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1
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Hong WL, Huang H, Zeng X, Duan CY. Targeting mitochondrial quality control: new therapeutic strategies for major diseases. Mil Med Res 2024; 11:59. [PMID: 39164792 PMCID: PMC11337860 DOI: 10.1186/s40779-024-00556-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 07/13/2024] [Indexed: 08/22/2024] Open
Abstract
Mitochondria play a crucial role in maintaining the normal physiological state of cells. Hence, ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases. Previous reviews on this topic have however been inconsistencies and lack of systematic organization. Therefore, this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases. This review systematically summarizes three fundamental characteristics of mitochondrial quality control, including mitochondrial morphology and dynamics, function and metabolism, and protein expression and regulation. It also extensively examines how imbalances in mitochondrial quality are linked to major diseases, such as ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, degenerative conditions, and tumors. Additionally, the review explores innovative approaches to target mitochondrial quality control, including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality, nanomolecular materials designed for precise targeting of mitochondria, and novel cellular therapies, such as vesicle therapy and mitochondrial transplantation. This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.
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Affiliation(s)
- Wei-Long Hong
- Department of Anesthesiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - He Huang
- Department of Anesthesiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Xue Zeng
- Department of Anesthesiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Chen-Yang Duan
- Department of Anesthesiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
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2
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Lee YT, Savini M, Chen T, Yang J, Zhao Q, Ding L, Gao SM, Senturk M, Sowa JN, Wang JD, Wang MC. Mitochondrial GTP metabolism controls reproductive aging in C. elegans. Dev Cell 2023; 58:2718-2731.e7. [PMID: 37708895 PMCID: PMC10842941 DOI: 10.1016/j.devcel.2023.08.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/17/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023]
Abstract
Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.
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Affiliation(s)
- Yi-Tang Lee
- Integrative Program of Molecular and Biochemical Sciences, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
| | - Marzia Savini
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Tao Chen
- Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA
| | - Jin Yang
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Qian Zhao
- Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA
| | - Lang Ding
- Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA; Graduate Program in Chemical, Physical & Structural Biology, Graduate School of Biomedical Science, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shihong Max Gao
- Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA
| | - Mumine Senturk
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jessica N Sowa
- Department of Biology, West Chester University, West Chester, PA 19383, USA
| | - Jue D Wang
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Meng C Wang
- Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
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3
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He B, Gao R, Lv S, Chen A, Huang J, Wang L, Feng Y, Feng J, Liu B, Lei J, Deng B, He B, Cui B, Peng F, Yan M, Wang Z, Lam EWF, Jin B, Shao Z, Li Y, Jiao J, Wang X, Liu Q. Cancer cell employs a microenvironmental neural signal trans-activating nucleus-mitochondria coordination to acquire stemness. Signal Transduct Target Ther 2023; 8:275. [PMID: 37463926 PMCID: PMC10354099 DOI: 10.1038/s41392-023-01487-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 04/28/2023] [Accepted: 05/08/2023] [Indexed: 07/20/2023] Open
Abstract
Cancer cell receives extracellular signal inputs to obtain a stem-like status, yet how tumor microenvironmental (TME) neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive. Here, a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element (CRE) transcription factors are convergent activators for cancer stemness. Deconvolution of transcriptomic profiles, specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity. Specifically, neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis, where ATF1 serves as a conserved hub. Upon activation by norepinephrine, ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM, thereby orchestrating nuclear reprograming and mitochondrial rejuvenating. Accordingly, single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells. These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program, suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.
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Affiliation(s)
- Bin He
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Rui Gao
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
- Department of Medical Oncology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 510275, PR China
| | - Shasha Lv
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China
| | - Ailin Chen
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Junxiu Huang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, PR China
| | - Luoxuan Wang
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China
| | - Yunxiu Feng
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China
| | - Jiesi Feng
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, 100871, PR China
| | - Bing Liu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Jie Lei
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Bing Deng
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Bin He
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China
| | - Bai Cui
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China
| | - Fei Peng
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China
| | - Min Yan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Zifeng Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK
| | - Bilian Jin
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China
| | - Zhiming Shao
- Department of Breast Surgery, Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, 200032, PR China
| | - Yulong Li
- State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, 100871, PR China
| | - Jianwei Jiao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, PR China
| | - Xi Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
| | - Quentin Liu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
- Department of Medical Oncology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 510275, PR China.
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, 116023, PR China.
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Lee YT, Savini M, Chen T, Yang J, Zhao Q, Ding L, Gao SM, Senturk M, Sowa J, Wang JD, Wang MC. Mitochondrial GTP Metabolism Regulates Reproductive Aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.02.535296. [PMID: 37066227 PMCID: PMC10103970 DOI: 10.1101/2023.04.02.535296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS), promotes reproductive longevity in Caenorhabditis elegans. We further revealed an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by the GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mitochondrial GTP and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mitochondrial GTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and reveal mitochondrial fission induction as an effective strategy to improve reproductive health.
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Abstract
Microtubules (MTs) form rapidly adaptable, complex intracellular networks of filaments that not only provide structural support, but also form the tracks along which motors traffic macromolecular cargos to specific sub-cellular sites. These dynamic arrays play a central role in regulating various cellular processes including cell shape and motility as well as cell division and polarization. Given their complex organization and functional importance, MT arrays are carefully controlled by many highly specialized proteins that regulate the nucleation of MT filaments at distinct sites, their dynamic growth and stability, and their engagement with other subcellular structures and cargoes destined for transport. This review focuses on recent advances in our understanding of how MTs and their regulatory proteins function, including their active targeting and exploitation, during infection by viruses that utilize a wide variety of replication strategies that occur within different cellular sub-compartments or regions of the cell.
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Affiliation(s)
- Eveline Santos da Silva
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States; HIV Clinical and Translational Research, Luxembourg Institute of Health, Department of Infection and Immunity, Esch-sur-Alzette, Luxembourg
| | - Mojgan H Naghavi
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
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Takamatsu Y, Hayashi S, Kumamoto H, Imoto S, Tanaka Y, Mitsuya H, Higashi-Kuwata N. A novel anti-HBV agent, E-CFCP, restores Hepatitis B virus (HBV)-induced senescence-associated cellular marker perturbation in human hepatocytes. Virus Res 2023; 329:199094. [PMID: 36933835 DOI: 10.1016/j.virusres.2023.199094] [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: 03/08/2023] [Accepted: 03/14/2023] [Indexed: 03/20/2023]
Abstract
Cellular senescence is a cellular state with a broad spectrum of age-related physiological conditions that can be affected by various infectious diseases and treatments. Therapy of hepatitis B virus (HBV) infection with nucleos(t)ide analogs [NA(s)] is well established and benefits many HBV-infected patients, but requires long-term, perhaps lifelong, medication. In addition to the effects of HBV infection, the effects of NA administration on hepatocellular senescence are still unclear. This study investigated how HBV infection and NA treatment influence cellular senescence in human hepatocytes and humanized-liver chimeric mice chronically infected with live HBV. HBV infection upregulates or downregulates multiple cellular markers including senescence-associated β-galactosidase (SA-β-Gal) activity and cell cycle regulatory proteins (e.g., p21CIP1) expression level in hepatocellular nuclei and humanized-mice liver. A novel highly potent anti-HBV NA, E-CFCP, per se did not have significant disturbance on markers evaluated. Besides, E-CFCP treatment restored HBV-infected cells to their physiological phenotypes that are comparable to the HBV-uninfected cells. The results reported here demonstrate that, regardless of the mechanism(s), chronic HBV infection perturbates multiple senescence-associated markers in human hepatocytes and humanized-mice liver, but E-CFCP can restore this phenomenon.
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Affiliation(s)
- Yuki Takamatsu
- Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan
| | - Sanae Hayashi
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo, Kumamoto, 860-8556 Japan; Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho, Nagoya, 467-8601 Japan
| | - Hiroki Kumamoto
- Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, lna-machi, Kitaadachi-gun, Saitama, 362-0806 Japan
| | - Shuhei Imoto
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi, Kumamoto 860-0082 Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo, Kumamoto, 860-8556 Japan; Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho, Nagoya, 467-8601 Japan
| | - Hiroaki Mitsuya
- Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 5A11, Bethesda, MD 20892-1868 USA; Department of Clinical Sciences, Kumamoto University Hospital, 1-1-1 Honjo, Chuo, Kumamoto, 860-8556 Japan
| | - Nobuyo Higashi-Kuwata
- Department of Refractory Viral Diseases, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655 Japan.
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7
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Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis. Int J Mol Sci 2023; 24:ijms24054964. [PMID: 36902395 PMCID: PMC10003785 DOI: 10.3390/ijms24054964] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx-nuclear-, cytoplasmic- or mitochondria-associated-this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
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8
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Lin C, Huang Y, Luo L, Fang F, Zhang J, Xun Z, Fu Y, Shang H, Liu C, Ou Q. Adenosine Triphosphate in Serum as a Promising Biomarker for Differential Diagnosis of Hepatitis B Disease Progression. Front Immunol 2022; 13:927761. [PMID: 35844530 PMCID: PMC9284211 DOI: 10.3389/fimmu.2022.927761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/07/2022] [Indexed: 12/13/2022] Open
Abstract
The need to be diagnosed with liver biopsy makes the clinical progression of chronic HBV infection diagnosis a challenge. Existing HBV serum biochemical assays are used throughout clinical but have limited effects. Studies have shown that mitochondrial function is tightly coupled to HBV infection. Here, we verified the diagnostic value of serum Adenosine Triphosphate (ATP) as a potential marker for differential HBV infection progress by detecting the level of ATP in the serum from a wide spectrum of HBV-infected populations, and confirmed the role of ATP in the deterioration of HBV infection-related diseases through HBV-infected cells and mouse models. The results showed that there were significantly lower serum ATP levels in HBeAg-positive CHB patients compared with healthy controls. And during the progression of CHB to liver cirrhosis and hepatocellular carcinoma, the ATP level was increased but not higher than healthy controls. The area under the curve (AUC) of serum ATP was 0.9063 to distinguish HBeAg-positive CHB from healthy, and another AUC was 0.8328 in the CHB against the HCC group. Preliminary exploration of the mechanism indicated that the decline of serum ATP was due to impaired mitochondria in CHB patients. Our data provide evidence that serum ATP distinguishes the various progress of HBV infection-related diseases and expands diagnostic biomarkers for HBeAg-positive CHB patients with healthy controls.
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Affiliation(s)
- Caorui Lin
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Ying Huang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Linjie Luo
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Fengling Fang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Jiawei Zhang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Zhen Xun
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Ya Fu
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Hongyan Shang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Can Liu
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
| | - Qishui Ou
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- First Clinical College, Fujian Medical University, Fuzhou, China
- *Correspondence: Qishui Ou,
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Host Cytoskeleton Gene Expression Is Correlated with the Formation of Ascovirus Reproductive Viral Vesicles. Viruses 2022; 14:v14071444. [PMID: 35891423 PMCID: PMC9319082 DOI: 10.3390/v14071444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 01/10/2023] Open
Abstract
Ascoviruses are large DNA viruses that primarily infect lepidopteran larvae. They differ markedly from other plant or animal viruses by initiating replication in the nucleus, then inducing nuclear lysis followed by extensive cellular hypertrophy and subsequent cleavage of the entire enlarged cell into numerous viral vesicles. Most progeny virions are assembled in these vesicles as they circulate in the hemolymph. Here, we report transcriptome studies of host cytoskeletal genes in larvae infected with ascoviruses from 6 h to 21 days post-infection (dpi). We focused on the cabbage looper, Trichoplusia ni, infected with the Trichoplusia ni ascovirus (TnAV), along with supporting studies on the fall armyworm, Spodoptera frugiperda, infected with the Spodoptera frugiperda ascovirus (SfAV). In T. ni, many cytoskeleton genes were upregulated at 48 hours post-infection (hpi), including 29 tubulins, 21 actins, 21 dyneins, and 13 kinesins. Mitochondrial genes were upregulated as much as two-fold at 48 hpi and were expressed at levels comparable to controls in both T. ni and S. frugiperda, even after 21 dpi, when several cytoskeleton genes remained upregulated. Our studies suggest a temporal correlation between increases in the expression of certain host cytoskeletal genes and viral vesicle formation. However, these results need confirmation through functional genetic studies of proteins encoded by these genes.
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10
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2022; 28:276-331. [PMID: 35430783 PMCID: PMC9013624 DOI: 10.3350/cmh.2022.0084] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 01/10/2023] Open
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11
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Sirakanyan S, Arabyan E, Hakobyan A, Hakobyan T, Chilingaryan G, Sahakyan H, Sargsyan A, Arakelov G, Nazaryan K, Izmailyan R, Abroyan L, Karalyan Z, Arakelova E, Hakobyan E, Hovakimyan A, Serobian A, Neves M, Ferreira J, Ferreira F, Zakaryan H. A new microtubule-stabilizing agent shows potent antiviral effects against African swine fever virus with no cytotoxicity. Emerg Microbes Infect 2021; 10:783-796. [PMID: 33706677 PMCID: PMC8079068 DOI: 10.1080/22221751.2021.1902751] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 03/09/2021] [Accepted: 03/09/2021] [Indexed: 11/25/2022]
Abstract
African swine fever virus (ASFV) is the causal agent of a fatal disease of domestic swine for which no effective antiviral drugs are available. Recently, it has been shown that microtubule-targeting agents hamper the infection cycle of different viruses. In this study, we conducted in silico screening against the colchicine binding site (CBS) of tubulin and found three new compounds with anti-ASFV activity. The most promising antiviral compound (6b) reduced ASFV replication in a dose-dependent manner (IC50 = 19.5 μM) with no cellular (CC50 > 500 μM) and animal toxicity (up to 100 mg/kg). Results also revealed that compound 6b interfered with ASFV attachment, internalization and egress, with time-of-addition assays, showing that compound 6b has higher antiviral effects when added within 2-8 h post-infection. This compound significantly inhibited viral DNA replication and disrupted viral protein synthesis. Experiments with ASFV-infected porcine macrophages disclosed that antiviral effects of the compound 6b were similar to its effects in Vero cells. Tubulin polymerization assay and confocal microscopy demonstrated that compound 6b promoted tubulin polymerization, acting as a microtubule-stabilizing, rather than a destabilizing agent in cells. In conclusion, this work emphasizes the idea that microtubules can be targets for drug development against ASFV.
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Affiliation(s)
- Samvel Sirakanyan
- Scientific Technological Center of Organic and Pharmaceutical Chemistry of NAS, Institute of Fine Organic Chemistry of A.L. Mnjoyan, Yerevan, Armenia
| | - Erik Arabyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Astghik Hakobyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Tamara Hakobyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Garri Chilingaryan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Harutyun Sahakyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Arsen Sargsyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Grigor Arakelov
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Karen Nazaryan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
- Russian-Armenian University, Yerevan, Armenia
| | - Roza Izmailyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Liana Abroyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Zaven Karalyan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
- Department of Medical Biology, Yerevan State Medical University, Yerevan, Armenia
| | - Elina Arakelova
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
| | - Elmira Hakobyan
- Scientific Technological Center of Organic and Pharmaceutical Chemistry of NAS, Institute of Fine Organic Chemistry of A.L. Mnjoyan, Yerevan, Armenia
| | - Anush Hovakimyan
- Scientific Technological Center of Organic and Pharmaceutical Chemistry of NAS, Institute of Fine Organic Chemistry of A.L. Mnjoyan, Yerevan, Armenia
| | - Andre Serobian
- Advanced Solutions Center, Foundation for Armenian Science and Technology, Yerevan, Armenia
| | - Marco Neves
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - João Ferreira
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Fernando Ferreira
- Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Avenida da Universidade Técnica, Lisboa, Portugal
| | - Hovakim Zakaryan
- Group of Antiviral Defense Mechanisms, Institute of Molecular Biology of NAS, Yerevan, Armenia
- Denovo Sciences, Yerevan, Armenia
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12
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Menati Rashno M, Mehraban H, Naji B, Radmehr M. Microbiome in human cancers. Access Microbiol 2021; 3:000247. [PMID: 34888478 PMCID: PMC8650843 DOI: 10.1099/acmi.0.000247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
A microbiome is defined as the aggregate of all microbiota that reside in human digestive system and other tissues. This microbiota includes viruses, bacteria, fungi that live in various human organs and tissues like stomach, guts, oesophagus, mouth cavity, urinary tract, vagina, lungs, and skin. Almost 20 % of malignant cancers worldwide are related to microbial infections including bacteria, parasites, and viruses. The human body is constantly being attacked by microbes during its lifetime and microbial pathogens that have tumorigenic effects in 15-20 % of reported cancer cases. Recent scientific advances and the discovery of the effect of microbes on cancer as a pathogen or as a drug have significantly contributed to our understanding of the complex relationship between microbiome and cancer. The aim of this study is to overview some microbiomes that reside in the human body and their roles in cancer.
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Affiliation(s)
| | - Hamed Mehraban
- Department of Biology, Payame Noor University (PNU), Tehran, Iran
| | - Behnaz Naji
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Mohadeseh Radmehr
- Department of Microbiology, Damghan Branch, Islamic Azad University, Damghan, Iran
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13
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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14
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Lyamzaev KG, Knorre DA, Chernyak BV. Mitoptosis, Twenty Years After. BIOCHEMISTRY (MOSCOW) 2021; 85:1484-1498. [PMID: 33705288 DOI: 10.1134/s0006297920120020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In 1999 V. P. Skulachev proposed the term "mitoptosis" to refer to the programmed elimination of mitochondria in living cells. According to the initial thought, mitoptosis serves to protect cells from malfunctioning of the damaged mitochondria. At the same time, a new mechanism of the complete mitochondria elimination was found under the conditions of massive mitochondrial damage associated with oxidative stress. In this experimental model, mitochondrial cluster formation in the perinuclear region leads to the formation of "mitoptotic body" surrounded by a single-layer membrane and subsequent release of mitochondria from the cell. Later, it was found that mitoptosis plays an important role in various normal and pathological processes that are not necessarily associated with the mitochondrial damage. It was found that mitoptosis takes place during cell differentiation, self-maintenance of hematopoietic stem cells, metabolic remodelling, and elimination of the paternal mitochondria in organisms with the maternal inheritance of the mitochondrial DNA. Moreover, the associated with mitoptosis release of mitochondrial components into the blood may be involved in the transmission of signals between cells, but also leads to the development of inflammatory and autoimmune diseases. Mitoptosis can be attributed to the asymmetric inheritance of mitochondria in the division of yeast and some animal cells, when the defective mitochondria are transferred to one of the newly formed cells. Finally, a specific form of mitoptosis appears to be selective elimination of mitochondria with deleterious mutations in whole follicular ovarian cells in mammals. During formation of the primary follicle, the mitochondrial DNA copy number is significantly reduced. After division, the cells that receive predominantly mitochondria with deleterious mutations in their mtDNA die, thereby reducing the likelihood of transmission of these mutations to offspring. Further study of the mechanisms of mitoptosis in normal and pathological conditions is important both for understanding the processes of development and aging, and for designing therapeutic approaches for inflammatory, neurodegenerative and other diseases.
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Affiliation(s)
- K G Lyamzaev
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia
| | - D A Knorre
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.,Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, 119991, Russia
| | - B V Chernyak
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
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15
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Siddiqui ZI, Azam SA, Khan WH, Afroz M, Farooqui SR, Amir F, Azmi MI, Anwer A, Khan S, Mehmankhah M, Parveen S, Kazim SN. An in vitro Study on the Role of Hepatitis B Virus X Protein C-Terminal Truncation in Liver Disease Development. Front Genet 2021; 12:633341. [PMID: 33777103 PMCID: PMC7994528 DOI: 10.3389/fgene.2021.633341] [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: 11/26/2020] [Accepted: 02/02/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis B virus X protein C-terminal 127 amino acid truncation is often found expressed in hepatocellular carcinoma (HCC) tissue samples. The present in vitro study tried to determine the role of this truncation mutant in the hepatitis B-related liver diseases such as fibrosis, cirrhosis, HCC, and metastasis. HBx gene and its 127 amino acid truncation mutant were cloned in mammalian expression vectors and transfected in human hepatoma cell line. Changes in cell growth/proliferation, cell cycle phase distribution, expression of cell cycle regulatory genes, mitochondrial depolarization, and intracellular reactive oxygen species (ROS) level were analyzed. Green fluorescent protein (GFP)-tagged version of HBx and the truncation mutant were also created and the effects of truncation on HBx intracellular expression pattern and localization were studied. Effect of time lapse on protein expression pattern was also analyzed. The truncation mutant of HBx is more efficient in inducing cell proliferation, and causes more ROS production and less mitochondrial depolarization as compared with wild type (wt) HBx. In addition, gene expression is altered in favor of carcinogenesis in the presence of the truncation mutant. Furthermore, mitochondrial perinuclear aggregation is achieved earlier in the presence of the truncation mutant. Therefore, HBx C-terminal 127 amino acid truncation might be playing important roles in the development of hepatitis B-related liver diseases by inducing cell proliferation, altering gene expression, altering mitochondrial potential, inducing mitochondrial clustering and oxidative stress, and changing HBx expression pattern.
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Affiliation(s)
- Zaheenul Islam Siddiqui
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.,Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Syed Ali Azam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Wajihul Hasan Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Masarrat Afroz
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Sabihur Rahman Farooqui
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Fatima Amir
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Md Iqbal Azmi
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ayesha Anwer
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Saniya Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Mahboubeh Mehmankhah
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Shama Parveen
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Syed Naqui Kazim
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
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16
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Mo CF, Li J, Yang SX, Guo HJ, Liu Y, Luo XY, Wang YT, Li MH, Li JY, Zou Q. IQGAP1 promotes anoikis resistance and metastasis through Rac1-dependent ROS accumulation and activation of Src/FAK signalling in hepatocellular carcinoma. Br J Cancer 2020; 123:1154-1163. [PMID: 32632148 PMCID: PMC7525663 DOI: 10.1038/s41416-020-0970-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 04/01/2020] [Accepted: 06/18/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) has a crucial role in the progression of hepatocellular carcinoma (HCC). Tumour cells must develop anoikis resistance in order to survive before metastasis. This study aimed to investigate the mechanism of IQGAP1 in HBV-mediated anoikis evasion and metastasis in HCC cells. METHODS IQGAP1 expression was detected by immunohistochemistry, real-time PCR and immunoblot analysis. Lentiviral-mediated stable upregulation or knockdown of IGAQP1, immunoprecipitation, etc. were used in function and mechanism study. RESULTS IQGAP1 was markedly upregulated in HBV-positive compared with HBV-negative HCC cells and tissues. IQGAP1 was positively correlated to poor prognosis of HBV-associated HCC patients. IQGAP1 overexpression significantly enhanced the anchorage-independent growth and metastasis, whereas IQGAP1-deficient HCC cells are more sensitive to anoikis. Mechanistically, we found that HBV-induced ROS enhanced the association of IQGAP1 and Rac1 that activated Rac1, leading to phosphorylation of Src/FAK pathway. Antioxidants efficiently inhibited IQGAP1-mediated anoikis resistance and metastasis. CONCLUSIONS Our study indicated an important mechanism by which upregulated IQGAP1 by HBV promoted anoikis resistance, migration and invasion of HCC cells through Rac1-dependent ROS accumulation and activation of Src/FAK signalling, suggesting IQGAP1 as a prognostic indicator and a novel therapeutic target in HCC patients with HBV infection.
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Affiliation(s)
- Chun-Fen Mo
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China.
| | - Jun Li
- Department of Gastroenterology, The first affiliated hospital of Chengdu medical college, Chengdu, China
| | - Shu-Xia Yang
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Hui-Jie Guo
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Yang Liu
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Xing-Yan Luo
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Yan-Tang Wang
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Min-Hui Li
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Jing-Yi Li
- Department of Urology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China. .,School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, China.
| | - Qiang Zou
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China.
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17
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Novel Insights into the Roles of Bcl-2 Homolog Nr-13 (vNr-13) Encoded by Herpesvirus of Turkeys in the Virus Replication Cycle, Mitochondrial Networks, and Apoptosis Inhibition. J Virol 2020; 94:JVI.02049-19. [PMID: 32161176 PMCID: PMC7199394 DOI: 10.1128/jvi.02049-19] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/28/2020] [Indexed: 02/07/2023] Open
Abstract
The Bcl-2 (B cell lymphoma 2)-related protein Nr-13 plays a major role in the regulation of cell death in developing avian B cells. With over 65% sequence similarity to the chicken Nr-13, herpesvirus of turkeys (HVT) vNr-13, encoded by the HVT079 and HVT096 genes, is the first known alphaherpesvirus-encoded Bcl-2 homolog. HVT-infected cells were reported to be relatively more resistant to serum starvation, suggested that vNr-13 could be involved in protecting the cells. Here, we describe CRISPR/Cas9-based editing of exon 1 of the HVT079 and HVT096 genes from the HVT genome to generate the mutant HVT-ΔvNr-13 to gain insights into its functional roles. Overall, wild-type HVT and HVT-ΔvNr-13 showed similar growth kinetics; however, at early time points, HVT-ΔvNr-13 showed 1.3- to 1.7-fold-lower growth of cell-associated virus and 3- to 6.2-fold-lower growth of cell-free virus. In transfected cells, HVT vNr-13 showed a mainly diffuse cytoplasmic distribution with faint nuclear staining. Further, vNr-13 localized to the mitochondria and endoplasmic reticulum (ER) and disrupted mitochondrial network morphology in the transfected cells. In the wild-type HVT-infected cells, vNr-13 expression appeared to be directly involved in the disruption of the mitochondrial network, as the mitochondrial network morphology was substantially restored in the HVT-ΔvNr-13-infected cells. IncuCyte S3 real-time apoptosis monitoring demonstrated that vNr-13 is unequivocally involved in the apoptosis inhibition, and it is associated with an increase of PFU, especially under serum-free conditions in the later stages of the viral replication cycle. Furthermore, HVT blocks apoptosis in infected cells but activates apoptosis in noninfected bystander cells.IMPORTANCE B cell lymphoma 2 (Bcl-2) family proteins play important roles in regulating apoptosis during homeostasis, tissue development, and infectious diseases. Several viruses encode homologs of cellular Bcl-2-proteins (vBcl-2) to inhibit apoptosis, which enable them to replicate and persist in the infected cells and to evade/modulate the immune response of the host. Herpesvirus of turkeys (HVT) is a nonpathogenic alphaherpesvirus of turkeys and chickens that is widely used as a live vaccine against Marek's disease and as recombinant vaccine viral vectors for protecting against multiple avian diseases. Identical copies of the HVT genes HVT079 and HVT096 encode the Bcl-2 homolog vNr-13. While previous studies have identified the potential ability of vNr-13 in inhibiting apoptosis induced by serum deprivation, there have been no detailed investigations on the functions of vNr-13. Using CRISPR/Cas9-based ablation of the vNr-13 gene, we demonstrated the roles of HVT vNr-13 in early stages of the viral replication cycle, mitochondrial morphology disruption, and apoptosis inhibition in later stages of viral replication.
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18
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Immunopathogenesis of HBV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:71-107. [DOI: 10.1007/978-981-13-9151-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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19
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Yang Y, Cong H, Du N, Han X, Song L, Zhang W, Li C, Tien P. Mitochondria Redistribution in Enterovirus A71 Infected Cells and Its Effect on Virus Replication. Virol Sin 2019; 34:397-411. [PMID: 31069716 DOI: 10.1007/s12250-019-00120-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/25/2019] [Indexed: 10/26/2022] Open
Abstract
Enterovirus A71 (EV-A71) is one of the main causative agents of hand, foot and mouth disease (HFMD) and it also causes severe neurologic complications in infected children. The interactions between some viruses and the host mitochondria are crucial for virus replication and pathogenicity. In this study, it was observed that EV-A71 infection resulted in a perinuclear redistribution of the mitochondria. The mitochondria rearrangement was found to require the microtubule network, the dynein complex and a low cytosolic calcium concentration. Subsequently, the EV-A71 non-structural protein 2BC was identified as the viral protein capable of inducing mitochondria clustering. The protein was found localized on mitochondria and interacted with the mitochondrial Rho GTPase 1 (RHOT1) that is a key protein required for attachment between the mitochondria and the motor proteins, which are responsible for the control of mitochondria movement. Additionally, suppressing mitochondria clustering by treating cells with nocodazole, EHNA, thapsigargin or A23187 consistently inhibited EV-A71 replication, indicating that mitochondria recruitment played a crucial role in the EV-A71 life cycle. This study identified a novel function of the EV-A71 2BC protein and provided a potential model for the regulation of mitochondrial motility in EV-A71 infection.
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Affiliation(s)
- Yang Yang
- Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of the Chinese Academy of Sciences, Beijing, 100101, China
| | - Haolong Cong
- Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Ning Du
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiaodong Han
- College of Life Sciences, Inner Mongolia Agriculture University, Hohhot, 010018, China
| | - Lei Song
- Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Wenliang Zhang
- Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chunrui Li
- Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of the Chinese Academy of Sciences, Beijing, 100101, China
| | - Po Tien
- Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China. .,University of the Chinese Academy of Sciences, Beijing, 100101, China.
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20
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Chaturvedi VK, Singh A, Dubey SK, Hetta HF, John J, Singh M. Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb Pathog 2019; 128:184-194. [PMID: 30611768 DOI: 10.1016/j.micpath.2019.01.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/30/2018] [Accepted: 01/02/2019] [Indexed: 02/07/2023]
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21
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Human Immunodeficiency Virus Type 1 gp120 and Tat Induce Mitochondrial Fragmentation and Incomplete Mitophagy in Human Neurons. J Virol 2018; 92:JVI.00993-18. [PMID: 30158296 DOI: 10.1128/jvi.00993-18] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 08/27/2018] [Indexed: 02/07/2023] Open
Abstract
HIV enters the central nervous system (CNS) during the early stages of infection and can cause neurological dysfunction, including neurodegeneration and neurocognitive impairment. The specific autophagy responsible for removal of damaged mitochondria (mitophagy) and mitochondrial dynamics constitute neuronal mitochondrial quality control mechanisms and are impaired in neurodegenerative disorders and numerous other diseases. The release of HIV proteins gp120 and Tat from infected cells is thought to play an important role in HIV-associated neurocognitive disorders (HAND), but the mechanism(s) leading to impairment are poorly understood. Here, we report that exposure of human primary neurons (HPNs) to HIV gp120 and Tat accelerates the balance of mitochondrial dynamics toward fission (fragmented mitochondria) and induces perinuclear aggregation of mitochondria and mitochondrial translocation of dynamin-related protein 1 (DRP1), leading to neuronal mitochondrial fragmentation. HIV gp120 and Tat increased the expression of microtubule-associated protein 1 light chain 3 beta (LC3B) protein and induced selective recruitment of Parkin/SQSTM1 to the damaged mitochondria. Using either a dual fluorescence reporter system expressing monomeric red fluorescent protein and enhanced green fluorescent protein targeted to mitochondria (mito-mRFP-EGFP) or a tandem light chain 3 (LC3) vector (mCherry-EGFP-LC3), both HIV proteins were found to inhibit mitophagic flux in human primary neurons. HIV gp120 and Tat induced mitochondrial damage and altered mitochondrial dynamics by decreasing mitochondrial membrane potential (ΔΨm). These findings indicate that HIV gp120 and Tat initiate the activation and recruitment of mitophagy markers to damaged mitochondria in neurons but impair the delivery of mitochondria to the lysosomal compartment. Altered mitochondrial dynamics associated with HIV infection and incomplete neuronal mitophagy may play a significant role in the development of HAND and accelerated aging associated with HIV infection.IMPORTANCE Despite viral suppression by antiretrovirals, HIV proteins continue to be detected in infected cells and neurologic complications remain common in infected people. Although HIV is unable to infect neurons, viral proteins, including gp120 and Tat, can enter neurons and can cause neuronal degeneration and neurocognitive impairment. Neuronal health is dependent on the functional integrity of mitochondria, and damaged mitochondria are subjected to mitochondrial control mechanisms. Multiple lines of evidence suggest that specific elimination of damaged mitochondria through mitophagy and mitochondrial dynamics play an important role in CNS diseases. Here, we show that in human primary neurons, gp120 and Tat favor the balance of mitochondrial dynamics toward enhanced fragmentation through the activation of mitochondrial translocation of DRP1 to the damaged mitochondria. However, mitophagy fails to go to completion, leading to neuronal damage. These findings support a role for altered mitophagy in HIV-associated neurological disorders and provide novel targets for potential intervention.
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Glingston RS, Deb R, Kumar S, Nagotu S. Organelle dynamics and viral infections: at cross roads. Microbes Infect 2018; 21:20-32. [PMID: 29953921 PMCID: PMC7110583 DOI: 10.1016/j.micinf.2018.06.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/14/2018] [Accepted: 06/15/2018] [Indexed: 01/12/2023]
Abstract
Viruses are obligate intracellular parasites of the host cells. A commonly accepted view is the requirement of internal membranous structures for various aspects of viral life cycle. Organelles enable favourable intracellular environment for several viruses. However, studies reporting organelle dynamics upon viral infections are scant. In this review, we aim to summarize and highlight modulations caused to various organelles upon viral infection or expression of its proteins.
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Affiliation(s)
- R Sahaya Glingston
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Rachayeeta Deb
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Sachin Kumar
- Viral Immunology Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
| | - Shirisha Nagotu
- Organelle Biology and Cellular Ageing Lab, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
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23
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Abstract
Cytoplasmic dynein 1 is an important microtubule-based motor in many eukaryotic cells. Dynein has critical roles both in interphase and during cell division. Here, we focus on interphase cargoes of dynein, which include membrane-bound organelles, RNAs, protein complexes and viruses. A central challenge in the field is to understand how a single motor can transport such a diverse array of cargoes and how this process is regulated. The molecular basis by which each cargo is linked to dynein and its cofactor dynactin has started to emerge. Of particular importance for this process is a set of coiled-coil proteins - activating adaptors - that both recruit dynein-dynactin to their cargoes and activate dynein motility.
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24
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Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells. Cell Death Dis 2018; 9:287. [PMID: 29459695 PMCID: PMC5833722 DOI: 10.1038/s41419-018-0331-5] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/09/2018] [Accepted: 01/11/2018] [Indexed: 11/23/2022]
Abstract
Aims Blue light is an identified risk factor for age-related macular degeneration (AMD). We investigated oxidative stress markers and mitochondrial changes in A2E-loaded retinal pigment epithelium cells under the blue–green part of the solar spectrum that reaches the retina to better understand the mechanisms underlying light-elicited toxicity. Results Primary retinal pigment epithelium cells were loaded with a retinal photosensitizer, AE2, to mimic aging. Using a custom-made illumination device that delivers 10 nm-wide light bands, we demonstrated that A2E-loaded RPE cells generated high levels of both hydrogen peroxide (H2O2) and superoxide anion (O2•−) when exposed to blue–violet light. In addition, they exhibited perinuclear clustering of mitochondria with a decrease of both their mitochondrial membrane potential and their respiratory activities. The increase of oxidative stress resulted in increased levels of the oxidized form of glutathione and decreased superoxide dismutase (SOD) and catalase activities. Furthermore, mRNA expression levels of the main antioxidant enzymes (SOD2, catalase, and GPX1) also decreased. Conclusions Using an innovative illumination device, we measured the precise action spectrum of the oxidative stress mechanisms on A2E-loaded retinal pigment epithelium cells. We defined 415–455 nm blue–violet light, within the solar spectrum reaching the retina, to be the spectral band that generates the highest amount of reactive oxygen species and produces the highest level of mitochondrial dysfunction, explaining its toxic effect. This study further highlights the need to filter these wavelengths from the eyes of AMD patients.
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25
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Milev MP, Yao X, Berthoux L, Mouland AJ. Impacts of virus-mediated manipulation of host Dynein. DYNEINS 2018. [PMCID: PMC7150161 DOI: 10.1016/b978-0-12-809470-9.00010-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In general viruses' modus operandi to propagate is achieved by the co-opting host cell components, membranes, proteins, and machineries to their advantage. This is true for virtually every aspect of a virus' replication cycle from virus entry to the budding or release of progeny virus particles. In this chapter, we will discuss new information on the impacts of virus-mediated manipulation of Dynein motor complexes and associated machineries and factors. We will highlight how these host cell components impact on pathogenicity and immune responses, as many of the virus-mediated hijacked components also play pivotal roles in immune responses to pathogen insult. There are several comprehensive reviews that define virus–Dynein interactions including the first edition of this book that describes how viruses manipulate the host cell machineries their advantage. An updated table is included to summarize these virus–host interactions. Notably, barriers to intracellular translocation represent major hurdles to viral components during de novo infection and during active replication and the generation of progeny virus particles. Clearly, the subversion of host cell molecular motor protein activities takes advantage of constitutive and regulated membrane trafficking events and will target virus components to intracytoplasmic locales and membrane assembly. Broadening our understanding of the interplay between viruses, Dynein and the cytoskeleton will likely inform on new types of therapies. Continual enhancement of the breadth of new information on how viruses manipulate host cell biology will inevitably aid in the identification of new targets that can be poisoned to block old, new, and emerging viruses alike in their tracks.
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Kim SY, Kyaw YY, Cheong J. Functional interaction of endoplasmic reticulum stress and hepatitis B virus in the pathogenesis of liver diseases. World J Gastroenterol 2017; 23:7657-7665. [PMID: 29209107 PMCID: PMC5703926 DOI: 10.3748/wjg.v23.i43.7657] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 09/01/2017] [Accepted: 11/01/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is a non-cytopathic virus that causes acute and chronic inflammatory liver diseases, often leading to the pathogenesis of hepatocellular carcinoma (HCC). Although many studies for the roles of HBV on pathogenesis of the liver diseases, such as non-alcoholic fatty liver disease (NAFLD), hepatic inflammation, cirrhosis, and HCC, have been reported, the mechanisms are not fully understood. Endoplasmic reticulum (ER) and mitochondria have the protective mechanisms to restore their damaged function by intrinsic or extrinsic stresses, but their chronic dysfunctions are associated with the pathogenesis of the various diseases. Furthermore, HBV can affect intra- or extracellular homeostasis through induction of ER and mitochondrial dysfunctions, leading to liver injury. Therefore, the mechanism by which HBV induces ER or mitochondrial stresses may be a therapeutic target for treatment of liver diseases.
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Affiliation(s)
- So Young Kim
- Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea
| | - Yi Yi Kyaw
- Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea
| | - Jaehun Cheong
- Department of Molecular Biology, Pusan National University, Busan 609-735, South Korea
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27
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Kasai S, Richardson MJE, Torii S, Yasumoto KI, Shima H, Igarashi K, Itoh K, Sogawa K, Murayama K. Increase in proapoptotic activity of inhibitory PAS domain protein via phosphorylation by MK2. FEBS J 2017; 284:4115-4127. [PMID: 29054108 DOI: 10.1111/febs.14300] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 08/29/2017] [Accepted: 10/17/2017] [Indexed: 11/29/2022]
Abstract
Inhibitory PAS domain protein (IPAS) is a bifunctional protein that downregulates hypoxic gene expression and exerts proapoptotic activity by preventing prosurvival activity of Bcl-xL and its related factors. Proapoptotic activity of IPAS is attenuated by the activation of the PINK1-Parkin pathway, and involved in neuronal degeneration in an experimental mouse model of Parkinson's disease. The current study shows that phosphorylation of IPAS at Ser184 by MAPK-activated protein kinase 2 (MK2 or MAPKAPK2) enhances the proapoptotic function of IPAS. Perinuclear clustering of mitochondria and activation of caspase-3 caused by the transient expression of EGFP-IPAS were increased by UVB irradiation. The C-terminal region of IPAS mediated the UVB susceptibility of IPAS. Increase in IPAS-induced mitochondrial clustering by UVB was completly inhibited by the p38 MAPK inhibitor SB203580. Mass spectrometry analysis of UVB-activated IPAS identified several phosphorylation sites in the C-terminal region containing p38 MAPK consensus phosphorylation sites at Ser219 and Ser223, and an MK2 consensus site at Ser184. Although mutations of Ser219 and Ser223 to Ala did not suppress the UVB-induced mitochondrial clustering, replacement of Ser184 with Ala blocked it. A phosphomimetic substitution at Ser184 enhanced mitochondrial clustering and activation of caspase-3 without UVB exposure. Furthermore, binding affinity to Bcl-xL was increased by the mutation. Treatment of PC12 cells with CoCl2 caused activation of MK2 and mitochondrial clustering. IPAS-dependent cell death induced by CoCl2 in PC12 cells was decreased by the treatment with the MK2 inhibitor MK2 inhibitor III and by siRNA-directed silencing of MK2.
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Affiliation(s)
- Shuya Kasai
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.,Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Mary J E Richardson
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Satoru Torii
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.,Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Ken-Ichi Yasumoto
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Hiroki Shima
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.,Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.,AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Kazuhiko Igarashi
- Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.,Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.,AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Ken Itoh
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, Aomori, Japan
| | - Kazuhiro Sogawa
- Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Kazutaka Murayama
- Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
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28
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O'Mealey GB, Plafker KS, Berry WL, Janknecht R, Chan JY, Plafker SM. A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking. J Cell Sci 2017; 130:3467-3480. [PMID: 28839075 DOI: 10.1242/jcs.203216] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 08/20/2017] [Indexed: 12/12/2022] Open
Abstract
The Nrf2 transcription factor is a master regulator of the cellular anti-stress response. A population of the transcription factor associates with the mitochondria through a complex with KEAP1 and the mitochondrial outer membrane histidine phosphatase, PGAM5. To determine the function of this mitochondrial complex, we knocked down each component and assessed mitochondrial morphology and distribution. We discovered that depletion of Nrf2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition. Mechanistically, this disrupted motility results from aberrant degradation of Miro2, a mitochondrial GTPase that links mitochondria to microtubules. Rescue experiments demonstrate that this Miro2 degradation involves the KEAP1-cullin-3 E3 ubiquitin ligase and the proteasome. These data are consistent with a model in which an intact complex of PGAM5-KEAP1-Nrf2 preserves mitochondrial motility by suppressing dominant-negative KEAP1 activity. These data further provide a mechanistic explanation for how age-dependent declines in Nrf2 expression impact mitochondrial motility and induce functional deficits commonly linked to neurodegeneration.
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Affiliation(s)
- Gary B O'Mealey
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73118, USA.,Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73118, USA
| | - Kendra S Plafker
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73118, USA
| | - William L Berry
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73118, USA
| | - Ralf Janknecht
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73118, USA
| | - Jefferson Y Chan
- Department of Pathology, University of Irvine School of Medicine, Irvine, CA 92697, USA
| | - Scott M Plafker
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73118, USA
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29
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Mitochondrial protein p32/HAPB1/gC1qR/C1qbp is required for efficient respiratory syncytial virus production. Biochem Biophys Res Commun 2017; 489:460-465. [DOI: 10.1016/j.bbrc.2017.05.171] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 05/29/2017] [Indexed: 11/21/2022]
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30
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Abstract
Microtubules (MTs) form a rapidly adaptable network of filaments that radiate throughout the cell. These dynamic arrays facilitate a wide range of cellular processes, including the capture, transport, and spatial organization of cargos and organelles, as well as changes in cell shape, polarity, and motility. Nucleating from MT-organizing centers, including but by no means limited to the centrosome, MTs undergo rapid transitions through phases of growth, pause, and catastrophe, continuously exploring and adapting to the intracellular environment. Subsets of MTs can become stabilized in response to environmental cues, acquiring distinguishing posttranslational modifications and performing discrete functions as specialized tracks for cargo trafficking. The dynamic behavior and organization of the MT array is regulated by MT-associated proteins (MAPs), which include a subset of highly specialized plus-end-tracking proteins (+TIPs) that respond to signaling cues to alter MT behavior. As pathogenic cargos, viruses require MTs to transport to and from their intracellular sites of replication. While interactions with and functions for MT motor proteins are well characterized and extensively reviewed for many viruses, this review focuses on MT filaments themselves. Changes in the spatial organization and dynamics of the MT array, mediated by virus- or host-induced changes to MT regulatory proteins, not only play a central role in the intracellular transport of virus particles but also regulate a wider range of processes critical to the outcome of infection.
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31
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Mitochondrial Heterogeneity: Evaluating Mitochondrial Subpopulation Dynamics in Stem Cells. Stem Cells Int 2017; 2017:7068567. [PMID: 28757879 PMCID: PMC5516713 DOI: 10.1155/2017/7068567] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 05/03/2017] [Indexed: 01/29/2023] Open
Abstract
Although traditionally viewed as the “powerhouse” of the cell, an accruing body of evidence in the rapidly growing field of mitochondrial biology supports additional roles of mitochondria as key participants in a multitude of cellular functions. While it has been well established that mitochondria in different tissues have distinctive ultrastructural features consistent with differential bioenergetic demands, recent and emerging technical advances in flow cytometry, imaging, and “-omics”-based bioinformatics have only just begun to explore the complex and divergent properties of mitochondria within tissues and cell types. Moreover, contemporary studies evaluating the role of mitochondria in pluripotent stem cells, cellular reprogramming, and differentiation point to a potential importance of mitochondrial subpopulations and heterogeneity in the field of stem cell biology. This review assesses the current literature regarding mitochondrial subpopulations within cell and tissue types and evaluates the current understanding of how mitochondrial diversity and heterogeneity might impact cell fate specification in pluripotent stem cells.
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32
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Popkov VA, Zorova LD, Korvigo IO, Silachev DN, Jankauskas SS, Babenko VA, Pevzner IB, Danilina TI, Zorov SD, Plotnikov EY, Zorov DB. Do Mitochondria Have an Immune System? BIOCHEMISTRY (MOSCOW) 2016; 81:1229-1236. [PMID: 27908248 DOI: 10.1134/s0006297916100217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The question if mitochondria have some kind of immune system is not trivial. The basis for raising this question is the fact that bacteria, which are progenitors of mitochondria, do have an immune system. The CRISPR system in bacteria based on the principle of RNA interference serves as an organized mechanism for destroying alien nucleic acids, primarily those of viral origin. We have shown that mitochondria are also a target for viral attacks, probably due to a related organization of genomes in these organelles and bacteria. Bioinformatic analysis performed in this study has not given a clear answer if there is a CRISPR-like immune system in mitochondria. However, this does not preclude the possibility of mitochondrial immunity that can be difficult to decipher or that is based on some principles other than those of CRISPR.
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Affiliation(s)
- V A Popkov
- Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow, 119991, Russia.
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33
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Skoge RH, Ziegler M. SIRT2 inactivation reveals a subset of hyperacetylated perinuclear microtubules inaccessible to HDAC6. J Cell Sci 2016; 129:2972-82. [PMID: 27311481 DOI: 10.1242/jcs.187518] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 06/10/2016] [Indexed: 01/07/2023] Open
Abstract
Deacetylation of α-tubulin at lysine 40 is catalyzed by two enzymes, the NAD-dependent deacetylase SIRT2 and the NAD-independent deacetylase HDAC6, in apparently redundant reactions. In the present study, we tested whether these two enzymes might have distinguishable preferences for the deacetylation of different microtubule structures. Using various agents, we induced tubulin hyperacetylation and analyzed the ensuing formation of distinct microtubule structures. HDAC6 inhibition led to general hyperacetylation of the microtubule network throughout the cell, whereas hyperacetylation induced by SIRT2 inactivation was limited to perinuclear microtubules. Hyperacetylation of these perinuclear microtubules was undiminished following HDAC6 overexpression, whereas reactivation of SIRT2 restored the basal acetylation level and a normal microtubule network. By contrast, SIRT2 and HDAC6 acted similarly on the morphologically different, hyperacetylated microtubule structures induced by taxol, MAP2c overexpression or hyperosmotic stress. These results indicate overlapping and distinct functions of HDAC6 and SIRT2. We propose that the differential activity of the two deacetylases, which target the same acetylated lysine residue, might be related to the recognition of specific structural contexts.
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Affiliation(s)
- Renate Hvidsten Skoge
- Department of Molecular Biology, University of Bergen, Postbox 7803, Bergen 5020, Norway
| | - Mathias Ziegler
- Department of Molecular Biology, University of Bergen, Postbox 7803, Bergen 5020, Norway
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34
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35
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Slagle BL, Bouchard MJ. Hepatitis B Virus X and Regulation of Viral Gene Expression. Cold Spring Harb Perspect Med 2016; 6:a021402. [PMID: 26747833 DOI: 10.1101/cshperspect.a021402] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The efficient replication of hepatitis B virus (HBV) requires the HBV regulatory hepatitis B virus X (HBx) protein. The exact contributions of HBx are not fully understood, in part because of the limitations of the assays used for its study. When HBV replication is driven from a plasmid DNA, the contribution of HBx is modest. However, there is an absolute requirement for HBx in assays that recapitulate the infectious virus life cycle. There is much evidence that HBx can contribute directly to HBV replication by acting on viral promoters embedded within protein coding sequences. In addition, HBx may also contribute indirectly by modulating cellular pathways to benefit virus replication. Understanding the mechanism(s) of HBx action during virus replication may provide insight into novel ways to disrupt chronic HBV replication.
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Affiliation(s)
- Betty L Slagle
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030
| | - Michael J Bouchard
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102
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36
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Abstract
SummaryMeiotic maturation of oocytes requires a variety of ATP-dependent reactions, such as germinal vesicle breakdown, spindle formation, and rearrangement of plasma membrane structure, which is required for fertilization. Mitochondria are accordingly expected be localized to subcellular sites of energy utilization. Although microtubule-dependent cellular traffic for mitochondria has been studied extensively in cultured neuronal (and some other somatic) cells, the molecular mechanism of their dynamics in mammalian oocytes at different stages of maturation remains obscure. The present work describes dynamic aspects of mitochondria in porcine oocytes at the germinal vesicle stage. After incubation of oocytes with MitoTracker Orange followed by centrifugation, mitochondria-enriched ooplasm was obtained using a glass needle and transferred into a recipient oocyte. The intracellular distribution of the fluorescent mitochondria was then observed over time using a laser scanning confocal microscopy equipped with an incubator. Kinetic analysis revealed that fluorescent mitochondria moved from central to subcortical areas of oocytes and were dispersed along plasma membranes. Such movement of mitochondria was inhibited by either cytochalasin B or cytochalasin D but not by colcemid, suggesting the involvement of microfilaments. This method of visualizing mitochondrial dynamics in live cells permits study of the pathophysiology of cytoskeleton-dependent intracellular traffic of mitochondria and associated energy metabolism during meiotic maturation of oocytes.
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37
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Hepatitis B virus X protein enhances Myc stability by inhibiting SCFSkp2 ubiquitin E3 ligase-mediated Myc ubiquitination and contributes to oncogenesis. Oncogene 2015; 35:1857-67. [DOI: 10.1038/onc.2015.251] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 05/05/2015] [Accepted: 05/22/2015] [Indexed: 01/19/2023]
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38
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Zou LY, Zheng BY, Fang XF, Li D, Huang YH, Chen ZX, Zhou LY, Wang XZ. HBx co-localizes with COXIII in HL-7702 cells to upregulate mitochondrial function and ROS generation. Oncol Rep 2015; 33:2461-7. [PMID: 25778742 DOI: 10.3892/or.2015.3852] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2014] [Accepted: 02/19/2015] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant diseases, and HBx leads to the development of HBV-associated HCC. Mitochondria are key organelles that regulate apoptosis, cellular energetics and signal transduction pathways, and are the source of HBx-induced reactive oxygen species (ROS). Recent findings have shown that HBx interacts with the inner mitochondrial membrane protein, COXIII, via the yeast two-hybrid system, mating experiment and coimmunoprecipitation. The aim of the present study was to examine the co-localizaiton of HBx and COXIII in HL-7702 cells and to investigate ensuing alterations of mitochondrial function. An HL-7702 cell line stably expressing the HBx gene by lentivirus vectors was constructed. Confocal microscopy was utilized to assess the interaction between HBx protein and COXIII. Expression of COXIII, activities of cytochrome c oxidase (COX) and the mitochondrial membrane potential, which were functionally relevant to the HBx protein-COXIII interaction, were investigated in cell cultures. Moreover, the intracellular ROS levels were detected by flow cytometry. The results demonstrated that HBx co-localized with the inner mitochondrial protein, COXIII, in HL-7702 cells, causing the upregulation of COXIII protein expression as well as COX activity. However, HBx did not alter the mitochondrial membrane potential and mitochondria exhibited only slight swelling in HL-7702-HBx cells. Moreover, HBx elevated the generation of mitochondrial ROS in HL-7702-HBx cells. The main finding of the present study was that the co-localization of HBx and COXIII leads to upregulation of the mitochondrial function and ROS generation, which are associated with the oncogenesis of HBV-associated HCC.
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Affiliation(s)
- Lai-Yu Zou
- Department of Infection, Union Hospital of Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
| | - Bi-Yun Zheng
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
| | - Xue-Fen Fang
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
| | - Dan Li
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
| | - Yue-Hong Huang
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
| | - Zhi-Xin Chen
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
| | - Lin-Ying Zhou
- Laboratory of Electron Microscopy, Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
| | - Xiao-Zhong Wang
- Department of Gastroenterology, Union Hospital of Fujian Medical University, Gulou, Fuzhou, Fujian 350001, P.R. China
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39
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Volle R, Archimbaud C, Couraud PO, Romero IA, Weksler B, Mirand A, Pereira B, Henquell C, Peigue-Lafeuille H, Bailly JL. Differential permissivity of human cerebrovascular endothelial cells to enterovirus infection and specificities of serotype EV-A71 in crossing an in vitro model of the human blood-brain barrier. J Gen Virol 2015; 96:1682-95. [PMID: 25711966 DOI: 10.1099/vir.0.000103] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Human cerebral microvascular endothelial cells (hCMEC/D3 cell line) form a steady polarized barrier when cultured in vitro on a permeable membrane. Their susceptibility to enterovirus (EV) strains was analysed to investigate how these viruses may cross the blood-brain barrier. A sample of 88 virus strains was selected on phylogenetic features amongst 43 epidemiologically relevant types of the four EV species A-D. The EV-A71 genome was replicated at substantial rates, whilst the infectious virus was released at extremely low but sustained rates at both barrier sides for at least 4 days. EV-A71 antigens were detected in a limited number of cells. The properties of the endothelial barrier (structure and permeability) remained intact throughout infection. The chronic EV-A71 infection was in sharp contrast to the productive infection of cytolytic EVs (e.g. echoviruses E-6 and E-30). The hCMEC/D3 barriers infected with the latter EVs exhibited elevated proportions of apoptotic and necrotic cells, which resulted in major injuries to the endothelial barriers with a dramatic increase of paracellular permeability and virus crossing to the abluminal side. The following intracellular rearrangements were also seen: early destruction of the actin cytoskeleton, remodelling of intracellular membranes and reorganization of the mitochondrion network in a small cluster near the perinuclear space.
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Affiliation(s)
- Romain Volle
- 1Clermont Université, Université d'Auvergne, EPIE, EA 4843, Clermont-Ferrand, France 2CHU Clermont-Ferrand, Service de Virologie, Clermont-Ferrand, France
| | - Christine Archimbaud
- 1Clermont Université, Université d'Auvergne, EPIE, EA 4843, Clermont-Ferrand, France 2CHU Clermont-Ferrand, Service de Virologie, Clermont-Ferrand, France
| | | | - Ignacio A Romero
- 5Department of Life, Health and Chemical Sciences, Open University, Milton Keynes, UK
| | | | - Audrey Mirand
- 1Clermont Université, Université d'Auvergne, EPIE, EA 4843, Clermont-Ferrand, France 2CHU Clermont-Ferrand, Service de Virologie, Clermont-Ferrand, France
| | - Bruno Pereira
- 3CHU Clermont-Ferrand, DRCI, Clermont-Ferrand, France
| | - Cécile Henquell
- 2CHU Clermont-Ferrand, Service de Virologie, Clermont-Ferrand, France
| | - Hélène Peigue-Lafeuille
- 1Clermont Université, Université d'Auvergne, EPIE, EA 4843, Clermont-Ferrand, France 2CHU Clermont-Ferrand, Service de Virologie, Clermont-Ferrand, France
| | - Jean-Luc Bailly
- 1Clermont Université, Université d'Auvergne, EPIE, EA 4843, Clermont-Ferrand, France 2CHU Clermont-Ferrand, Service de Virologie, Clermont-Ferrand, France
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40
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Wang Q, Xu Y, Zhou W, Zhong L, Wen Z, Yu H, Chen S, Shen J, Chen H, She Q, Jiang J, Miao J, Wei W. The viral oncoprotein HBx of Hepatitis B virus promotes the growth of hepatocellular carcinoma through cooperating with the cellular oncoprotein RMP. Int J Biol Sci 2014; 10:1181-92. [PMID: 25516716 PMCID: PMC4261202 DOI: 10.7150/ijbs.10275] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 10/14/2014] [Indexed: 01/28/2023] Open
Abstract
The smallest gene HBx of Hepatitis B virus (HBV) is recognized as an important viral oncogene (V-oncogene) in the hepatocarcinogenesis. Our previous work demonstrated that RMP is a cellular oncogene (C-oncogene) required for the proliferation of hepatocellular carcinoma (HCC) cells. Here we presented the collaboration between V-oncogene HBx and C-oncogene RMP in the development of HCC. The coexpression of HBx and RMP resulted in the cooperative effect of antiapoptosis and proliferation of HCC cells. In vivo, overexpression of RMP accelerated the growth of HBx-induced xenograft tumors in nude mice and vice versa HBx promoted the growth of RMP-driven xenograft tumors. Although HBx didn't regulate the expression of RMP, HBx and RMP interact with each other and collocalized in the cytoplasm of HCC cells. HBx and RMP collaboratively inhibited the expression of apoptotic factors and promoted the expression of antiapoptotic factors. This finding suggests that HBV may induce, or at least partially contributes to the carcinogenesis of HCC, through its V-oncoprotein HBx interacting with the C-oncoprotein RMP.
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Affiliation(s)
- Qi Wang
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China ; 2. Department of Tumor Biotherapy, Third Affiliated Hospital of Soochow University, Changzhou, 213003 China
| | - Yi Xu
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Wei Zhou
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Lei Zhong
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Zengqing Wen
- 3. Eastern Hepatobiliary Surgery Hospital, Shanghai, 200433, China
| | - Huijun Yu
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Shaomu Chen
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Jian Shen
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Han Chen
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Qinying She
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Jingting Jiang
- 2. Department of Tumor Biotherapy, Third Affiliated Hospital of Soochow University, Changzhou, 213003 China
| | - Jingcheng Miao
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
| | - Wenxiang Wei
- 1. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, 215123 China
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41
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Cheng ML, Weng SF, Kuo CH, Ho HY. Enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication. PLoS One 2014; 9:e113234. [PMID: 25401329 PMCID: PMC4234665 DOI: 10.1371/journal.pone.0113234] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 10/22/2014] [Indexed: 12/16/2022] Open
Abstract
Redox homeostasis is an important host factor determining the outcome of infectious disease. Enterovirus 71 (EV71) infection has become an important endemic disease in Southeast Asia and China. We have previously shown that oxidative stress promotes viral replication, and progeny virus induces oxidative stress in host cells. The detailed mechanism for reactive oxygen species (ROS) generation in infected cells remains elusive. In the current study, we demonstrate that mitochondria were a major ROS source in EV71-infected cells. Mitochondria in productively infected cells underwent morphologic changes and exhibited functional anomalies, such as a decrease in mitochondrial electrochemical potential ΔΨm and an increase in oligomycin-insensitive oxygen consumption. Respiratory control ratio of mitochondria from infected cells was significantly lower than that of normal cells. The total adenine nucleotide pool and ATP content of EV71-infected cells significantly diminished. However, there appeared to be a compensatory increase in mitochondrial mass. Treatment with mito-TEMPO reduced eIF2α phosphorylation and viral replication, suggesting that mitochondrial ROS act to promote viral replication. It is plausible that EV71 infection induces mitochondrial ROS generation, which is essential to viral replication, at the sacrifice of efficient energy production, and that infected cells up-regulate biogenesis of mitochondria to compensate for their functional defect.
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Affiliation(s)
- Mei-Ling Cheng
- Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
- Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan
- Metabolomics Core Laboratory, Chang Gung University, Tao-Yuan, Taiwan
| | - Shiue-Fen Weng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Chih-Hao Kuo
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Hung-Yao Ho
- Healthy Aging Research Center, Chang Gung University, Tao-Yuan, Taiwan
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
- Office of Research and Development, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
- * E-mail:
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42
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Choi YB, Harhaj EW. Functional implications of mitochondrial reactive oxygen species generated by oncogenic viruses. ACTA ACUST UNITED AC 2014; 9:423-436. [PMID: 25580106 DOI: 10.1007/s11515-014-1332-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Between 15-20% of human cancers are associated with infection by oncogenic viruses. Oncogenic viruses, including HPV, HBV, HCV and HTLV-1, target mitochondria to influence cell proliferation and survival. Oncogenic viral gene products also trigger the production of reactive oxygen species which can elicit oxidative DNA damage and potentiate oncogenic host signaling pathways. Viral oncogenes may also subvert mitochondria quality control mechanisms such as mitophagy and metabolic adaptation pathways to promote virus replication. Here, we will review recent progress on viral regulation of mitophagy and metabolic adaptation and their roles in viral oncogenesis.
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Affiliation(s)
- Young Bong Choi
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns HopkinsSchool of Medicine, Baltimore, MD 21287, USA
| | - Edward William Harhaj
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns HopkinsSchool of Medicine, Baltimore, MD 21287, USA
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43
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Xu C, Zhou W, Wang Y, Qiao L. Hepatitis B virus-induced hepatocellular carcinoma. Cancer Lett 2014; 345:216-222. [PMID: 23981576 DOI: 10.1016/j.canlet.2013.08.035] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/10/2013] [Accepted: 08/18/2013] [Indexed: 12/12/2022]
Abstract
Many factors are considered to contribute to hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), including products of HBV, HBV integration and mutation, and host susceptibility. HBV X protein (HBx) can interfere with several signal pathways that associated with cell proliferation and apoptosis, and the impact of HBx C-terminal truncation in the development of HCC has been implicated. Recent studies by advanced sequencing technologies have revealed recurrent HBV DNA integration sites in hepatoma cells and susceptible genes/SNPs play an important role in the pathogenesis of liver cancer. Epigenetic changes, immune and inflammatory factors are also important contributing factors for liver cancer. This mini-review provides an overview on the recent development of HBV induced HCC.
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Affiliation(s)
- Cheng Xu
- Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Wence Zhou
- The Department of General Surgery II, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yuming Wang
- Institute for Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
| | - Liang Qiao
- Storr Liver Unit, University of Sydney, Westmead Millennium Institute, Westmead Hospital, Westmead, NSW 2145, Australia.
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44
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Wu HC, Tsai HW, Teng CF, Hsieh WC, Lin YJ, Wang LHC, Yuan Q, Su IJ. Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis. Hum Pathol 2014; 45:1294-301. [PMID: 24767856 DOI: 10.1016/j.humpath.2013.10.039] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 10/14/2013] [Accepted: 10/16/2013] [Indexed: 12/11/2022]
Abstract
Hepatitis B virus (HBV) X protein (HBx) and pre-S2 deletion mutant large surface antigens are oncoproteins that induce hepatocellular carcinoma (HCC). The interaction of these two oncoproteins in hepatocytes and its significance in tumorigenesis remain to be elucidated. In this study, we observed the co-expression of HBx with surface antigens in ground-glass hepatocytes in 5 of 20 hepatitis B surface antigen-positive livers. In vitro, hepatocytes co-expressing HBx and a pre-S2 mutant showed enhanced expression of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated mammalian target of rapamycin signals. Transgenic mice harboring both HBx and pre-S2 mutant construct plasmids developed HCCs at an average of 15.1 months, earlier than animals carrying either HBx (16.9 months) or pre-S2 mutant (24.5 months) alone. The oncogenic signals of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated mammalian target of rapamycin were sequentially and differentially activated at different stages in tumorigenesis. Phosphorylated mTOR was consistently activated in transgenic and human HCCs. We conclude that ground-glass hepatocytes co-expressing HBx and surface antigens exhibit enhanced oncogenic effects and tumorigenesis in chronic HBV infections. The mTOR signal cascade may be the key regulator in HBV tumorigenesis and may be useful targets in the design of HCC therapy.
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Affiliation(s)
- Han-Chieh Wu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Chiao-Fang Teng
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan
| | - Wen-Chuan Hsieh
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Lily Hui-Ching Wang
- Institute of Molecular and Cellular Biology and Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Quan Yuan
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen 361102, China
| | - Ih-Jen Su
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan; Department of Surgery, National Cheng Kung University Hospital, Tainan 70403, Taiwan.
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45
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Claus C, Liebert UG. A renewed focus on the interplay between viruses and mitochondrial metabolism. Arch Virol 2013; 159:1267-77. [PMID: 24343264 DOI: 10.1007/s00705-013-1841-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 07/26/2013] [Indexed: 01/26/2023]
Abstract
Mitochondria fulfil several key functions within cellular metabolic and antiviral signalling pathways, including their central role in ATP generation. Viruses, as intracellular parasites, require from their cellular host the building blocks for generation of their viral progeny and the energy that drives viral replication and assembly. While some viruses have adopted ways to manipulate the infected cell such that cellular metabolism supports optimal virus production, other viruses simply exhaust cellular resources. The association of viruses with mitochondria is influenced by several important factors such as speed of the viral replication cycle and viral dependence on cellular enzymes and metabolites. This review will highlight the complex interconnectivity of viral life cycles with the three main mitochondrial metabolic pathways, namely β-oxidation, the tricarboxylic (TCA) cycle, and oxidative phosphorylation. This interconnectivity has the potential to reveal interesting points for antiviral therapy with either prometabolites or antimetabolites and highlights the importance of the viral association with mitochondrial metabolism.
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Affiliation(s)
- C Claus
- Institute of Virology, University of Leipzig, Johannisallee 30, 04317, Leipzig, Germany,
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46
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Kim SJ, Khan M, Quan J, Till A, Subramani S, Siddiqui A. Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis. PLoS Pathog 2013; 9:e1003722. [PMID: 24339771 PMCID: PMC3855539 DOI: 10.1371/journal.ppat.1003722] [Citation(s) in RCA: 231] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 09/08/2013] [Indexed: 12/14/2022] Open
Abstract
Human hepatitis B virus (HBV) causes chronic hepatitis and is associated with the development of hepatocellular carcinoma. HBV infection alters mitochondrial metabolism. The selective removal of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. Here, we report that HBV shifts the balance of mitochondrial dynamics toward fission and mitophagy to attenuate the virus-induced apoptosis. HBV induced perinuclear clustering of mitochondria and triggered mitochondrial translocation of the dynamin-related protein (Drp1) by stimulating its phosphorylation at Ser616, leading to mitochondrial fission. HBV also stimulated the gene expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria. Upon translocation to mitochondria, Parkin, an E3 ubiquitin ligase, underwent self-ubiquitination and facilitated the ubiquitination and degradation of its substrate Mitofusin 2 (Mfn2), a mediator of mitochondrial fusion. In addition to conventional immunofluorescence, a sensitive dual fluorescence reporter expressing mito-mRFP-EGFP fused in-frame to a mitochondrial targeting sequence was employed to observe the completion of the mitophagic process by delivery of the engulfed mitochondria to lysosomes for degradation. Furthermore, we demonstrate that viral HBx protein plays a central role in promoting aberrant mitochondrial dynamics either when expressed alone or in the context of viral genome. Perturbing mitophagy by silencing Parkin led to enhanced apoptotic signaling, suggesting that HBV-induced mitochondrial fission and mitophagy promote cell survival and possibly viral persistence. Altered mitochondrial dynamics associated with HBV infection may contribute to mitochondrial injury and liver disease pathogenesis.
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Affiliation(s)
- Seong-Jun Kim
- Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Mohsin Khan
- Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Jun Quan
- Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
| | - Andreas Till
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
- San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, United States of America
| | - Suresh Subramani
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California, United States of America
- San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, United States of America
| | - Aleem Siddiqui
- Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America
- * E-mail:
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47
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Anand SK, Tikoo SK. Viruses as modulators of mitochondrial functions. Adv Virol 2013; 2013:738794. [PMID: 24260034 PMCID: PMC3821892 DOI: 10.1155/2013/738794] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 08/30/2013] [Indexed: 02/07/2023] Open
Abstract
Mitochondria are multifunctional organelles with diverse roles including energy production and distribution, apoptosis, eliciting host immune response, and causing diseases and aging. Mitochondria-mediated immune responses might be an evolutionary adaptation by which mitochondria might have prevented the entry of invading microorganisms thus establishing them as an integral part of the cell. This makes them a target for all the invading pathogens including viruses. Viruses either induce or inhibit various mitochondrial processes in a highly specific manner so that they can replicate and produce progeny. Some viruses encode the Bcl2 homologues to counter the proapoptotic functions of the cellular and mitochondrial proteins. Others modulate the permeability transition pore and either prevent or induce the release of the apoptotic proteins from the mitochondria. Viruses like Herpes simplex virus 1 deplete the host mitochondrial DNA and some, like human immunodeficiency virus, hijack the host mitochondrial proteins to function fully inside the host cell. All these processes involve the participation of cellular proteins, mitochondrial proteins, and virus specific proteins. This review will summarize the strategies employed by viruses to utilize cellular mitochondria for successful multiplication and production of progeny virus.
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Affiliation(s)
- Sanjeev K. Anand
- Vaccine & Infection Disease Organization-International Vaccine Center (VIDO-InterVac), University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
- Veterinary Microbiology, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
| | - Suresh K. Tikoo
- Vaccine & Infection Disease Organization-International Vaccine Center (VIDO-InterVac), University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
- Veterinary Microbiology, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
- School of Public Health, University of Saskatchewan, 120 Veterinary Road, Saskatoon, SK, Canada S7E 5E3
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48
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Lu G, Matsuura SE, Barrientos A, Scott WA. HIV-1 infection is blocked at an early stage in cells devoid of mitochondrial DNA. PLoS One 2013; 8:e78035. [PMID: 24205077 PMCID: PMC3804459 DOI: 10.1371/journal.pone.0078035] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 09/16/2013] [Indexed: 11/19/2022] Open
Abstract
Human immunodeficiency virus type I (HIV-1) exploits various host cellular pathways for efficient infection. Here we report that the absence of mitochondrial DNA (mtDNA) in ρ(0) cells markedly attenuates HIV-1 infection. Importantly, reduced infection efficiency in ρ(0) cells is not simply the result of impaired oxidative phosphorylation (OXPHOS) because pharmacological OXPHOS inhibition did not inhibit HIV-1 infection. Analysis of the early steps of virus infection by real-time PCR quantification of stage-specific HIV-1 DNA products in the infected ρ(0) and parental cell line have allowed us to conclude that HIV-1 infection in ρ(0) cells is blocked at the steps that occur after reverse transcription and prior to nuclear import. Additionally, confocal fluorescence microscope analysis showed that the majority of viral complexes containing HIV-1 p24 co-localize with mitochondria in target cells, suggesting an interaction between the two. Collectively, our data strongly indicate that mitochondria play an important role during early stages of HIV-1 infection, probably through direct association with HIV-1 intracellular complexes.
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Affiliation(s)
- Gaofei Lu
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Suzanne E. Matsuura
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
| | - Antoni Barrientos
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
- * E-mail:
| | - Walter A. Scott
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America
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Shen L, Zhang X, Hu D, Feng T, Li H, Lu Y, Huang J. Hepatitis B virus X (HBx) play an anti-apoptosis role in hepatic progenitor cells by activating Wnt/β-catenin pathway. Mol Cell Biochem 2013; 383:213-22. [PMID: 23934090 DOI: 10.1007/s11010-013-1769-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 08/02/2013] [Indexed: 12/16/2022]
Abstract
Increasing evidence has shown that normal stem cells may act as cancer-initiating cells and contribute to the development and progression of cancer. HBx has a close relationship with hepatocellular carcinoma, however, the role of HBx in hepatic progenitor cells (HPCs) is poorly understood. In this study, we sought to determine the role of HBx in regulating HPCs apoptosis and the underlying molecular mechanism(s) using HPCs derived from mouse fetal liver. The apoptotic ratio of HPCs infected with adenovirus-expressing HBx (Ad-HBx) was examined using flow cytometry. Results showed that the Ad-HBx treatment led to substantially decreased apoptotic ratio of HPCs, as confirmed by the Hoechst 33342 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). Possible alterations of relative proteins were examined using Western blot and real-time PCR assays. The HBx expression in HPCs increased the expression levels of Bcl2 and Mcl1 while decreasing the expression levels of Bax and cleaved caspase-9 and -3. In addition, the mRNA and protein expression levels of β-catenin were both increased. The β-catenin protein were mainly accumulated in cytoplasm and tended to transfer into cell nucleus after Ad-HBx treatment. The over-expression of β-catenin decreased the apoptotic ratio of HPCs and inhibited the expression of cleaved caspase-9 and -3 while blocking β-catenin expression resulted in the opposite results. Taken together, our results strongly suggested that the HBx protein may inhibits apoptosis of hepatic progenitor cells, at least in part by activating the WNT/β-catenin pathway. This provided a new insight into the molecular mechanism of HBx-mediated live carcinogenesis.
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Affiliation(s)
- Lihong Shen
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, People's Republic of China
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50
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Hepatitis C virus-induced mitochondrial dysfunctions. Viruses 2013; 5:954-80. [PMID: 23518579 PMCID: PMC3705306 DOI: 10.3390/v5030954] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 03/15/2013] [Accepted: 03/20/2013] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis C is characterized by metabolic disorders and a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that lead in the long term to hepatocellular carcinoma. Many lines of evidence suggest that mitochondrial dysfunctions, including modification of metabolic fluxes, generation and elimination of oxidative stress, Ca2+ signaling and apoptosis, play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory, probably due to the use of artificial expression and replication systems. In vivo studies are hampered by the fact that innate and adaptive immune responses will overlay mitochondrial dysfunctions induced directly in the hepatocyte by HCV. Thus, the molecular aspects underlying HCV-induced mitochondrial dysfunctions and their roles in viral replication and the associated pathology need yet to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems.
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