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Mukherjee AG, Gopalakrishnan AV. The mechanistic insights of the antioxidant Keap1-Nrf2 pathway in oncogenesis: a deadly scenario. Med Oncol 2023; 40:248. [PMID: 37480500 DOI: 10.1007/s12032-023-02124-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 07/06/2023] [Indexed: 07/24/2023]
Abstract
The Nuclear factor erythroid 2-related factor 2 (Nrf2) protein has garnered significant interest due to its crucial function in safeguarding cells and tissues. The Nrf2 protein is crucial in preserving tissue integrity by safeguarding cells against metabolic, xenobiotic and oxidative stress. Due to its various functions, Nrf2 is a potential pharmacological target for reducing the incidence of diseases such as cancer. However, mutations in Keap1-Nrf2 are not consistently favored in all types of cancer. Instead, they seem to interact with specific driver mutations of tumors and their respective tissue origins. The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway mutations are a powerful cancer adaptation that utilizes inherent cytoprotective pathways, encompassing nutrient metabolism and ROS regulation. The augmentation of Nrf2 activity elicits significant alterations in the characteristics of neoplastic cells, such as resistance to radiotherapy and chemotherapy, safeguarding against apoptosis, heightened invasiveness, hindered senescence, impaired autophagy and increased angiogenesis. The altered activity of Nrf2 can arise from diverse genetic and epigenetic modifications that instantly impact Nrf2 regulation. The present study aims to showcase the correlation between the Keap1-Nrf2 pathway and the progression of cancers, emphasizing genetic mutations, metabolic processes, immune regulation, and potential therapeutic strategies. This article delves into the intricacies of Nrf2 pathway anomalies in cancer, the potential ramifications of uncontrolled Nrf2 activity, and therapeutic interventions to modulate the Keap1-Nrf2 pathway.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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Tostes K, dos Santos AC, Alves LO, Bechara LRG, Marascalchi R, Macabelli CH, Grejo MP, Festuccia WT, Gottlieb RA, Ferreira JCB, Chiaratti MR. Autophagy deficiency abolishes liver mitochondrial DNA segregation. Autophagy 2022; 18:2397-2408. [PMID: 35220898 PMCID: PMC9542960 DOI: 10.1080/15548627.2022.2038501] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Mutations in the mitochondrial genome (mtDNA) are ubiquitous in humans and can lead to a broad spectrum of disorders. However, due to the presence of multiple mtDNA molecules in the cell, co-existence of mutant and wild-type mtDNAs (termed heteroplasmy) can mask disease phenotype unless a threshold of mutant molecules is reached. Importantly, the mutant mtDNA level can change across lifespan as mtDNA segregates in an allele- and cell-specific fashion, potentially leading to disease. Segregation of mtDNA is mainly evident in hepatic cells, resulting in an age-dependent increase of mtDNA variants, including non-synonymous potentially deleterious mutations. Here we modeled mtDNA segregation using a well-established heteroplasmic mouse line with mtDNA of NZB/BINJ and C57BL/6N origin on a C57BL/6N nuclear background. This mouse line showed a pronounced age-dependent NZB mtDNA accumulation in the liver, thus leading to enhanced respiration capacity per mtDNA molecule. Remarkably, liver-specific atg7 (autophagy related 7) knockout abolished NZB mtDNA accumulat ion, resulting in close-to-neutral mtDNA segregation through development into adulthood. prkn (parkin RBR E3 ubiquitin protein ligase) knockout also partially prevented NZB mtDNA accumulation in the liver, but to a lesser extent. Hence, we propose that age-related liver mtDNA segregation is a consequence of macroautophagic clearance of the less-fit mtDNA. Considering that NZB/BINJ and C57BL/6N mtDNAs have a level of divergence comparable to that between human Eurasian and African mtDNAs, these findings have potential implications for humans, including the safe use of mitochondrial replacement therapy.Abbreviations: Apob: apolipoprotein B; Atg1: autophagy-related 1; Atg7: autophagy related 7; Atp5a1: ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1; BL6: C57BL/6N mouse strain; BNIP3: BCL2/adenovirus E1B interacting protein 3; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; mt-Atp8: mitochondrially encoded ATP synthase 8; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MT-CO2: mitochondrially encoded cytochrome c oxidase II; mt-Co3: mitochondrially encoded cytochrome c oxidase III; mt-Cytb: mitochondrially encoded cytochrome b; mtDNA: mitochondrial DNA; MUL1: mitochondrial ubiquitin ligase activator of NFKB 1; nDNA: nuclear DNA; Ndufa9: NADH:ubiquinone oxireductase subunit A9; NDUFB8: NADH:ubiquinone oxireductase subunit B8; Nnt: nicotinamide nucleotide transhydrogenase; NZB: NZB/BINJ mouse strain; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced putative kinase 1; Polg2: polymerase (DNA directed), gamma 2, accessory subunit; Ppara: peroxisome proliferator activated receptor alpha; Ppia: peptidylprolyl isomerase A; Prkn: parkin RBR E3 ubiquitin protein ligase; P10: post-natal day 10; P21: post-natal day 21; P100: post-natal day 100; qPCR: quantitative polymerase chain reaction; Rpl19: ribosomal protein L19; Rps18: ribosomal protein S18; SD: standard deviation; SEM: standard error of the mean; SDHB: succinate dehydrogenase complex, subunit B, iron sulfur (Ip); SQSTM1: sequestosome 1; Ssbp1: single-stranded DNA binding protein 1; TFAM: transcription factor A, mitochondrial; Tfb1m: transcription factor B1, mitochondrial; Tfb2m: transcription factor B2, mitochondrial; TOMM20: translocase of outer mitochondrial membrane 20; UQCRC2: ubiquinol cytochrome c reductase core protein 2; WT: wild-type.
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Affiliation(s)
- Katiane Tostes
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Angélica C. dos Santos
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Lindomar O. Alves
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Luiz R. G. Bechara
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Rachel Marascalchi
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Carolina H. Macabelli
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - Mateus P. Grejo
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil
| | - William T. Festuccia
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Roberta A. Gottlieb
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Julio C. B. Ferreira
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil,Department of Chemical and Systems Biology, Stanford University School of Medicine, CA, USA
| | - Marcos R. Chiaratti
- Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos, Brazil,CONTACT Marcos R. Chiaratti Departamento de Genética e Evolução, Universidade Federal de São Carlos, São Carlos13565-905, Brazil
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Huang Y, Jiang J, Wang W, Guo J, Yang N, Zhang J, Liu Q, Chen Y, Hu T, Rao C. Zanthoxylum armatum DC. extract induces liver injury via autophagy suppression and oxidative damage by activation of mTOR/ULK1 pathway. Toxicon 2022; 217:162-172. [PMID: 35977614 DOI: 10.1016/j.toxicon.2022.08.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/02/2022] [Accepted: 08/10/2022] [Indexed: 11/15/2022]
Abstract
Zanthoxylum armatum DC. (ZADC) has anti-inflammatory, antioxidative, and antibacterial effects. The cytotoxicity of methanol extract of Zanthoxylum armatum DC. (MZADC) has been reported for BRL 3 A cell lines. However, whether MZADC can induce liver damage in vivo remains unclear. Therefore, it is essential to explore whether ZADC causes liver injury and, if the results confirm hepatotoxicity, to further study the potential mechanisms for the in-vitro cytotoxicity of the BRL 3 A cell lines. In vivo, different doses (0.346, 0.519, and 1.038 g/kg/day) of MZADC treatment were given by intragastric administration among male Sprague Dawley rats for 28 days. Levels of serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in the high dose group increased. Steatosis and focal necrosis were found in liver cells in rats in the high dose group. In vitro, BRL 3 A cells were cultivated with MZADC at different concentrations (30, 50, and 70 μg/mL) for 24 h. The cell viability, the number of autophagosomes, and the expression levels of LC3 and Beclin-1 were on a decreasing trend. Besides, proportions of p-mTOR/mTOR and p-ULK1/ULK1 increased. Meanwhile, reactive oxygen species (ROS) accumulation and the content of malondialdehyde (MDA) were on the rise while the activity of superoxide dismutase (SOD) and the content of glutathione (GSH) was on the decline. This research suggests that MZADC may cause rats liver injury and inhibit autophagy in BRL 3 A cells by the mTOR/ULK1 pathway, and further induce intracellular oxidative damage.
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Affiliation(s)
- Yan Huang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Jialuo Jiang
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Wenlin Wang
- Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Jiafu Guo
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Nannan Yang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Jian Zhang
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Qiuyan Liu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Yan Chen
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Tingting Hu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Chaolong Rao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China; R&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China.
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4
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Collier JJ, Suomi F, Oláhová M, McWilliams TG, Taylor RW. Emerging roles of ATG7 in human health and disease. EMBO Mol Med 2021; 13:e14824. [PMID: 34725936 PMCID: PMC8649875 DOI: 10.15252/emmm.202114824] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/08/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
The cardinal stages of macroautophagy are driven by core autophagy-related (ATG) proteins, whose ablation largely abolishes intracellular turnover. Disrupting ATG genes is paradigmatic of studying autophagy deficiency, yet emerging data suggest that ATG proteins have extensive biological importance beyond autophagic elimination. An important example is ATG7, an essential autophagy effector enzyme that in concert with other ATG proteins, also regulates immunity, cell death and protein secretion, and independently regulates the cell cycle and apoptosis. Recently, a direct association between ATG7 dysfunction and disease was established in patients with biallelic ATG7 variants and childhood-onset neuropathology. Moreover, a prodigious body of evidence supports a role for ATG7 in protecting against complex disease states in model organisms, although how dysfunctional ATG7 contributes to manifestation of these diseases, including cancer, neurodegeneration and infection, in humans remains unclear. Here, we systematically review the biological functions of ATG7, discussing the impact of its impairment on signalling pathways and human pathology. Future studies illuminating the molecular relationship between ATG7 dysfunction and disease will expedite therapies for disorders involving ATG7 deficiency and/or impaired autophagy.
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Affiliation(s)
- Jack J Collier
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research InstituteNewcastle UniversityNewcastle upon TyneUK
- Present address:
Department of Neurology and NeurosurgeryMontreal Neurological InstituteMcGill UniversityMontrealQCCanada
| | - Fumi Suomi
- Translational Stem Cell Biology & Metabolism Program, Research Programs UnitUniversity of HelsinkiHelsinkiFinland
| | - Monika Oláhová
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research InstituteNewcastle UniversityNewcastle upon TyneUK
| | - Thomas G McWilliams
- Translational Stem Cell Biology & Metabolism Program, Research Programs UnitUniversity of HelsinkiHelsinkiFinland
- Department of AnatomyFaculty of MedicineUniversity of HelsinkiHelsinkiFinland
| | - Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research InstituteNewcastle UniversityNewcastle upon TyneUK
- NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and ChildrenNewcastle UniversityNewcastle upon TyneUK
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5
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Zhang Z, Costa M. p62 functions as a signal hub in metal carcinogenesis. Semin Cancer Biol 2021; 76:267-278. [PMID: 33894381 PMCID: PMC9161642 DOI: 10.1016/j.semcancer.2021.04.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 04/06/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022]
Abstract
A number of metals are toxic and carcinogenic to humans. Reactive oxygen species (ROS) play an important role in metal carcinogenesis. Oxidative stress acts as the converging point among various stressors with ROS being the main intracellular signal transducer. In metal-transformed cells, persistent expression of p62 and erythroid 2-related factor 2 (Nrf2) result in apoptosis resistance, angiogenesis, inflammatory microenvironment, and metabolic reprogramming, contributing to overall mechanism of metal carcinogenesis. Autophagy, a conserved intracellular process, maintains cellular homeostasis by facilitating the turnover of protein aggregates, cellular debris, and damaged organelles. In addition to being a substrate of autophagy, p62 is also a crucial molecule in a myriad of cellular functions and in molecular events, which include oxidative stress, inflammation, apoptosis, cell proliferation, metabolic reprogramming, that modulate cell survival and tumor growth. The multiple functions of p62 are appreciated by its ability to interact with several key components involved in various oncogenic pathways. This review summarizes the current knowledge and progress in studies of p62 and metal carcinogenesis with emphasis on oncogenic pathways related to oxidative stress, inflammation, apoptosis, and metabolic reprogramming.
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Affiliation(s)
- Zhuo Zhang
- Department of Environmental Medicine, NYU School of Medicine, 341 East 25th Street, New York, NY 10010, USA
| | - Max Costa
- Department of Environmental Medicine, NYU School of Medicine, 341 East 25th Street, New York, NY 10010, USA.
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6
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Macrophage Autophagy and Silicosis: Current Perspective and Latest Insights. Int J Mol Sci 2021; 22:ijms22010453. [PMID: 33466366 PMCID: PMC7795780 DOI: 10.3390/ijms22010453] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 12/16/2022] Open
Abstract
Silicosis is an urgent public health problem in many countries. Alveolar macrophage (AM) plays an important role in silicosis progression. Autophagy is a balanced mechanism for regulating the cycle of synthesis and degradation of cellular components. Our previous study has shown that silica engulfment results in lysosomal rupture, which may lead to the accumulation of autophagosomes in AMs of human silicosis. The excessive accumulation of autophagosomes may lead to apoptosis in AMs. Herein, we addressed some assumptions concerning the complex function of autophagy-related proteins on the silicosis pathogenesis. We also recapped the molecular mechanism of several critical proteins targeting macrophage autophagy in the process of silicosis fibrosis. Furthermore, we summarized several exogenous chemicals that may cause an aggravation or alleviation for silica-induced pulmonary fibrosis by regulating AM autophagy. For example, lipopolysaccharides or nicotine may have a detrimental effect combined together with silica dust via exacerbating the blockade of AM autophagic degradation. Simultaneously, some natural product ingredients such as atractylenolide III, dioscin, or trehalose may be the potential AM autophagy regulators, protecting against silicosis fibrosis. In conclusion, the deeper molecular mechanism of these autophagy targets should be explored in order to provide feasible clues for silicosis therapy in the clinical setting.
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7
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Jaeger K, Sukseree S, Zhong S, Phinney BS, Mlitz V, Buchberger M, Narzt MS, Gruber F, Tschachler E, Rice RH, Eckhart L. Cornification of nail keratinocytes requires autophagy for bulk degradation of intracellular proteins while sparing components of the cytoskeleton. Apoptosis 2020; 24:62-73. [PMID: 30552537 PMCID: PMC6373260 DOI: 10.1007/s10495-018-1505-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Epidermal keratinocytes undergo cornification to form the cellular building blocks of hard skin appendages such as nails and the protective layer on the surface of the skin. Cornification requires the cross-linking of structural proteins and the removal of other cellular components to form mechanically rigid and inert corneocytes. Autophagy has been proposed to contribute to this intracellular remodelling process, but its molecular targets in keratinocytes, if any, have remained elusive. Here, we deleted the essential autophagy factor Atg7 in K14-positive epithelia of mice and determined by proteomics the impact of this deletion on the abundance of individual proteins in cornified nails. The genetic suppression of autophagy in keratinocytes resulted in a significant increase in the number of proteins that survived cornification and in alterations of their abundance in the nail proteome. A broad range of enzymes and other non-structural proteins were elevated whereas the amounts of cytoskeletal proteins of the keratin and keratin-associated protein families, cytolinker proteins and desmosomal proteins were either unaltered or decreased in nails of mice lacking epithelial autophagy. Among the various types of non-cytoskeletal proteins, the subunits of the proteasome and of the TRiC/CCT chaperonin were most strongly elevated in mutant nails, indicating a particularly important role of autophagy in removing these large protein complexes during normal cornification. Taken together, the results of this study suggest that autophagy is active during nail keratinocyte cornification and its substrate specificity depends on the accessibility of proteins outside of the cytoskeleton and their presence in large complexes.
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Affiliation(s)
- Karin Jaeger
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria
| | - Supawadee Sukseree
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria
| | - Shaomin Zhong
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria
| | - Brett S Phinney
- Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, CA, USA
| | - Veronika Mlitz
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria
| | - Maria Buchberger
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria
| | - Marie Sophie Narzt
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria.,Christian Doppler Laboratory on Biotechnology of Skin Aging, Vienna, Austria
| | - Florian Gruber
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria.,Christian Doppler Laboratory on Biotechnology of Skin Aging, Vienna, Austria
| | - Erwin Tschachler
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria
| | - Robert H Rice
- Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, CA, 95616-8588, USA.
| | - Leopold Eckhart
- Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090, Vienna, Austria.
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8
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Ke PY. Diverse Functions of Autophagy in Liver Physiology and Liver Diseases. Int J Mol Sci 2019; 20:E300. [PMID: 30642133 PMCID: PMC6358975 DOI: 10.3390/ijms20020300] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 01/05/2019] [Accepted: 01/08/2019] [Indexed: 01/09/2023] Open
Abstract
Autophagy is a catabolic process by which eukaryotic cells eliminate cytosolic materials through vacuole-mediated sequestration and subsequent delivery to lysosomes for degradation, thus maintaining cellular homeostasis and the integrity of organelles. Autophagy has emerged as playing a critical role in the regulation of liver physiology and the balancing of liver metabolism. Conversely, numerous recent studies have indicated that autophagy may disease-dependently participate in the pathogenesis of liver diseases, such as liver hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. This review summarizes the current knowledge on the functions of autophagy in hepatic metabolism and the contribution of autophagy to the pathophysiology of liver-related diseases. Moreover, the impacts of autophagy modulation on the amelioration of the development and progression of liver diseases are also discussed.
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Affiliation(s)
- Po-Yuan Ke
- Department of Biochemistry & Molecular Biology and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
- Division of Allergy, Immunology, and Rheumatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
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9
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Han YF, Zhao YB, Li J, Li L, Li YG, Li SP, Li ZD. Stat3-Atg5 signal axis inducing autophagy to alleviate hepatic ischemia-reperfusion injury. J Cell Biochem 2017; 119:3440-3450. [PMID: 29143976 DOI: 10.1002/jcb.26516] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 11/13/2017] [Indexed: 12/16/2022]
Abstract
In performing our experiment, impaired autophagy increased hepatocellular damage during the reperfusion period. It was demonstrated by the effect of blocking autophagy using bafilomycin A1 or knocking Atg5 gene out reduces the anti-apoptotic effect of Stat3. Here we focus on the role of signal transducer and activator of transcription 3 (Stat3) in regulating autophagy to alleviate hepatic IRI. We found that Stat3 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling pathway. This increased Stat3 expression, which was allied with high autophagic activity, alleviated liver damage to IR, an effect which was abrogated by Stat3 epletion as demonstrated in both in vivo and in vitro methods. The levels of Atg5 protein were decreased when Stat3 was inhibited by HO 3867 or siStat3. We conclude that Stat3 appeared to exert a pivotal role in hepatic IRI, by activating autophagy to alleviate hepatic IRI, and Atg5 was required for this process. The identification of this novel pathway, that links expression levels of Stat3 with Atg5-mediated autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.
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Affiliation(s)
- Yu-Fang Han
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Yan-Bing Zhao
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Jun Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Li Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Yong-Gan Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Shi-Peng Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
| | - Zhong-Dong Li
- Second Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo, Henan, China
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10
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Wong YK, Zhang J, Hua ZC, Lin Q, Shen HM, Wang J. Recent advances in quantitative and chemical proteomics for autophagy studies. Autophagy 2017; 13:1472-1486. [PMID: 28820289 DOI: 10.1080/15548627.2017.1313944] [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] [Indexed: 12/20/2022] Open
Abstract
Macroautophagy/autophagy is an evolutionarily well-conserved cellular degradative process with important biological functions that is closely implicated in health and disease. In recent years, quantitative mass spectrometry-based proteomics and chemical proteomics have emerged as important tools for the study of autophagy, through large-scale unbiased analysis of the proteome or through highly specific and accurate analysis of individual proteins of interest. At present, a variety of approaches have been successfully applied, including (i) expression and interaction proteomics for the study of protein post-translational modifications, (ii) investigating spatio-temporal dynamics of protein synthesis and degradation, and (iii) direct determination of protein activity and profiling molecular targets in the autophagic process. In this review, we attempted to provide an overview of principles and techniques relevant to the application of quantitative and chemical proteomics methods to autophagy, and outline the current landscape as well as future outlook of these methods in autophagy research.
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Affiliation(s)
- Yin-Kwan Wong
- a Department of Physiology, Yong Loo Lin School of Medicine , National University of Singapore , Singapore
| | - Jianbin Zhang
- b Department of Oncology, Clinical Research Institute , Zhejiang Provincial People's Hospital , Hangzhou , China
| | - Zi-Chun Hua
- c Changzhou High-Tech Research Institute of Nanjing University and the State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences , Nanjing University , Nanjing , China
| | - Qingsong Lin
- d Department of Biological Sciences , National University of Singapore , Singapore
| | - Han-Ming Shen
- a Department of Physiology, Yong Loo Lin School of Medicine , National University of Singapore , Singapore.,e NUS Graduate School for Integrative Sciences and Engineering , National University of Singapore , Singapore
| | - Jigang Wang
- a Department of Physiology, Yong Loo Lin School of Medicine , National University of Singapore , Singapore.,c Changzhou High-Tech Research Institute of Nanjing University and the State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences , Nanjing University , Nanjing , China
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11
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Doxorubicin Regulates Autophagy Signals via Accumulation of Cytosolic Ca 2+ in Human Cardiac Progenitor Cells. Int J Mol Sci 2016; 17:ijms17101680. [PMID: 27735842 PMCID: PMC5085713 DOI: 10.3390/ijms17101680] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/19/2016] [Accepted: 09/28/2016] [Indexed: 12/12/2022] Open
Abstract
Doxorubicin (DOXO) is widely used to treat solid tumors. However, its clinical use is limited by side effects including serious cardiotoxicity due to cardiomyocyte damage. Resident cardiac progenitor cells (hCPCs) act as key regulators of homeostasis in myocardial cells. However, little is known about the function of hCPCs in DOXO-induced cardiotoxicity. In this study, we found that DOXO-mediated hCPC toxicity is closely related to calcium-related autophagy signaling and was significantly attenuated by blocking mTOR signaling in human hCPCs. DOXO induced hCPC apoptosis with reduction of SMP30 (regucalcin) and autophagosome marker LC3, as well as remarkable induction of the autophagy-related markers, Beclin-1, APG7, and P62/SQSTM1 and induction of calcium-related molecules, CaM (Calmodulin) and CaMKII (Calmodulin kinase II). The results of an LC3 puncta assay further indicated that DOXO reduced autophagosome formation via accumulation of cytosolic Ca2+. Additionally, DOXO significantly induced mTOR expression in hCPCs, and inhibition of mTOR signaling by rapamycin, a specific inhibitor, rescued DOXO-mediated autophagosome depletion in hCPCs with significant reduction of DOXO-mediated cytosolic Ca2+ accumulation in hCPCs, and restored SMP30 and mTOR expression. Thus, DOXO-mediated hCPC toxicity is linked to Ca2+-related autophagy signaling, and inhibition of mTOR signaling may provide a cardio-protective effect against DOXO-mediated hCPC toxicity.
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Li SP, He JD, Wang Z, Yu Y, Fu SY, Zhang HM, Zhang JJ, Shen ZY. miR-30b inhibits autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate. World J Gastroenterol 2016; 22:4501-14. [PMID: 27182160 PMCID: PMC4858632 DOI: 10.3748/wjg.v22.i18.4501] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 01/30/2016] [Accepted: 03/01/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the role and potential mechanism of miR-30b regulation of autophagy in hepatic ischemia-reperfusion injury (IRI). METHODS An animal model of hepatic IRI was generated in C57BL/6 mice. For in vitro studies, AML12 cells were immersed in mineral oil for 1 h and then cultured in complete Dulbecco's Modified Eagle's Medium (DMEM)/F12 to simulate IRI. Mice and cells were transfected with miR-30b agomir/mimics or antagomir/inhibitor to examine the effect of miR-30b on autophagy to promote hepatic IRI. The expression of miR-30b was measured by real-time polymerase chain reaction. Apoptotic cells were detected by terminal uridine nick-end labeling (TUNEL) staining, and cell viability was detected by methylthiazole tetrazolium assay. The expression of light chain 3, autophagy-related gene (Atg)12, Atg5, P62, and caspase-3 were detected by western blotting analysis. RESULTS miR-30b levels were significantly downregulated after hepatic IRI, and the numbers of autophagosomes were increased in response to IRI both in vivo and in vitro. These findings demonstrate that low levels of miR-30b could promote hepatic IRI. Furthermore, we found that miR-30b interacted with Atg12-Atg5 conjugate by binding to Atg12. Overexpression of miR-30b diminished Atg12 and Atg12-Atg5 conjugate levels, which promoted autophagy in response to IR. In contrast, downregulation of miR-30b was associated with increased Atg12-Atg5 conjugate levels and increased autophagy. CONCLUSION miR-30b inhibited autophagy to alleviate hepatic ischemia-reperfusion injury via decreasing the Atg12-Atg5 conjugate.
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Jiang T, Harder B, Rojo de la Vega M, Wong PK, Chapman E, Zhang DD. p62 links autophagy and Nrf2 signaling. Free Radic Biol Med 2015; 88:199-204. [PMID: 26117325 PMCID: PMC4628872 DOI: 10.1016/j.freeradbiomed.2015.06.014] [Citation(s) in RCA: 460] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 12/15/2022]
Abstract
The Nrf2-Keap1-ARE pathway is a redox and xenobiotic sensitive signaling axis that functions to protect cells against oxidative stress, environmental toxicants, and harmful chemicals through the induction of cytoprotective genes. To enforce strict regulation, cells invest a great deal of energy into the maintenance of the Nrf2 pathway to ensure rapid induction upon cellular insult and rapid return to basal levels once the insult is mitigated. Because of the protective role of Nrf2 transcriptional programs, controlled activation of the pathway has been recognized as a means for chemoprevention. On the other hand, constitutive activation of Nrf2, due to somatic mutations of genes that control Nrf2 degradation, promotes carcinogenesis and imparts chemoresistance to cancer cells. Autophagy, a bulk protein degradation process, is another tightly regulated complex cellular process that functions as a cellular quality control system to remove damaged proteins or organelles. Low cellular nutrient levels can also activate autophagy, which acts to restore metabolic homeostasis through the degradation of macromolecules to provide nutrients. Recently, these two cellular pathways were shown to intersect through the direct interaction between p62 (an autophagy adaptor protein) and Keap1 (the Nrf2 substrate adaptor for the Cul3 E3 ubiquitin ligase). Dysregulation of autophagy was shown to result in prolonged Nrf2 activation in a p62-dependent manner. In this review, we will discuss the progress that has been made in dissecting the intersection of these two pathways and the potential tumor-promoting role of prolonged Nrf2 activation.
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Affiliation(s)
- Tao Jiang
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Bryan Harder
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | | | - Pak K Wong
- Department of Aerospace and Mechanical Engineering, The University of Arizona, Tucson, AZ 85721, USA
| | - Eli Chapman
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA
| | - Donna D Zhang
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA; Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
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Xiong J. Atg7 in development and disease: panacea or Pandora's Box? Protein Cell 2015; 6:722-34. [PMID: 26404030 PMCID: PMC4598325 DOI: 10.1007/s13238-015-0195-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 07/13/2015] [Indexed: 01/15/2023] Open
Abstract
Macroautophagy is an evolutionarily conserved intracellular degradation system used by life ranging from yeasts to mammals. The core autophagic machinery is composed of ATG (autophagy-related) protein constituents. One particular member of the ATG protein family, Atg7, has been the focus of recent research. Atg7 acts as an E1-like activating enzyme facilitating both microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine and ATG12 conjugation. Thus, Atg7 stands at the hub of these two ubiquitin-like systems involving LC3 and Atg12 in autophagic vesicle expansion. In this review, I focus on the pleiotropic function of Atg7 in development, maintenance of health, and alternations of such control in disease.
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Affiliation(s)
- Jianhua Xiong
- Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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Lim YM, Lim H, Hur KY, Quan W, Lee HY, Cheon H, Ryu D, Koo SH, Kim HL, Kim J, Komatsu M, Lee MS. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat Commun 2014; 5:4934. [PMID: 25255859 DOI: 10.1038/ncomms5934] [Citation(s) in RCA: 142] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 08/06/2014] [Indexed: 02/06/2023] Open
Abstract
Despite growing interest in the relationship between autophagy and systemic metabolism, how global changes in autophagy affect metabolism remains unclear. Here we show that mice with global haploinsufficiency of an essential autophagy gene (Atg7(+/-) mice) do not show metabolic abnormalities but develop diabetes when crossed with ob/ob mice. Atg7(+/-)-ob/ob mice show aggravated insulin resistance with increased lipid content and inflammatory changes, suggesting that autophagy haploinsufficiency impairs the adaptive response to metabolic stress. We further demonstrate that intracellular lipid content and insulin resistance after lipid loading are increased as a result of autophagy insufficiency, and provide evidence for increased inflammasome activation in Atg7(+/-)-ob/ob mice. Imatinib or trehalose improves metabolic parameters of Atg7(+/-)-ob/ob mice and enhances autophagic flux. These results suggest that systemic autophagy insufficiency could be a factor in the progression from obesity to diabetes, and autophagy modulators have therapeutic potential against diabetes associated with obesity and inflammation.
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Affiliation(s)
- Yu-Mi Lim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
| | - Hyejin Lim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
| | - Kyu Yeon Hur
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
| | - Wenying Quan
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
| | - Hae-Youn Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
| | - Hwanju Cheon
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
| | - Dongryeol Ryu
- Department of Molecular Cellular Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea
| | - Seung-Hoi Koo
- Division of Life Science, Korea University, Seoul 136-713, Korea
| | - Hong Lim Kim
- Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
| | - Jin Kim
- Department of Anatomy and Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
| | - Masaaki Komatsu
- Department of Biochemistry, Niigata University School of Medicine, Niigata 950-2181, Japan
| | - Myung-Shik Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea
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Abstract
Studies performed in the liver in the 1960s led to the identification of lysosomes and the discovery of autophagy, the process by which intracellular proteins and organelles are degraded in lysosomes. Early studies in hepatocytes also uncovered how nutritional status regulates autophagy and how various circulating hormones modulate the activity of this catabolic process in the liver. The intensive characterization of hepatic autophagy over the years has revealed that lysosome-mediated degradation is important not only for maintaining liver homeostasis in normal physiological conditions, but also for an adequate response of this organ to stressors such as proteotoxicity, metabolic dysregulation, infection and carcinogenesis. Autophagic malfunction has also been implicated in the pathogenesis of common liver diseases, suggesting that chemical manipulation of this process might hold potential therapeutic value. In this Review--intended as an introduction to the topic of hepatic autophagy for clinical scientists--we describe the different types of hepatic autophagy, their role in maintaining homeostasis in a healthy liver and the contribution of autophagic malfunction to liver disease.
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Proteomics analysis of autophagy-deficient Atg7-/- MEFs reveals a close relationship between F-actin and autophagy. Biochem Biophys Res Commun 2013; 437:482-8. [PMID: 23850690 DOI: 10.1016/j.bbrc.2013.06.111] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 06/28/2013] [Indexed: 12/20/2022]
Abstract
Autophagy plays a crucial role in a wide array of physiological processes. To uncover the complex regulatory networks and mechanisms underlying basal autophagy, we performed a quantitative proteomics analysis of autophagy-deficient mouse embryonic fibroblast cells (MEFs) using iTRAQ labeling coupled with on-line 2D LC/MS/MS. We quantified a total of 1234 proteins and identified 114 proteins that were significantly altered (90% confidence interval), including 48 up-regulated proteins and 66 down-regulated proteins. We determined that F-actin was disassembled in autophagy-deficient Atg7(-/-) MEFs. Treatment of the WT MEFs with cytochalasin D (CD), which induces F-actin depolymerization, significantly induced autophagosome formation. However, treatment with cytochalasin D also increased the protein level of p62 under starvation conditions, suggesting that depolymerization of F-actin impaired autophagosome maturation and that the intact F-actin network is required for basal and starvation-induced autophagy. Our results demonstrate a close relationship between F-actin and autophagy and provide the basis for further investigation of their interactions.
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Zhou S, Liu R, Yuan K, Yi T, Zhao X, Huang C, Wei Y. Proteomics analysis of tumor microenvironment: Implications of metabolic and oxidative stresses in tumorigenesis. MASS SPECTROMETRY REVIEWS 2012; 32:267-311. [PMID: 23165949 DOI: 10.1002/mas.21362] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Revised: 08/22/2012] [Accepted: 08/22/2012] [Indexed: 02/05/2023]
Abstract
Tumorigenesis is always concomitant with microenvironmental alterations. The tumor microenvironment is a heterogeneous and complex milieu, which exerts a variety of stresses on tumor cells for proliferation, survival, or death. Recently, accumulated evidence revealed that metabolic and oxidative stresses both play significant roles in tumor development and progression that converge on a common autophagic pathway. Tumor cells display increased metabolic autonomy, and the hallmark is the exploitation of aerobic glycolysis (termed Warburg effect), which increased glucose consumption and decreased oxidative phosphorylation to support growth and proliferation. This characteristic renders cancer cells more aggressive; they devour tremendous amounts of nutrients from microenvironment to result in an ever-growing appetite for new tumor vessel formation and the release of more "waste," including key determinants of cell fate like lactate and reactive oxygen species (ROS). The intracellular ROS level of cancer cells can also be modulated by a variety of stimuli in the tumor microenvironment, such as pro-growth and pro-inflammatory factors. The intracellular redox state serves as a double-edged sword in tumor development and progression: ROS overproduction results in cytotoxic effects and might lead to apoptotic cell death, whereas certain level of ROS can act as a second-messenger for regulation of such cellular processes as cell survival, proliferation, and metastasis. The molecular mechanisms for cancer cell responses to metabolic and oxidative stresses are complex and are likely to involve multiple molecules or signaling pathways. In addition, the expression and modification of these proteins after metabolic or oxidative stress challenge are diverse in different cancer cells and endow them with different functions. Therefore, MS-based high-throughput platforms, such as proteomics, are indispensable in the global analysis of cancer cell responses to metabolic and oxidative stress. Herein, we highlight recent advances in the understanding of the metabolic and oxidative stresses associated with tumor progression with proteomics-based systems biology approaches.
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Affiliation(s)
- Shengtao Zhou
- The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
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19
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Jaeschke H, Ding WX. Autophagy and acetaminophen hepatotoxicity: how useful are Atg7-deficient mice? J Gastroenterol 2012; 47:845-6; author reply 847-8. [PMID: 22565638 DOI: 10.1007/s00535-012-0606-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 01/10/2012] [Indexed: 02/04/2023]
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20
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Rath E, Haller D. Mitochondria at the interface between danger signaling and metabolism: role of unfolded protein responses in chronic inflammation. Inflamm Bowel Dis 2012; 18:1364-77. [PMID: 22183876 DOI: 10.1002/ibd.21944] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Accepted: 10/19/2011] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel diseases (IBDs), like many other chronic diseases, feature multiple cellular stress responses including endoplasmic reticulum (ER) unfolded protein response (UPR). Maintaining protein homeostasis is indispensable for cell survival and, consequently, distinct signaling pathways have evolved to transmit organelle stress. While the ER UPR, aiming to restore ER homeostasis after challenges to ER function, has been extensively studied in the context of chronic diseases, only recently the related mitochondrial UPR (mtUPR), induced by disturbances of mitochondrial proteostasis, has drawn some attention. ER and mitochondria are in close contact and interact physically and functionally. Accumulating data have placed mitochondria at the center of diverse cellular functions and suggest mitochondria as integrators of signaling pathways such as autophagy and inflammation. Consequently, it is likely that mitochondrial stress and ER stress cannot be regarded separately and that mitochondrial stress, as well as ER stress, participates in the pathology of IBD. Protein homeostasis is particularly sensitive toward infections, oxidative stress, and energy deficiency. Thus, environmental disturbances impacting organelle function lead to the concerted activation of distinct UPRs. The metabolic status might therefore serve as an innate mechanism to sense the epithelial environment, including luminal-derived and host-derived factors. This review highlights mtUPR and its interrelation with ER UPR, focuses on recent studies identifying mitochondria as integrators of cellular danger signaling, and, furthermore, illustrates the importance ER UPR and mitochondrial dysfunction in IBD.
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Affiliation(s)
- Eva Rath
- Technische Universität München, Chair for Biofunctionality, ZIEL, Research Center for Nutrition and Food Science, CDD, Center for Diet and Disease, Freising-Weihenstephan, Germany
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Chen S, Yuan HM, Liu GF, Li HY, Jiang J. A label-free differential quantitative proteomics analysis of a TaLEA-introduced transgenic Populus simonii × Populus nigra dwarf mutant. Mol Biol Rep 2012; 39:7657-64. [DOI: 10.1007/s11033-012-1600-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Accepted: 01/31/2012] [Indexed: 01/10/2023]
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Ueno T, Ezaki J, Kominami E. Metabolic contribution of hepatic autophagic proteolysis: old wine in new bottles. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2011; 1824:51-8. [PMID: 21767672 DOI: 10.1016/j.bbapap.2011.06.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 06/27/2011] [Accepted: 06/28/2011] [Indexed: 10/18/2022]
Abstract
Pioneering work on autophagy was achieved soon after the discovery of lysosomes more than 50 years ago. Due to its prominent lysosomal activity and technical ease of handling, the liver has been at the center of continuous and vigorous investigations into autophagy. Many important discoveries, including suppression by insulin and plasma amino acids and stimulation by glucagon, have been made through in vivo and in vitro studies using perfused liver and cultured hepatocytes. The long-term controversy about the origin and nature of the autophagosome membrane has finally led to the conclusion of "phagophore," through extensive molecular cell biological approaches enlightened by the discovery of autophagy-essential ATG genes. Furthermore, recent studies using liver-specific autophagy-deficient mice have thrown light on the unique role of a selective substrate of autophagy, p62. The stabilized p62 accumulating in autophagy-deficient liver manipulates Nrf2-dependent transcription activation through specific binding to Keap1, which results in the elevated gene expression involved in detoxification. This is the first example of the dysregulation of gene expression under autophagy deficiency. Thus, basal liver autophagy makes a large contribution to the maintenance of cell homeostasis and health. Meanwhile, precise comparisons of wild-type and liver-specific autophagy-deficient mice under starvation conditions have revealed that amino acids released by autophagic degradation can be metabolized to produce glucose via gluconeogenesis for the maintenance of blood glucose, and can also be excreted to the circulation to supply serum amino acids. These results strongly confirm that induced liver autophagy plays a pivotal role in metabolic compensation. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
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Affiliation(s)
- Takashi Ueno
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
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Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, Eishi Y, Hino O, Tanaka K, Mizushima N. Autophagy-deficient mice develop multiple liver tumors. Genes Dev 2011; 25:795-800. [PMID: 21498569 DOI: 10.1101/gad.2016211] [Citation(s) in RCA: 1039] [Impact Index Per Article: 74.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autophagy is a major pathway for degradation of cytoplasmic proteins and organelles, and has been implicated in tumor suppression. Here, we report that mice with systemic mosaic deletion of Atg5 and liver-specific Atg7⁻/⁻ mice develop benign liver adenomas. These tumor cells originate autophagy-deficient hepatocytes and show mitochondrial swelling, p62 accumulation, and oxidative stress and genomic damage responses. The size of the Atg7⁻/⁻ liver tumors is reduced by simultaneous deletion of p62. These results suggest that autophagy is important for the suppression of spontaneous tumorigenesis through a cell-intrinsic mechanism, particularly in the liver, and that p62 accumulation contributes to tumor progression.
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Affiliation(s)
- Akito Takamura
- Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
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Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 2011; 16:123-40. [PMID: 21251164 DOI: 10.1111/j.1365-2443.2010.01473.x] [Citation(s) in RCA: 1135] [Impact Index Per Article: 81.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.
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Affiliation(s)
- Keiko Taguchi
- Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan
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Kang JH, Li M, Chen X, Yin XM. Proteomics analysis of starved cells revealed Annexin A1 as an important regulator of autophagic degradation. Biochem Biophys Res Commun 2011; 407:581-6. [PMID: 21420379 DOI: 10.1016/j.bbrc.2011.03.067] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 03/14/2011] [Indexed: 11/18/2022]
Abstract
Macroautophagy is involved in the bulk degradation of long-lived cytosolic proteins and subcellular organelles, which is important for the survival of cells during starvation. To identify potential players of the autophagy process, we subjected HCT116 cells cultured in complete medium and in Earle's balanced salt solution to proteomics analysis. In approximately 1500 protein spots detected, we characterized 52 unique proteins, whose expression levels were significantly changed following starvation. Notably, we found that Annexin A1 was significantly upregulated following starvation at both mRNA and protein levels. Inhibition of Annexin A1 expression with specific siRNA did not alter starvation-induced autophagy as measured by the level of lipidated LC3, but significantly reversed autophagy degradation as measured by the level of p62/SQSTM 1. Thus Annexin A1 seemed to be positively upregulated during starvation to promote autophagic degradation. Overall, the data presented in this study established a expression profile of the proteome in starved cells, which allowed the identification of proteins with potential significance in starvation-induced autophagy.
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Affiliation(s)
- Jeong-Han Kang
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, PA 15261, United States
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Hidvegi T, Mukherjee A, Ewing M, Kemp C, Perlmutter DH. The Role of Autophagy in Alpha-1-Antitrypsin Deficiency. Methods Enzymol 2011; 499:33-54. [DOI: 10.1016/b978-0-12-386471-0.00003-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Signaling pathways in mitochondrial dysfunction and aging. Mech Ageing Dev 2010; 131:536-43. [PMID: 20655326 DOI: 10.1016/j.mad.2010.07.003] [Citation(s) in RCA: 182] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 07/01/2010] [Accepted: 07/14/2010] [Indexed: 12/23/2022]
Abstract
Mitochondria are central players in the determination of cell life and death. They are essential for energy production, since most cellular ATP is produced in their matrix by the oxidative phosphorylation pathway. At the same time, mitochondria are the main regulators of apoptotic cell death, mediating both extrinsic (cell-surface receptor mediated) and intrinsic apoptotic pathways. Reactive oxygen species (ROS) accumulate as side products of the electron transport chain, causing mitochondrial damage. Non-functional mitochondria accumulate in aged individuals, and cell homeostasis is maintained by removing damaged mitochondria by an autophagic process called "mitophagy". In addition, mitochondrial ROS represent signaling molecules leading to autophagy, consisting in the bulk degradation of cytosolic portions. When cell homeostasis is perturbed, and cytosolic components are damaged, autophagy represents a defense mechanism aimed at removing non-functional proteins and organelles. If this is not sufficient, cell death occurs with distinct morphological hallmarks from apoptosis. This binary choice integrates a number of critical information converging on a number of common regulatory elements. In this review, the focus will be placed on the central role of mitochondria in the cross-talk between autophagy and apoptosis, highlighting the signaling pathways and molecular machinery impinging on these organelles.
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Kongara S, Kravchuk O, Teplova I, Lozy F, Schulte J, Moore D, Barnard N, Neumann CA, White E, Karantza V. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors. Mol Cancer Res 2010; 8:873-84. [PMID: 20530580 DOI: 10.1158/1541-7786.mcr-09-0494] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism. Defective autophagy is implicated in human pathology, as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation, oxidative stress, genomic damage, and inflammation. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells are susceptible to metabolic stress, DNA damage, and genomic instability. We now report that autophagy deficiency is associated with endoplasmic reticulum (ER) and oxidative stress, and with deregulation of p62-mediated keratin homeostasis in mammary cells, allograft tumors, and mammary tissues from genetically engineered mice. In human breast tumors, high phospho(Ser73)-K8 levels are inversely correlated with Beclin 1 expression. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and, as such, could have therapeutic implications for breast cancer patients.
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Affiliation(s)
- Sameera Kongara
- Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA
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Rodríguez-Navarro JA, Rodríguez L, Casarejos MJ, Solano RM, Gómez A, Perucho J, Cuervo AM, García de Yébenes J, Mena MA. Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis 2010; 39:423-38. [PMID: 20546895 DOI: 10.1016/j.nbd.2010.05.014] [Citation(s) in RCA: 236] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Revised: 04/29/2010] [Accepted: 05/11/2010] [Indexed: 01/14/2023] Open
Abstract
Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms. We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK(-/-)/Tau(VLW)). At 3 months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12 months old, plaques of murine beta-amyloid in the hippocampus. Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK(-/-)/Tau(VLW) phenotype. The treatment with trehalose of 3-month-old PK(-/-)/Tau(VLW) mice for 2.5 months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK(-/-)/Tau(VLW) and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4 months of 3-month-old PK(-/-)/Tau(VLW) mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK(-/-)/Tau(VLW) mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine beta-amyloid plaques. Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.
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Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, Sou YS, Ueno I, Sakamoto A, Tong KI, Kim M, Nishito Y, Iemura SI, Natsume T, Ueno T, Kominami E, Motohashi H, Tanaka K, Yamamoto M. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 2010; 12:213-23. [PMID: 20173742 DOI: 10.1038/ncb2021] [Citation(s) in RCA: 1853] [Impact Index Per Article: 123.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Accepted: 02/01/2010] [Indexed: 02/07/2023]
Abstract
Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.
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Affiliation(s)
- Masaaki Komatsu
- Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.
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Periyasamy-Thandavan S, Jiang M, Schoenlein P, Dong Z. Autophagy: molecular machinery, regulation, and implications for renal pathophysiology. Am J Physiol Renal Physiol 2009; 297:F244-56. [PMID: 19279132 PMCID: PMC5243206 DOI: 10.1152/ajprenal.00033.2009] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Autophagy is a cellular process of "self-eating." During autophagy, a portion of cytoplasm is enveloped in double membrane-bound structures called autophagosomes, which undergo maturation and fusion with lysosomes for degradation. At the core of the molecular machinery of autophagy is a specific family of genes or proteins called Atg. Originally identified in yeast, Atg orthologs are now being discovered in mammalian cells and have been shown to play critical roles in autophagy. Traditionally, autophagy is recognized as a cellular response to nutrient deprivation or starvation whereby cells digest cytoplasmic organelles and macromolecules to recycle nutrients for self-support. However, studies during the last few years have indicated that autophagy is a general cellular response to stress. Interestingly, depending on experimental conditions, especially stress levels, autophagy can directly induce cell death or act as a mechanism of cell survival. In this review, we discuss the molecular machinery, regulation, and function of autophagy. In addition, we analyze the recent findings of autophagy in renal systems and its possible role in renal pathophysiology.
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Affiliation(s)
- Sudharsan Periyasamy-Thandavan
- Department of Cellular Biology and Anatomy, Medical College of Georgia and
Charlie Norwood Department of Veterans Affairs Medical Center, Augusta, Georgia
| | - Man Jiang
- Department of Cellular Biology and Anatomy, Medical College of Georgia and
Charlie Norwood Department of Veterans Affairs Medical Center, Augusta, Georgia
| | - Patricia Schoenlein
- Department of Cellular Biology and Anatomy, Medical College of Georgia and
Charlie Norwood Department of Veterans Affairs Medical Center, Augusta, Georgia
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia and
Charlie Norwood Department of Veterans Affairs Medical Center, Augusta, Georgia
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Rajawat YS, Hilioti Z, Bossis I. Aging: central role for autophagy and the lysosomal degradative system. Ageing Res Rev 2009; 8:199-213. [PMID: 19427410 DOI: 10.1016/j.arr.2009.05.001] [Citation(s) in RCA: 178] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Revised: 05/01/2009] [Accepted: 05/01/2009] [Indexed: 12/19/2022]
Abstract
The lysosomal network is the major intracellular proteolytic system accounting for more than 98% of long-lived bulk protein degradation and recycling particularly in tissues such as liver and muscles. Lysosomes are the final destination of intracellular damaged structures, identified and sequestered by the processes of macroautophagy and chaperone-mediated autophagy (CMA). In the process of macroautophagy, long-lived proteins and other macromolecular aggregates and damaged intracellular organelles are first engulfed by autophagosomes. Autophagosomes themselves have limited degrading capacity and rely on fusion with lysosomes. Unlike macroautophagy, CMA does not require intermediate vesicle formation and the cytosolic proteins recognized by this pathway are directly translocated to the lysosomal membrane. Aging is a universal phenomenon characterized by progressive deterioration of cells and organs due to accumulation of macromolecular and organelle damage. The continuous removal of worn-out components and replacement with newly synthesized ones ensures cellular homeostasis and delays the aging process. Growing evidence indicate that the rate of autophagosome formation and maturation and the efficiency of autophagosome/lysosome fusion decline with age. In addition, a progressive increase in intralysosomal concentration of free radicals and the age pigment lipofuscin further diminish the efficiency of lysosomal protein degradation. Therefore, integrity of the autophagosomal-lysosomal network appears to be critical in the progression of aging. Discovery of the genes involved in the process of autophagy has provided insight into the various molecular pathways that may be involved in aging and senescence. In this review, we discuss the cellular and molecular mechanisms involved in autophagy and the role of autophagosome/lysosome network in the aging process.
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Affiliation(s)
- Yogendra S Rajawat
- University of Maryland, Department of Veterinary Medicine, College Park, MD 20742, United States
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Abstract
Mammalian autophagy has been well characterized in the liver and in hepatocytes. Autophagy plays important roles in the normal physiology of the liver and in the pathogenesis of several liver diseases. This chapter will discuss the commonly used methods for analysis of autophagy in hepatocytes and in the liver.
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Affiliation(s)
- Wen-Xing Ding
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Abstract
Dying cells often display a large-scale accumulation of autophagosomes and hence adopt a morphology called autophagic cell death. In many cases, it is agreed that this autophagic cell death is cell death with autophagy rather than cell death by autophagy. Here, we evaluate the accumulating body of literature that argues that cell death occurs by autophagy. We also list the caveats that must be considered when deciding whether or not autophagy is an important effector mechanism of cell death.
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Abstract
Dying cells often display a large-scale accumulation of autophagosomes and hence adopt a morphology called autophagic cell death. In many cases, it is agreed that this autophagic cell death is cell death with autophagy rather than cell death by autophagy. Here, we evaluate the accumulating body of literature that argues that cell death occurs by autophagy. We also list the caveats that must be considered when deciding whether or not autophagy is an important effector mechanism of cell death.
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