from the blood into the brain. In addition, it is considered that MCTs located in astrocytic and neuronal cells play a key role in the shuttling of energy metabolites between neurons and astrocytes. However, roles of lactate in the brain remain to be clarified. In this study, the localization of lactate transporters and a receptor for cellular uptake of lactate was immunohistochemically examined in autopsied human brains. Immunoreactivity for MCT1 was observed in the apical cytoplasmic membrane of some epithelial cells in the choroid plexus as well as astrocytes and the capillary wall, whereas that for MCT4 was found in the basolateral cytoplasmic membrane of small number of epithelial cells as well as astrocytes and the capillary wall. In addition, immunoreactivity for the hydroxy-carboxylic acid 1 receptor (HCA1 receptor), a receptor for cellular uptake of lactate, was also found on the basolateral cytoplasmic membrane of epithelial cells as well as astrocytic and neuronal cells. Immunoreactivity for lactate dehydrogenase (LDH)-B was observed in the cytoplasm of epithelial cells in the choroid plexus as well as astrocytes and the capillary wall. These immunohistochemical findings indicate the localization of MCT1, MCT4, the HCA1 receptor, and LDH-B in epithelial cells of the choroid plexus as well as astrocytes, and suggest the transport of intravascular lactate into the brain through epithelial cells of the choroid plexus as well as cerebral vessels and the possibility of lactate being utilized in epithelial cells.
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19
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Rose J, Brian C, Pappa A, Panayiotidis MI, Franco R. Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance. Front Neurosci 2020; 14:536682. [PMID: 33224019 PMCID: PMC7674659 DOI: 10.3389/fnins.2020.536682] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 10/14/2020] [Indexed: 01/17/2023] Open
Abstract
In the brain, mitochondrial metabolism has been largely associated with energy production, and its dysfunction is linked to neuronal cell loss. However, the functional role of mitochondria in glial cells has been poorly studied. Recent reports have demonstrated unequivocally that astrocytes do not require mitochondria to meet their bioenergetics demands. Then, the question remaining is, what is the functional role of mitochondria in astrocytes? In this work, we review current evidence demonstrating that mitochondrial central carbon metabolism in astrocytes regulates overall brain bioenergetics, neurotransmitter homeostasis and redox balance. Emphasis is placed in detailing carbon source utilization (glucose and fatty acids), anaplerotic inputs and cataplerotic outputs, as well as carbon shuttles to neurons, which highlight the metabolic specialization of astrocytic mitochondria and its relevance to brain function.
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Affiliation(s)
- Jordan Rose
- Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, United States.,School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United States
| | - Christian Brian
- Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, United States.,School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United States
| | - Aglaia Pappa
- Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Mihalis I Panayiotidis
- Department of Electron Microscopy & Molecular Pathology, Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
| | - Rodrigo Franco
- Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE, United States.,School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, United States
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20
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Jha MK, Morrison BM. Lactate Transporters Mediate Glia-Neuron Metabolic Crosstalk in Homeostasis and Disease. Front Cell Neurosci 2020; 14:589582. [PMID: 33132853 PMCID: PMC7550678 DOI: 10.3389/fncel.2020.589582] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 09/09/2020] [Indexed: 12/28/2022] Open
Abstract
Research over the last couple of decades has provided novel insights into lactate neurobiology and the implications of lactate transport-driven neuroenergetics in health and diseases of peripheral nerve and the brain. The expression pattern of lactate transporters in glia and neurons has now been described, though notable controversies and discrepancies remain. Importantly, down- and up-regulation experiments are underway to better understand the function of these transporters in different systems. Lactate transporters in peripheral nerves are important for maintenance of axon and myelin integrity, motor end-plate integrity, the development of diabetic peripheral neuropathy (DPN), and the functional recovery following nerve injuries. Similarly, brain energy metabolism and functions ranging from development to synaptic plasticity to axonal integrity are also dependent on lactate transport primarily between glia and neurons. This review is focused on critically analysing the expression pattern and the functions of lactate transporters in peripheral nerves and the brain and highlighting their role in glia-neuron metabolic crosstalk in physiological and pathological conditions.
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Affiliation(s)
- Mithilesh Kumar Jha
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Brett M Morrison
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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21
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Netzahualcoyotzi C, Pellerin L. Neuronal and astroglial monocarboxylate transporters play key but distinct roles in hippocampus-dependent learning and memory formation. Prog Neurobiol 2020; 194:101888. [PMID: 32693190 DOI: 10.1016/j.pneurobio.2020.101888] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/07/2020] [Accepted: 07/16/2020] [Indexed: 01/26/2023]
Abstract
Brain lactate formation, intercellular exchange and utilization has been implicated in memory formation. However, the individual role of either neuronal or astroglial monocarboxylate transporters for the acquisition and consolidation of information remains incomplete. Using novel transgenic mice and a viral vector approach to decrease the expression of each transporter in a cell-specific manner within the dorsal hippocampus, we show that both neuronal MCT2 and astroglial MCT4 are required for spatial information acquisition and retention (at 24 h post-training) in distinct hippocampus-dependent tasks. Intracerebral infusion of lactate rescued spatial learning in mice with reduced levels of astroglial MCT4 but not of neuronal MCT2, suggesting that lactate transfer from astrocytes and utilization in neurons contribute to hippocampal-dependent learning. In contrast, only neuronal MCT2 was shown to be required for long-term (7 days post training) memory formation. Interestingly, reduced MCT2 expression levels in mature neurons result in a heterologous effect as it blunts hippocampal neurogenesis associated with memory consolidation. These results suggest important but distinct contributions of both neuronal MCT2 and astroglial MCT4 in learning and memory processes, going beyond a simple passive role as alternative energy substrate suppliers or in waste product disposal.
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Affiliation(s)
| | - Luc Pellerin
- Department of Physiology, University of Lausanne, 7 Rue du Bugnon, 1005 Lausanne, Switzerland; Centre de Résonance Magnétique des Systèmes Biologiques, UMR 5536, CNRS/Université de Bordeaux, 146 rue Léo Saignat, Bordeaux 33076, France.
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22
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Xu J, Zheng Y, Lv S, Kang J, Yu Y, Hou K, Li Y, Chi G. Lactate Promotes Reactive Astrogliosis and Confers Axon Guidance Potential to Astrocytes under Oxygen-Glucose Deprivation. Neuroscience 2020; 442:54-68. [PMID: 32634533 DOI: 10.1016/j.neuroscience.2020.06.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/08/2020] [Accepted: 06/24/2020] [Indexed: 12/25/2022]
Abstract
During cerebral ischemia, brain lactate concentration increases, and astrogliosis is triggered. Herein, we investigated lactate's role in astrogliosis and explored the functions of lactate-activated astrocytes in vitro. In rat models of cerebral ischemia, we observed increased glial fibrillary acidic protein (GFAP) expression, reflecting astrogliosis, and increased lactate levels in the ischemic brain region. Lactate upregulated GFAP and SRY-box transcription factor 9 (SOX9) expression and activated Akt and signal transducer and activator of transcription 3 (STAT3) signaling pathways in astrocytes cultured under oxygen-glucose deprivation (OGD); these effects were abrogated upon monocarboxylate transporter 1 (MCT1) knockdown. RNA-Seq analysis revealed 221 differentially expressed genes (DEGs) between lactate-treated and untreated astrocytes. Genes upregulated by lactate treatment included those regulating astrogliosis and axon guidance. Consistently, lactate-treated astrocytes induced neuronal outgrowth upon coculture. Our results suggest that lactate promotes reactive astrogliosis and confers axon guidance potential to astrocytes under OGD.
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Affiliation(s)
- Jinying Xu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, PR China
| | - Yangyang Zheng
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, PR China
| | - Shuang Lv
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, PR China
| | - Juanjuan Kang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, PR China
| | - Yifei Yu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, PR China
| | - Kun Hou
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130021, PR China
| | - Yulin Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, PR China.
| | - Guangfan Chi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, PR China.
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23
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Ohk TG, Ahn JH, Park YE, Lee TK, Kim B, Lee JC, Cho JH, Park JH, Won MH, Lee CH. Comparison of neuronal death and expression of TNF‑α and MCT4 in the gerbil hippocampal CA1 region induced by ischemia/reperfusion under hyperthermia to those under normothermia. Mol Med Rep 2020; 22:1044-1052. [PMID: 32468005 PMCID: PMC7339721 DOI: 10.3892/mmr.2020.11182] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/12/2020] [Indexed: 12/19/2022] Open
Abstract
Monocarboxylate transporter 4 (MCT4) is a high-capacity lactate transporter in cells and the alteration in MCT4 expression harms cellular survival. The present study investigated whether hypothermia affects tumor necrosis factor-α (TNF-α) and MCT4 immunoreactivity in the subfield cornu ammonis 1 (CA1) following cerebral ischemia/reperfusion (IR) in gerbils. Hypothermia was induced for 30 min before and during ischemia. It was found that IR-induced death of pyramidal neurons was markedly augmented and occurred faster under hyperthermia than under normothermia. TNF-α immunoreactivity in the pyramidal cells started to increase at 3 h after IR and peaked at 1 day after IR under normothermia. However, in hyperthermic control and sham operated gerbils, TNF-α immunoreactivity was significantly increased compared with the normothermic gerbils, and IR under hyperthermia caused a more rapid and significant increase in TNF-α immunoreactivity in pyramidal neurons than under normothermia. In addition, in the normothermic gerbils, MCT4 immunoreactivity began to decrease in pyramidal neurons from 3 h after IR and markedly increased at 1 and 2 days after IR. On the other hand, MCT4 immunoreactivity in pyramidal neurons of the hyperthermic gerbils was significantly increased from 3 h after IR, maintained until 1 day after IR and markedly decreased at 2 days after IR. These results indicate that acceleration of IR-induced neuronal death under hyperthermia might be closely associated with early alteration of TNF-α and MCT4 protein expression in the gerbil hippocampus after IR.
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Affiliation(s)
- Taek Geun Ohk
- Department of Emergency Medicine, and Institute of Medical Sciences, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24289, Republic of Korea
| | - Ji Hyeon Ahn
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
| | - Young Eun Park
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Tae-Kyeong Lee
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea
| | - Bora Kim
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Jae-Chul Lee
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Jun Hwi Cho
- Department of Emergency Medicine, and Institute of Medical Sciences, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24289, Republic of Korea
| | - Joon Ha Park
- Department of Anatomy, College of Korean Medicine, Dongguk University, Gyeongju, Gyeongbuk 38066, Republic of Korea
| | - Moo-Ho Won
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Choong-Hyun Lee
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Chungcheongnam 31116, Republic of Korea
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24
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Avnet S, Lemma S, Errani C, Falzetti L, Panza E, Columbaro M, Nanni C, Baldini N. Benign albeit glycolytic: MCT4 expression and lactate release in giant cell tumour of bone. Bone 2020; 134:115302. [PMID: 32112988 DOI: 10.1016/j.bone.2020.115302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 02/15/2020] [Accepted: 02/25/2020] [Indexed: 10/24/2022]
Abstract
Giant cell tumour of bone (GCTB) is a histologically benign, locally aggressive skeletal lesion with an unpredictable propensity to relapse after surgery and a rare metastatic potential. The microscopic picture of GCTB shows different cell types, including multinucleated giant cells, mononuclear cells of the macrophage-monocyte lineage, and spindle cells. The histogenesis of GCTB is still debated, and morphologic, radiographic or molecular features are not predictive of the clinical course. Characterization of the unexplored cell metabolism of GCTB offers significant clues for the understanding of this elusive pathologic entity. In this study we aimed to characterize GCTB energetic metabolism, with a particular focus on lactate release and the expression of monocarboxylate transporters, to lie down a novel path for understanding the pathophysiology of this tumour. We measured the expression of glycolytic markers (GAPDH, PKM2, MCT4, GLUT1, HK1, LDHA, lactate release) in 25 tissue samples of GCTB by immunostaining and by mRNA and ELISA analyses. We also evaluated MCT1 and MCT4 expression and oxidative markers (JC1 staining and Bec index) in tumour-derived spindle cell cultures and CD14+ monocytic cells. Finally, we quantified the intratumoural and circulating levels of lactate in a series of 17 subjects with GCTB. In sharp contrast to the benign histological features of GCTB, we found a high expression of glycolytic markers, with particular reference to MCT4. Unexpectedly, this was mainly confined to the giant cell, not proliferating cell component. Accordingly, GCTB patients showed higher levels of blood lactate as compared to healthy subjects. In conclusion, taken together, our data indicate that GCTB is characterized by a highly glycolytic metabolism of its giant cell component, opening new perspectives on the pathogenesis, the natural history, and the treatment of this lesion.
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Affiliation(s)
- Sofia Avnet
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
| | - Silvia Lemma
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Costantino Errani
- Orthopaedic Oncology Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Luigi Falzetti
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Emanuele Panza
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Marta Columbaro
- Musculoskeletal Cell Biology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Cristina Nanni
- Nuclear Medicine Unit, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Nicola Baldini
- Orthopaedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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25
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Hartmann DD, Gonçalves DF, Da Rosa PC, Martins RP, Courtes AA, Franco JL, A Soares FA, Puntel GO. A single muscle contusion promotes an immediate alteration in mitochondrial bioenergetics response in skeletal muscle fibres with different metabolism. Free Radic Res 2020; 54:137-149. [PMID: 32037913 DOI: 10.1080/10715762.2020.1723795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Skeletal muscle is the most abundant tissue in the human body and mechanical injuries are common; these are frequently of mechanical origins, such as contusion. However, the immediate mitochondrial response to injury and energetic substrate utilisation is still unclear. We evaluated the acute response in mitochondrial function after a single muscle contusion, either in fast twitch fibres (glycolytic metabolism), fast and slow twitch (oxidative and glycolytic metabolism), or slow twitch fibres (oxidative metabolism). Rats were assigned to two groups: control and Lesion (muscle contusion). We collected the gastrocnemius and soleus muscles. The fibres were analysed for mitochondrial respiration, lactate dehydrogenase (LDH), citrate synthase (CS) activity, Ca2+ uptake, and H2O2 production. We found that muscle injury was able to increase ATP synthesis-dependent and OXPHOS oxygen flux in the oxidative fibres when stimulated by complex I + II substrates. On the other hand, the muscle injury increased hydrogen peroxide (H2O2) production when compared to control fibres, and reduced citrate synthase activity; however, it did not change Ca2+ uptake. Surprisingly, injury in mixed fibres increased the OXPHOS and ATP synthesis oxygen consumption, and H2O2 production, but it reduced Ca2+ uptake. The injury in glycolytic fibres did not affect oxygen flux coupled to ATP synthesis, citrate synthase, and lactate dehydrogenase activity, but did reduce Ca2+ uptake. Finally, we demonstrated distinct mitochondrial responses between the different muscle fibres, indicating that the mitochondrial dynamics is related to flexibilities in metabolism, and that reactive oxygen species directly affect physiology and normal function.
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Affiliation(s)
- Diane D Hartmann
- Centro de Ciências Naturais e Exatas, Departamento de Bioquímica, Universidade Federal de Santa Maria, Brazil e Biologia Molecular, Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Camobi, Brazil
| | - Débora F Gonçalves
- Centro de Ciências Naturais e Exatas, Departamento de Bioquímica, Universidade Federal de Santa Maria, Brazil e Biologia Molecular, Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Camobi, Brazil
| | - Pamela C Da Rosa
- Centro de Ciências Naturais e Exatas, Departamento de Bioquímica, Universidade Federal de Santa Maria, Brazil e Biologia Molecular, Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Camobi, Brazil
| | - Rodrigo P Martins
- Centro de Ciências Naturais e Exatas, Departamento de Bioquímica, Universidade Federal de Santa Maria, Brazil e Biologia Molecular, Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Camobi, Brazil
| | - Aline A Courtes
- Centro de Ciências Naturais e Exatas, Departamento de Bioquímica, Universidade Federal de Santa Maria, Brazil e Biologia Molecular, Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Camobi, Brazil
| | - Jeferson L Franco
- Centro Interdisciplinar de Pesquisa em Biotecnologia- CIPBIOTEC, Universidade Federal do Pampa, São Gabriel, Brazil
| | - Félix A A Soares
- Centro de Ciências Naturais e Exatas, Departamento de Bioquímica, Universidade Federal de Santa Maria, Brazil e Biologia Molecular, Programa de Pós-Graduação em Ciências Biológicas, Bioquímica Toxicológica, Camobi, Brazil
| | - Gustavo O Puntel
- Centro de Ciências da Saúde, Departamento Morfologia, Universidade Federal de Santa Maria, Camobi, Brazil
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26
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Contreras-Baeza Y, Sandoval PY, Alarcón R, Galaz A, Cortés-Molina F, Alegría K, Baeza-Lehnert F, Arce-Molina R, Guequén A, Flores CA, San Martín A, Barros LF. Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments. J Biol Chem 2019; 294:20135-20147. [PMID: 31719150 DOI: 10.1074/jbc.ra119.009093] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 11/09/2019] [Indexed: 11/06/2022] Open
Abstract
Monocarboxylate transporter 4 (MCT4) is an H+-coupled symporter highly expressed in metastatic tumors and at inflammatory sites undergoing hypoxia or the Warburg effect. At these sites, extracellular lactate contributes to malignancy and immune response evasion. Intriguingly, at 30-40 mm, the reported Km of MCT4 for lactate is more than 1 order of magnitude higher than physiological or even pathological lactate levels. MCT4 is not thought to transport pyruvate. Here we have characterized cell lactate and pyruvate dynamics using the FRET sensors Laconic and Pyronic. Dominant MCT4 permeability was demonstrated in various cell types by pharmacological means and by CRISPR/Cas9-mediated deletion. Respective Km values for lactate uptake were 1.7, 1.2, and 0.7 mm in MDA-MB-231 cells, macrophages, and HEK293 cells expressing recombinant MCT4. In MDA-MB-231 cells MCT4 exhibited a Km for pyruvate of 4.2 mm, as opposed to >150 mm reported previously. Parallel assays with the pH-sensitive dye 2',7'-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) indicated that previous Km estimates based on substrate-induced acidification were severely biased by confounding pH-regulatory mechanisms. Numerical simulation using revised kinetic parameters revealed that MCT4, but not the related transporters MCT1 and MCT2, endows cells with the ability to export lactate in high-lactate microenvironments. In conclusion, MCT4 is a high-affinity lactate transporter with physiologically relevant affinity for pyruvate.
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Affiliation(s)
| | - Pamela Y Sandoval
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile
| | - Romina Alarcón
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile.,Universidad Austral de Chile, Valdivia 5110566, Chile
| | - Alex Galaz
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile
| | | | - Karin Alegría
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile
| | - Felipe Baeza-Lehnert
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile.,Universidad Austral de Chile, Valdivia 5110566, Chile
| | - Robinson Arce-Molina
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile.,Universidad Austral de Chile, Valdivia 5110566, Chile
| | - Anita Guequén
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile
| | - Carlos A Flores
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile
| | | | - L Felipe Barros
- Centro de Estudios Científicos, CECs, Arturo Prat 514, Valdivia 5110466, Chile
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27
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Zhang M, Cheng X, Dang R, Zhang W, Zhang J, Yao Z. Lactate Deficit in an Alzheimer Disease Mouse Model: The Relationship With Neuronal Damage. J Neuropathol Exp Neurol 2019; 77:1163-1176. [PMID: 30383244 DOI: 10.1093/jnen/nly102] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 10/08/2018] [Indexed: 01/07/2023] Open
Abstract
Cerebral energy metabolism in Alzheimer disease (AD) has recently been given increasing attention. This study focuses on the alterations of cerebral lactate metabolism in the double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD. Immunofluorescence staining and Western blotting analysis were used to identify the alterations of lactate content and lactate transporters (MCT1, MCT2, MCT4) in APP/PS1 mouse brains, which display amyloid beta plaques, reduced amounts of neurons and oligodendrocytes, and increased quantity of astrocytes. We found that lactate content and expressions of cerebral MCT1, MCT2, and MCT4 were decreased in APP/PS1 mice. In particular, lactate dehydrogenase A (LDHA) and B (LDHB) were reduced in neurons with increased ratios of LDHA and LDHB. This study suggests that the decreases of cerebral lactate content and lactate transporters may lead to the blockage of lactate transport from glia to neurons, resulting in neuronal lactate deficit. The increased ratio of neuronal LDHA and LDHB may represent a reaction of neurons to lactate deficit, although it cannot reverse the energy deficiency in neurons.
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Affiliation(s)
- Mao Zhang
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaofang Cheng
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ruozhi Dang
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Weiwei Zhang
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jie Zhang
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhongxiang Yao
- Department of Physiology, Army Medical University (Third Military Medical University), Chongqing, China
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28
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Jollé C, Déglon N, Pythoud C, Bouzier-Sore AK, Pellerin L. Development of Efficient AAV2/DJ-Based Viral Vectors to Selectively Downregulate the Expression of Neuronal or Astrocytic Target Proteins in the Rat Central Nervous System. Front Mol Neurosci 2019; 12:201. [PMID: 31481874 PMCID: PMC6710342 DOI: 10.3389/fnmol.2019.00201] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 08/02/2019] [Indexed: 12/18/2022] Open
Abstract
Viral vectors have become very popular to overexpress or downregulate proteins of interest in different cell types. They conveniently allow the precise targeting of well-defined tissue areas, which is particularly useful in complex organs like the brain. In theory, each vector should have its own cell specificity that can be obtained by using different strategies (e.g., using a cell-specific promoter). For the moment, there is few vectors that have been developed to alternatively target, using the same capsid, neurons and astrocytes in the central nervous system. There is even fewer examples of adeno-associated viral vectors able to efficiently transduce cells both in vitro and in vivo. The development of viral vectors allowing the cell-specific downregulation of a protein in cultured cells of the central nervous system as well as in vivo within a large brain area would be highly desirable to address several important questions in neurobiology. Here we report that the use of the AAV2/DJ viral vector associated to an hybrid CMV/chicken β-actin promoter (CBA) or to a modified form of the glial fibrillary acidic protein promoter (G1B3) allows a specific transduction of neurons or astrocytes in more than half of the barrel field within the rat somatosensory cortex. Moreover, the use of the miR30E-shRNA technology led to an efficient downregulation of two proteins of interest related to metabolism both in vitro and in vivo. Our results demonstrate that it is possible to downregulate the expression of different protein isoforms in a cell-specific manner using a common serotype. It is proposed that such an approach could be extended to other cell types and used to target several proteins of interest within the same brain area.
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Affiliation(s)
- Charlotte Jollé
- Department of Physiology, Université de Lausanne, Lausanne, Switzerland
| | - Nicole Déglon
- Laboratory of Cellular and Molecular Neurotherapies (LCMN), Department of Clinical Neurosciences, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.,LCMN, Neurosciences Research Center, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Catherine Pythoud
- Laboratory of Cellular and Molecular Neurotherapies (LCMN), Department of Clinical Neurosciences, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.,LCMN, Neurosciences Research Center, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Anne-Karine Bouzier-Sore
- Centre de Résonance Magnétique des Systèmes Biologiques UMR 5536, CNRS-Université de Bordeaux, Bordeaux, France
| | - Luc Pellerin
- Department of Physiology, Université de Lausanne, Lausanne, Switzerland.,Centre de Résonance Magnétique des Systèmes Biologiques UMR 5536, CNRS-Université de Bordeaux, Bordeaux, France
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29
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Wilson DF, Matschinsky FM. Hyperbaric oxygen toxicity in brain: A case of hyperoxia induced hypoglycemic brain syndrome. Med Hypotheses 2019; 132:109375. [PMID: 31454640 DOI: 10.1016/j.mehy.2019.109375] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 08/09/2019] [Accepted: 08/18/2019] [Indexed: 12/25/2022]
Abstract
Hyperbaric oxygen exposure is a recent hazzard for higher animals that originated as humans began underwater construction, exploration, and sports. Exposure can lead to abnormal brain EEG, convulsions, and death, the time to onset of each stage of pathology decreasing with increase in oxygen pressure. We provide evidence that hyperoxia, through oxidative phosphorylation, increases the energy state ([ATP]/[ADP][Pi]) of cells critical to providing glucose to cells behind the blood brain barrier (BBB). Brain cells without an absolute dependence on glucose metabolism; i.e. those having sufficient ATP synthesis using lactate and glutamate as oxidizable substrates, are not themselves very adversely affected by hyperoxia. The increased energy state and decrease in free [AMP], however, suppress glucose transport through the blood brain barrier (BBB) and into cells behind the BBB. Glucose has to pass in sequence through three steps of transport by facilitated diffusion and transporter activity for each step is regulated in part by AMP dependent protein kinase. The physiological role of this regulation is to increase glucose transport in response to hypoxia and/or systemic hypoglycemia. Hyperoxia, however, through unphysiological decrease in free [AMP] suppresses 1) glucose transport through the BBB (endothelial GLUT1 transporters) into cerebrospinal fluid (CSF); 2) glucose transport from CSF into cells behind the BBB (GLUT3 transporters) and (GLUT4 transporters). Cumulative suppression of glucose transport results in local regions of hypoglycemia and induces hypoglycemic failure. It is suggested that failure is initiated at axons and synapses with insufficient mitochondria to meet their energy requirements.
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Affiliation(s)
- David F Wilson
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Franz M Matschinsky
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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30
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Guan X, Rodriguez-Cruz V, Morris ME. Cellular Uptake of MCT1 Inhibitors AR-C155858 and AZD3965 and Their Effects on MCT-Mediated Transport of L-Lactate in Murine 4T1 Breast Tumor Cancer Cells. AAPS JOURNAL 2019; 21:13. [PMID: 30617815 DOI: 10.1208/s12248-018-0279-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 11/24/2018] [Indexed: 12/11/2022]
Abstract
AR-C155858 and AZD3965, pyrrole pyrimidine derivatives, represent potent monocarboxylate transporter 1 (MCT1) inhibitors, with potential immunomodulatory and chemotherapeutic properties. Currently, there is limited information on the inhibitory properties of this new class of MCT1 inhibitors. The purpose of this study was to characterize the concentration- and time-dependent inhibition of L-lactate transport and the membrane permeability properties of AR-C155858 and AZD3965 in the murine 4T1 breast tumor cells that express MCT1. Our results demonstrated time-dependent inhibition of L-lactate uptake by AR-C155858 and AZD3965 with maximal inhibition occurring after a 5-min pre-incubation period and prolonged inhibition. Following removal of AR-C155858 or AZD3965 from the incubation buffer, inhibition of L-lactate uptake was only fully reversed after 3 and 12 h, respectively, indicating that these inhibitors are slowly reversible. The uptake of AR-C155858 was concentration-dependent in 4T1 cells, whereas the uptake of AZD3965 exhibited no concentration dependence over the range of concentrations examined. The uptake kinetics of AR-C155858 was best fitted to a Michaelis-Menten equation with a diffusional clearance component, P (Km = 0.399 ± 0.067 μM, Vmax = 4.79 ± 0.58 pmol/mg/min, and P = 0.330 ± 0.088 μL/mg/min). AR-C155858 uptake, but not AZD3965 uptake, was significantly inhibited by alpha-cyano-4-hydroxycinnamic acid, a known nonspecific inhibitor of MCTs 1, 2, and 4. AR-C155858 demonstrated a trend toward higher uptake at lower pH, a characteristic of proton-dependent MCT1. These findings provide evidence that AR-C155858 and AZD3965 exert slowly reversible inhibition of MCT1-mediated L-lactate uptake in 4T1 cells, with AR-C155858 representing a potential substrate of MCT1.
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Affiliation(s)
- Xiaowen Guan
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, NY, 14214, USA
| | - Vivian Rodriguez-Cruz
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, NY, 14214, USA
| | - Marilyn E Morris
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, NY, 14214, USA.
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31
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Perinatal Asphyxia and Brain Development: Mitochondrial Damage Without Anatomical or Cellular Losses. Mol Neurobiol 2018; 55:8668-8679. [PMID: 29582399 DOI: 10.1007/s12035-018-1019-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 03/16/2018] [Indexed: 01/05/2023]
Abstract
Perinatal asphyxia remains a significant cause of neonatal mortality and is associated with long-term neurodegenerative disorders. In the present study, we evaluated cellular and subcellular damages to brain development in a model of mild perinatal asphyxia. Survival rate in the experimental group was 67%. One hour after the insult, intraperitoneally injected Evans blue could be detected in the fetuses' brains, indicating disruption of the blood-brain barrier. Although brain mass and absolute cell numbers (neurons and non-neurons) were not reduced after perinatal asphyxia immediately and in late brain development, subcellular alterations were detected. Cortical oxygen consumption increased immediately after asphyxia, and remained high up to 7 days, returning to normal levels after 14 days. We observed an increased resistance to mitochondrial membrane permeability transition, and calcium buffering capacity in asphyxiated animals from birth to 14 days after the insult. In contrast to ex vivo data, mitochondrial oxygen consumption in primary cell cultures of neurons and astrocytes was not altered after 1% hypoxia. Taken together, our results demonstrate that although newborns were viable and apparently healthy, brain development is subcellularly altered by perinatal asphyxia. Our findings place the neonate brain mitochondria as a potential target for therapeutic protective interventions.
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Abstract
Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
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Affiliation(s)
- Alexei Verkhratsky
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
| | - Maiken Nedergaard
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
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Verkhratsky A, Nedergaard M. Physiology of Astroglia. Physiol Rev 2018; 98:239-389. [PMID: 29351512 PMCID: PMC6050349 DOI: 10.1152/physrev.00042.2016] [Citation(s) in RCA: 1062] [Impact Index Per Article: 151.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 03/22/2017] [Accepted: 04/27/2017] [Indexed: 02/07/2023] Open
Abstract
Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
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Affiliation(s)
- Alexei Verkhratsky
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
| | - Maiken Nedergaard
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
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Bordt EA. The importance of controlling in vitro oxygen tension to accurately model in vivo neurophysiology. Neurotoxicology 2017; 66:213-220. [PMID: 29102646 DOI: 10.1016/j.neuro.2017.10.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 10/27/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022]
Abstract
The majority of in vitro studies modeling in vivo conditions are performed on the lab bench in atmospheric air. However, the oxygen tension (pO2) present in atmospheric air (160mm Hg, ∼21% O2) is in great excess to the pO2 that permeates tissues within the brain (5-45mm Hg, ∼1-6% O2). This review will discuss the differentiation between pO2 in the in vivo environment and the pO2 commonly used during in vitro experiments, and how this could affect assay outcomes. Also highlighted are studies linking changes in pO2 to changes in cellular function, particularly the role of pO2 in mitochondrial function, reactive oxygen species production, and cellular growth and differentiation. The role of hypoxia inducible factor 1 and oxygen sensing is also presented. Finally, emerging literature exploring sex differences in tissue oxygenation is discussed.
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Affiliation(s)
- Evan A Bordt
- Department of Pediatrics, Lurie Center for Autism, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, 02129, USA.
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Yamagata K, Takahashi N, Akita N, Nabika T. Arginine vasopressin altered the expression of monocarboxylate transporters in cultured astrocytes isolated from stroke-prone spontaneously hypertensive rats and congenic SHRpch1_18 rats. J Neuroinflammation 2017; 14:176. [PMID: 28865453 PMCID: PMC5581459 DOI: 10.1186/s12974-017-0949-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 08/24/2017] [Indexed: 11/25/2022] Open
Abstract
Background Astrocytes support a range of brain functions as well as neuronal survival, but their detailed relationship with stroke-related edema is not well understood. We previously demonstrated that the release of lactate from astrocytes isolated from stroke-prone spontaneously hypertensive rats (SHRSP/Izm) was attenuated under stroke conditions. The supply of lactate to neurons is regulated by astrocytic monocarboxylate transporters (MCTs). The purpose of this study was to examine the contributions of arginine vasopressin (AVP) and/or hypoxia and reoxygenation (H/R) to the regulation of MCTs and neurotrophic factor in astrocytes obtained from SHRSP/Izm and congenic SHRpch1_18 rats. Methods We compared AVP-induced lactate levels, MCTs, and brain-derived neurotrophic factor (BDNF) in astrocytes isolated from SHRSP/Izm, SHRpch1_18, and Wistar Kyoto rats (WKY/Izm). The expression levels of genes and proteins were determined by PCR and Western blotting (WB). Results The production of lactate induced by AVP was increased in astrocytes from all three strains. However, the levels of lactate were lower in SHRSP/Izm and SHRpch1_18 animals compared with the WKY/Izm strain. Gene expression levels of Slc16a1, Slc16a4, and Bdnf were lowered by AVP in SHRSP/Izm and SHRpch1_18 rats compared with WKY/Izm. The increase of MCT4 that was induced by AVP was blocked by the addition of a specific nitric oxide (NO) chelator, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO). Furthermore, AVP increased the expression of iNOS and eNOS proteins in WKY/Izm and SHRSP/Izm rat astrocytes. However, the iNOS expression levels in SHRSP astrocytes differed from those of WKY/Izm astrocytes. The increase of MCT4 protein expression during AVP treatment was blocked by the addition of a specific NF-kB inhibitor, pyrrolidine dithiocarbamate (PDTC). The induction of MCT4 by AVP may be regulated by NO through NF-kB. Conclusions These results suggest that the expression of MCTs mediated by AVP may be regulated by NO. The data suggest that AVP attenuated the expression of MCTs in SHRSP/Izm and SHRpch1_18 astrocytes. Reduced expression of MCTs may be associated with decreased lactate production in SHRSP.
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Affiliation(s)
- Kazuo Yamagata
- Laboratory of Molecular Health of Food, Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), 1866, Kameino, Fujisawa, Kanagawa, 252-8510, Japan.
| | - Natsumi Takahashi
- Laboratory of Molecular Health of Food, Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), 1866, Kameino, Fujisawa, Kanagawa, 252-8510, Japan
| | - Nozomi Akita
- Laboratory of Molecular Health of Food, Department of Food Bioscience and Biotechnology, College of Bioresource Sciences, Nihon University (NUBS), 1866, Kameino, Fujisawa, Kanagawa, 252-8510, Japan
| | - Toru Nabika
- Department of Functional Pathology, Shimane University Faculty of Medicine, Matsue, Japan
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Gaspar LS, Álvaro AR, Moita J, Cavadas C. Obstructive Sleep Apnea and Hallmarks of Aging. Trends Mol Med 2017; 23:675-692. [PMID: 28739207 DOI: 10.1016/j.molmed.2017.06.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 06/12/2017] [Accepted: 06/16/2017] [Indexed: 12/16/2022]
Abstract
Obstructive sleep apnea (OSA) is one of the most common sleep disorders. Since aging is a risk factor for OSA development, it is expected that its prevalence will increase with the current increase in life span. In recent years, several studies have shown that OSA potentially contributes to functional decline, mainly prompted by chronic intermittent hypoxia and sleep fragmentation. Here, we propose that OSA might anticipate/aggravate aging by inducing cellular and molecular impairments that characterize the aging process, such as stem cell exhaustion, telomere attrition and epigenetic changes. We suggest that further knowledge on the impact of OSA on aging mechanisms might contribute to a better understanding of how OSA might putatively accelerate aging and aging-related diseases.
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Affiliation(s)
- Laetitia S Gaspar
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Ana Rita Álvaro
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Joaquim Moita
- Sleep Medicine Unit, Coimbra Hospital and University Center (CHUC), Coimbra, Portugal
| | - Cláudia Cavadas
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
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Zhu YM, Gao X, Ni Y, Li W, Kent TA, Qiao SG, Wang C, Xu XX, Zhang HL. Sevoflurane postconditioning attenuates reactive astrogliosis and glial scar formation after ischemia-reperfusion brain injury. Neuroscience 2017; 356:125-141. [PMID: 28501505 DOI: 10.1016/j.neuroscience.2017.05.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/02/2017] [Accepted: 05/02/2017] [Indexed: 01/21/2023]
Abstract
Cerebral ischemia leads to astrocyte's activation and glial scar formation. Glial scar can inhibit axonal regeneration during the recovery phase. It has demonstrated that sevoflurane has neuroprotective effects against ischemic stroke, but its effects on ischemia-induced formation of astrogliosis and glial scar are unknown. This study was designed to investigate the effect of sevoflurane postconditioning on astrogliosis and glial scar formation in ischemic stroke model both in vivo and in vitro. The results showed that 2.5% of sevoflurane postconditioning could significantly reduce infarction volume and improve neurologic deficits. And it could also decrease the expression of the glial scar marker glial fibrillary acidic protein (GFAP), neurocan and phosphacan in the peri-infarct region and markedly reduce the thickness of glial scar after ischemia/reperfusion (I/R). Consistent with the in vivo data, in the oxygen and glucose deprivation/reoxygenation (OGD/Re) model, sevoflurane postconditioning could protect astrocyte against OGD/Re-induced injury, decrease the expression of GFAP, neurocan and phosphacan. Further studies demonstrated that sevoflurane postconditioning could down-regulate the expression of Lamp1 and active cathepsin B, and block I/R or OGD/Re-induced release of cathepsin B from the lysosomes into cytoplasm. In order to confirm whether inhibition of cathepsin B could attenuate the formation of glial scar, we used cathepsin B inhibitor CA-074Me as a positive control. The results showed that inhibition of cathepsin B could decrease the expression of GFAP, neurocan and phosphacan. Taken together, sevoflurane postconditioning can attenuate astrogliosis and glial scar formation after ischemic stroke, associating with inhibition of the activation and release of lysosomal cathepsin B.
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Affiliation(s)
- Yong-Ming Zhu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China
| | - Xue Gao
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China
| | - Yong Ni
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China
| | - Wei Li
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China
| | - Thomas A Kent
- Stroke Outcomes Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX, United States; and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston 77030, TX, United States
| | - Shi-Gang Qiao
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China; Department of Anesthesiology and Perioperative Medicine, Suzhou Science and Technology Town Hospital; and Institute of Clinical Medicine, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu 215153, PR China
| | - Chen Wang
- Department of Anesthesiology and Perioperative Medicine, Suzhou Science and Technology Town Hospital; and Institute of Clinical Medicine, Suzhou Hospital Affiliated to Nanjing Medical University, Suzhou, Jiangsu 215153, PR China
| | - Xiao-Xuan Xu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China
| | - Hui-Ling Zhang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China.
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Kardos J, Héja L, Jemnitz K, Kovács R, Palkovits M. The nature of early astroglial protection-Fast activation and signaling. Prog Neurobiol 2017; 153:86-99. [PMID: 28342942 DOI: 10.1016/j.pneurobio.2017.03.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 09/22/2016] [Accepted: 03/05/2017] [Indexed: 12/14/2022]
Abstract
Our present review is focusing on the uniqueness of balanced astroglial signaling. The balance of excitatory and inhibitory signaling within the CNS is mainly determined by sharp synaptic transients of excitatory glutamate (Glu) and inhibitory γ-aminobutyrate (GABA) acting on the sub-second timescale. Astroglia is involved in excitatory chemical transmission by taking up i) Glu through neurotransmitter-sodium transporters, ii) K+ released due to presynaptic action potential generation, and iii) water keeping osmotic pressure. Glu uptake-coupled Na+ influx may either ignite long-range astroglial Ca2+ transients or locally counteract over-excitation via astroglial GABA release and increased tonic inhibition. Imbalance of excitatory and inhibitory drives is associated with a number of disease conditions, including prevalent traumatic and ischaemic injuries or the emergence of epilepsy. Therefore, when addressing the potential of early therapeutic intervention, astroglial signaling functions combating progress of Glu excitotoxicity is of critical importance. We suggest, that excitotoxicity is linked primarily to over-excitation induced by the impairment of astroglial Glu uptake and/or GABA release. Within this framework, we discuss the acute alterations of Glu-cycling and metabolism and conjecture the therapeutic promise of regulation. We also confer the role played by key carrier proteins and enzymes as well as their interplay at the molecular, cellular, and organ levels. Moreover, based on our former studies, we offer potential prospect on the emerging theme of astroglial succinate sensing in course of Glu excitotoxicity.
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Affiliation(s)
- Julianna Kardos
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Hungary.
| | - László Héja
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Hungary
| | - Katalin Jemnitz
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Hungary
| | - Richárd Kovács
- Institute of Neurophysiology, Charité - Universitätsmedizin, Berlin, Germany
| | - Miklós Palkovits
- Human Brain Tissue Bank and Laboratory, Semmelweis University, Budapest, Hungary
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Nonose Y, Gewehr PE, Almeida RF, da Silva JS, Bellaver B, Martins LAM, Zimmer ER, Greggio S, Venturin GT, Da Costa JC, Quincozes-Santos A, Pellerin L, de Souza DO, de Assis AM. Cortical Bilateral Adaptations in Rats Submitted to Focal Cerebral Ischemia: Emphasis on Glial Metabolism. Mol Neurobiol 2017; 55:2025-2041. [PMID: 28271402 DOI: 10.1007/s12035-017-0458-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Accepted: 02/13/2017] [Indexed: 11/30/2022]
Abstract
This study was performed to evaluate the bilateral effects of focal permanent ischemia (FPI) on glial metabolism in the cerebral cortex. Two and 9 days after FPI induction, we analyze [18F]FDG metabolism by micro-PET, astrocyte morphology and reactivity by immunohistochemistry, cytokines and trophic factors by ELISA, glutamate transporters by RT-PCR, monocarboxylate transporters (MCTs) by western blot, and substrate uptake and oxidation by ex vivo slices model. The FPI was induced surgically by thermocoagulation of the blood in the pial vessels of the motor and sensorimotor cortices in adult (90 days old) male Wistar rats. Neurochemical analyses were performed separately on both ipsilateral and contralateral cortical hemispheres. In both cortical hemispheres, we observed an increase in tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and glutamate transporter 1 (GLT-1) mRNA levels; lactate oxidation; and glutamate uptake and a decrease in brain-derived neurotrophic factor (BDNF) after 2 days of FPI. Nine days after FPI, we observed an increase in TNF-α levels and a decrease in BDNF, GLT-1, and glutamate aspartate transporter (GLAST) mRNA levels in both hemispheres. Additionally, most of the unilateral alterations were found only in the ipsilateral hemisphere and persisted until 9 days post-FPI. They include diminished in vivo glucose uptake and GLAST expression, followed by increased glial fibrillary acidic protein (GFAP) gray values, astrocyte reactivity, and glutamate oxidation. Astrocytes presented signs of long-lasting reactivity, showing a radial morphology. In the intact hemisphere, there was a decrease in MCT2 levels, which did not persist. Our study shows the bilateralism of glial modifications following FPI, highlighting the role of energy metabolism adaptations on brain recovery post-ischemia.
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Affiliation(s)
- Yasmine Nonose
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Pedro E Gewehr
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Roberto F Almeida
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Jussemara S da Silva
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Bruna Bellaver
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Leo A M Martins
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil
| | - Eduardo R Zimmer
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.,Brain Institute of Rio Grande do Sul, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, 90619-900, Brazil
| | - Samuel Greggio
- Brain Institute of Rio Grande do Sul, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, 90619-900, Brazil
| | - Gianina T Venturin
- Brain Institute of Rio Grande do Sul, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, 90619-900, Brazil
| | - Jaderson C Da Costa
- Brain Institute of Rio Grande do Sul, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, 90619-900, Brazil
| | - André Quincozes-Santos
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil
| | - Luc Pellerin
- Department of Physiology, University of Lausanne, 1005, Lausanne, Switzerland
| | - Diogo O de Souza
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil
| | - Adriano M de Assis
- Postgraduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - Anexo Santa Cecília, Porto Alegre, RS, 90035-003, Brazil.
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Ramljak S, Herlyn H, Zerr I. Cellular Prion Protein (PrP c) and Hypoxia: True to Each Other in Good Times and in Bad, in Sickness, and in Health. Front Cell Neurosci 2016; 10:292. [PMID: 28066187 PMCID: PMC5165248 DOI: 10.3389/fncel.2016.00292] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 12/05/2016] [Indexed: 12/20/2022] Open
Abstract
The cellular prion protein (PrPc) and hypoxia appear to be tightly intertwined. Beneficial effects of PrPc on neuronal survival under hypoxic conditions such as focal cerebral ischemia are strongly supported. Conversely, increasing evidence indicates detrimental effects of increased PrPc expression on cancer progression, another condition accompanied by low oxygen tensions. A switch between anaerobic and aerobic metabolism characterizes both conditions. A cellular process that might unite both is glycolysis. Putative role of PrPc in stimulation of glycolysis in times of need is indeed thought provoking. A significance of astrocytic PrPc expression for neuronal survival under hypoxic conditions and possible association of PrPc with the astrocyte-neuron lactate shuttle is considered. We posit PrPc-induced lactate production via transactivation of lactate dehydrogenase A by hypoxia inducible factor 1α as an important factor for survival of both neurons and tumor cells in hypoxic microenvironment. Concomitantly, we discuss a cross-talk between Wnt/β-catenin and PI3K/Akt signaling pathways in executing PrPc-induced activation of glycolysis. Finally, we would like to emphasize that we see a great potential in joining expertise from both fields, neuroscience and cancer research in revealing the mechanisms underlying hypoxia-related pathologies. PrPc may prove focal point for future research.
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Affiliation(s)
| | - Holger Herlyn
- Institute of Anthropology, Johannes Gutenberg University of Mainz Mainz, Germany
| | - Inga Zerr
- Department of Neurology, University Medical Center Göttingen and German Center for Neurodegenerative Diseases Göttingen, Germany
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Pérez-Escuredo J, Van Hée VF, Sboarina M, Falces J, Payen VL, Pellerin L, Sonveaux P. Monocarboxylate transporters in the brain and in cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1863:2481-97. [PMID: 26993058 PMCID: PMC4990061 DOI: 10.1016/j.bbamcr.2016.03.013] [Citation(s) in RCA: 295] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 03/01/2016] [Accepted: 03/12/2016] [Indexed: 12/20/2022]
Abstract
Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1-4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
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Affiliation(s)
- Jhudit Pérez-Escuredo
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52 box B1.53.09, 1200 Brussels, Belgium
| | - Vincent F Van Hée
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52 box B1.53.09, 1200 Brussels, Belgium
| | - Martina Sboarina
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52 box B1.53.09, 1200 Brussels, Belgium
| | - Jorge Falces
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52 box B1.53.09, 1200 Brussels, Belgium
| | - Valéry L Payen
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52 box B1.53.09, 1200 Brussels, Belgium
| | - Luc Pellerin
- Laboratory of Neuroenergetics, Department of Physiology, University of Lausanne, Rue du Bugnon 7, 1005 Lausanne, Switzerland.
| | - Pierre Sonveaux
- Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52 box B1.53.09, 1200 Brussels, Belgium.
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Quincozes-Santos A, Bobermin LD, de Assis AM, Gonçalves CA, Souza DO. Fluctuations in glucose levels induce glial toxicity with glutamatergic, oxidative and inflammatory implications. Biochim Biophys Acta Mol Basis Dis 2016; 1863:1-14. [PMID: 27663722 DOI: 10.1016/j.bbadis.2016.09.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 08/21/2016] [Accepted: 09/17/2016] [Indexed: 02/06/2023]
Abstract
Astrocytes are dynamic cells that maintain brain homeostasis by regulating neurotransmitter systems, antioxidant defenses, inflammatory responses and energy metabolism. Astroglial cells are also primarily responsible for the uptake and metabolism of glucose in the brain. Diabetes mellitus (DM) is a pathological condition characterized by hyperglycemia and is associated with several changes in the central nervous system (CNS), including alterations in glial function. Classically, excessive glucose concentrations are used to induce experimental models of astrocyte dysfunction; however, hypoglycemic episodes may also cause several brain injuries. The main focus of the present study was to evaluate how fluctuations in glucose levels induce cytotoxicity. The culture medium of astroglial cells was replaced twice as follows: (1) from 6mM (control) to 12mM (high glucose), and (2) from 12mM to 0mM (glucose deprivation). Cell viability, mitochondrial function, oxidative/nitrosative stress, glutamate metabolism, inflammatory responses, nuclear factor κB (NFκB) transcriptional activity and p38 mitogen-activated protein kinase (p38 MAPK) levels were assessed. Our in vitro experimental model showed that up and down fluctuations in glucose levels decreased cell proliferation, induced mitochondrial dysfunction, increased oxidative/nitrosative stress with consequent cellular biomolecular damage, impaired glutamate metabolism and increased pro-inflammatory cytokine release. Additionally, activation of the NFκB and p38 signaling pathways were putative mechanisms of the effects of glucose fluctuations on astroglial cells. In summary, for the first time, we show that changes in glucose concentrations, from high-glucose levels to glucose deprivation, exacerbate glial injury.
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Affiliation(s)
- André Quincozes-Santos
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
| | - Larissa Daniele Bobermin
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Adriano M de Assis
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Carlos-Alberto Gonçalves
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Diogo Onofre Souza
- Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Zeng L, Zhou HY, Tang NN, Zhang WF, He GJ, Hao B, Feng YD, Zhu H. Wortmannin influences hypoxia-inducible factor-1 alpha expression and glycolysis in esophageal carcinoma cells. World J Gastroenterol 2016; 22:4868-4880. [PMID: 27239113 PMCID: PMC4873879 DOI: 10.3748/wjg.v22.i20.4868] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 03/20/2016] [Accepted: 04/15/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of phosphatidylinositol-3-kinase protein kinase B (PI3K/AKT)-HIF-1α signaling pathway on glycolysis in esophageal carcinoma cells under hypoxia.
METHODS: Esophageal carcinoma cell lines Eca109 and TE13 were cultured under hypoxia environment, and the protein, mRNA and activity levels of hypoxia inducible factor-1 alpha (HIF-1α), glucose transporter 1, hexokinase-II, phosphofructokinase 2 and lactate dehydrogenase-A were determined. Supernatant lactic acid concentrations were also detected. The PI3K/AKT signaling pathway was then inhibited with wortmannin, and the effects of hypoxia on the expression or activities of HIF-1α, associated glycolytic enzymes and lactic acid concentrations were observed. Esophageal carcinoma cells were then transfected with interference plasmid with HIF-1α-targeting siRNA to assess impact of the high expression of HIF-1α on glycolysis.
RESULTS: HIF-1α is highly expressed in the esophageal carcinoma cell lines tested, and with decreasing levels of oxygen, the expression of HIF-1α and the associated glycolytic enzymes and the extracellular lactic acid concentration were enhanced in the esophageal carcinoma cell lines Eca109 and TE13. In both normoxia and hypoxic conditions, the level of glycolytic enzymes and the secretion of lactic acid were both reduced by wortmannin. The expression and activities of glycolytic enzymes and the lactic acid concentration in cells were reduced by inhibiting HIF-1α, especially the decreasing level of glycolysis was significant under hypoxic conditions.
CONCLUSION: The PI3K/AKT pathway and HIF-1α are both involved in the process of glycolysis in esophageal cancer cells.
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Jha MK, Lee IK, Suk K. Metabolic reprogramming by the pyruvate dehydrogenase kinase-lactic acid axis: Linking metabolism and diverse neuropathophysiologies. Neurosci Biobehav Rev 2016; 68:1-19. [PMID: 27179453 DOI: 10.1016/j.neubiorev.2016.05.006] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/11/2016] [Accepted: 05/09/2016] [Indexed: 12/12/2022]
Abstract
Emerging evidence indicates that there is a complex interplay between metabolism and chronic disorders in the nervous system. In particular, the pyruvate dehydrogenase (PDH) kinase (PDK)-lactic acid axis is a critical link that connects metabolic reprogramming and the pathophysiology of neurological disorders. PDKs, via regulation of PDH complex activity, orchestrate the conversion of pyruvate either aerobically to acetyl-CoA, or anaerobically to lactate. The kinases are also involved in neurometabolic dysregulation under pathological conditions. Lactate, an energy substrate for neurons, is also a recently acknowledged signaling molecule involved in neuronal plasticity, neuron-glia interactions, neuroimmune communication, and nociception. More recently, the PDK-lactic acid axis has been recognized to modulate neuronal and glial phenotypes and activities, contributing to the pathophysiologies of diverse neurological disorders. This review covers the recent advances that implicate the PDK-lactic acid axis as a novel linker of metabolism and diverse neuropathophysiologies. We finally explore the possibilities of employing the PDK-lactic acid axis and its downstream mediators as putative future therapeutic strategies aimed at prevention or treatment of neurological disorders.
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Affiliation(s)
- Mithilesh Kumar Jha
- Department of Pharmacology, Brain Science and Engineering Institute, BK21 PLUS KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea; Department of Neurology, Division of Neuromuscular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - In-Kyu Lee
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Kyoungho Suk
- Department of Pharmacology, Brain Science and Engineering Institute, BK21 PLUS KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
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Petit JM, Magistretti P. Regulation of neuron–astrocyte metabolic coupling across the sleep–wake cycle. Neuroscience 2016; 323:135-56. [DOI: 10.1016/j.neuroscience.2015.12.007] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 12/01/2015] [Accepted: 12/04/2015] [Indexed: 11/30/2022]
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Rosafio K, Castillo X, Hirt L, Pellerin L. Cell-specific modulation of monocarboxylate transporter expression contributes to the metabolic reprograming taking place following cerebral ischemia. Neuroscience 2016; 317:108-20. [DOI: 10.1016/j.neuroscience.2015.12.052] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/17/2015] [Accepted: 12/29/2015] [Indexed: 01/23/2023]
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Olson KA, Schell JC, Rutter J. Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies. Trends Biochem Sci 2016; 41:219-230. [PMID: 26873641 DOI: 10.1016/j.tibs.2016.01.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 01/11/2016] [Accepted: 01/12/2016] [Indexed: 01/11/2023]
Abstract
Dysregulated metabolism is an emerging hallmark of cancer, and there is abundant interest in developing therapies to selectively target these aberrant metabolic phenotypes. Sitting at the decision-point between mitochondrial carbohydrate oxidation and aerobic glycolysis (i.e., the 'Warburg effect'), the synthesis and consumption of pyruvate is tightly controlled and is often differentially regulated in cancer cells. This review examines recent efforts toward understanding and targeting mitochondrial pyruvate metabolism, and addresses some of the successes, pitfalls, and significant challenges of metabolic therapy to date.
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Affiliation(s)
- Kristofor A Olson
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA
| | - John C Schell
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA
| | - Jared Rutter
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA; Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
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Masur F, Benesch F, Pfannkuche H, Fuhrmann H, Gäbel G. Conjugated linoleic acids influence fatty acid metabolism in ovine ruminal epithelial cells. J Dairy Sci 2016; 99:3081-3095. [PMID: 26830749 DOI: 10.3168/jds.2015-10042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 12/11/2015] [Indexed: 12/31/2022]
Abstract
Conjugated linoleic acids (CLA), particularly cis-9,trans-11 (c9t11) and trans-10,cis-12 (t10c12), are used as feed additives to adapt to constantly increasing demands on the performance of lactating cows. Under these feeding conditions, the rumen wall, and the rumen epithelial cells (REC) in particular, are directly exposed to high amounts of CLA. This study determined the effect of CLA on the fatty acid (FA) metabolism of REC and expression of genes known to be modulated by FA. Cultured REC were incubated with c9t11, t10c12, and the structurally similar FA linoleic acid (LA), oleic acid (OA), and trans-vaccenic acid (TVA) for 48 h at a concentration of 100 µM. Cellular FA levels were determined by gas chromatography. Messenger RNA expression levels of stearoyl-CoA desaturase (SCD) and monocarboxylate transporter (MCT) 1 and 4 were quantified by reverse transcription-quantitative PCR. Fatty acid evaluation revealed significant effects of CLA, LA, OA, and TVA on the amount of FA metabolites of β-oxidation and elongation and of metabolites related to desaturation by SCD. The observed changes in FA content point (among others) to the ability of REC to synthesize c9t11 from TVA endogenously. The mRNA expression levels of SCD identified a decrease after CLA, LA, OA, or TVA treatment. In line with the changes in mRNA expression, we found reduced amounts of C16:1n-7 cis-9 and C18:1n-9 cis-9, the main products of SCD. The expression of MCT1 mRNA increased after c9t11 and t10c12 treatment, and CLA c9t11 induced an upregulation of MCT4. Application of peroxisome proliferator-activated receptor (PPAR) α antagonist suggested that activation of PPARα is involved in the changes of MCT1, MCT4, and SCD mRNA expression induced by c9t11. Participation of PPARγ in the changes of MCT1 and SCD mRNA expression was shown by the application of the respective antagonist. The study demonstrates that exposure to CLA affects both FA metabolism and regulatory pathways within REC.
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Affiliation(s)
- F Masur
- Institute of Veterinary Physiology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, 04103, Germany.
| | - F Benesch
- Institute of Veterinary Physiology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, 04103, Germany
| | - H Pfannkuche
- Institute of Veterinary Physiology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, 04103, Germany
| | - H Fuhrmann
- Institute of Physiological Chemistry, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, 04103, Germany
| | - G Gäbel
- Institute of Veterinary Physiology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, 04103, Germany
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Hong S, Ahn JY, Cho GS, Kim IH, Cho JH, Ahn JH, Park JH, Won MH, Chen BH, Shin BN, Tae HJ, Park SM, Cho JH, Choi SY, Lee JC. Monocarboxylate transporter 4 plays a significant role in the neuroprotective mechanism of ischemic preconditioning in transient cerebral ischemia. Neural Regen Res 2015; 10:1604-11. [PMID: 26692857 PMCID: PMC4660753 DOI: 10.4103/1673-5374.167757] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Monocarboxylate transporters (MCTs), which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning (IPC) on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups (sham-operated group, ischemia only group, IPC + sham-operated group and IPC + ischemia group). A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region (CA1), not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC + ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC + sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC + ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia.
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Affiliation(s)
- Seongkweon Hong
- Department of Surgery, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Ji Yun Ahn
- Department of Emergency Medicine, Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, South Korea ; Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Geum-Sil Cho
- Department of Neuroscience, College of Medicine, Korea University, Seoul, South Korea
| | - In Hye Kim
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Jeong Hwi Cho
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Ji Hyeon Ahn
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Joon Ha Park
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Moo-Ho Won
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Bai Hui Chen
- Department of Physiology, College of Medicine, Hallym University, Chuncheon, South Korea
| | - Bich-Na Shin
- Department of Physiology, College of Medicine, Hallym University, Chuncheon, South Korea
| | - Hyun-Jin Tae
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, South Korea
| | - Seung Min Park
- Department of Emergency Medicine, Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, South Korea ; Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Jun Hwi Cho
- Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon, South Korea
| | - Soo Young Choi
- Department of Biomedical Science, Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, South Korea
| | - Jae-Chul Lee
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, South Korea
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Quintard H, Patet C, Zerlauth JB, Suys T, Bouzat P, Pellerin L, Meuli R, Magistretti PJ, Oddo M. Improvement of Neuroenergetics by Hypertonic Lactate Therapy in Patients with Traumatic Brain Injury Is Dependent on Baseline Cerebral Lactate/Pyruvate Ratio. J Neurotrauma 2015; 33:681-7. [PMID: 26421521 PMCID: PMC4827289 DOI: 10.1089/neu.2015.4057] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Energy dysfunction is associated with worse prognosis after traumatic brain injury (TBI). Recent data suggest that hypertonic sodium lactate infusion (HL) improves energy metabolism after TBI. Here, we specifically examined whether the efficacy of HL (3h infusion, 30–40 μmol/kg/min) in improving brain energetics (using cerebral microdialysis [CMD] glucose as a main therapeutic end-point) was dependent on baseline cerebral metabolic state (assessed by CMD lactate/pyruvate ratio [LPR]) and cerebral blood flow (CBF, measured with perfusion computed tomography [PCT]). Using a prospective cohort of 24 severe TBI patients, we found CMD glucose increase during HL was significant only in the subgroup of patients with elevated CMD LPR >25 (n = 13; +0.13 [95% confidence interval (CI) 0.08–0.19] mmol/L, p < 0.001; vs. +0.04 [–0.05–0.13] in those with normal LPR, p = 0.33, mixed-effects model). In contrast, CMD glucose increase was independent from baseline CBF (coefficient +0.13 [0.04–0.21] mmol/L when global CBF was <32.5 mL/100 g/min vs. +0.09 [0.04–0.14] mmol/L at normal CBF, both p < 0.005) and systemic glucose. Our data suggest that improvement of brain energetics upon HL seems predominantly dependent on baseline cerebral metabolic state and support the concept that CMD LPR – rather than CBF – could be used as a diagnostic indication for systemic lactate supplementation following TBI.
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Affiliation(s)
- Hervé Quintard
- 1 Department of Intensive Care Medicine, Neuroscience Critical Care Research Group, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland .,2 Department of Anesthesia and Intensive Care, Nice University Hospital , Nice, France
| | - Camille Patet
- 1 Department of Intensive Care Medicine, Neuroscience Critical Care Research Group, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland
| | - Jean-Baptiste Zerlauth
- 3 Department of Medical Radiology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland
| | - Tamarah Suys
- 1 Department of Intensive Care Medicine, Neuroscience Critical Care Research Group, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland
| | - Pierre Bouzat
- 1 Department of Intensive Care Medicine, Neuroscience Critical Care Research Group, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland .,4 Department of Anesthesia and Intensive Care, Grenoble University Hospital , Grenoble, France
| | - Luc Pellerin
- 5 Institute of Physiology, University of Lausanne , Lausanne, Switzerland
| | - Reto Meuli
- 3 Department of Medical Radiology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland
| | - Pierre J Magistretti
- 6 Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology (KAUST) , Thuwal, Kingdom of Saudi Arabia .,7 Centre de Neurosciences Psychiatriques, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland .,8 Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute , Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Mauro Oddo
- 1 Department of Intensive Care Medicine, Neuroscience Critical Care Research Group, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital , Lausanne, Switzerland
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