{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:50:19Z","timestamp":1793314219575,"version":"4.5.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T00:00:00Z","timestamp":1586304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T00:00:00Z","timestamp":1586304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81470864"],"award-info":[{"award-number":["81470864"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>An imbalance in mitochondrial dynamics induced by oxidative stress may lead to hepatocyte epithelial mesenchymal transition (EMT) and liver fibrosis. However, the underlying molecular mechanisms have not been fully elucidated. This study investigated the role of mitochondrial dynamics in hepatocyte EMT and liver fibrosis using an in vitro human (L-02 cells, hepatic cell line) and an in vivo mouse model of liver fibrosis. Findings showed that oxidative stress-induced mitochondrial DNA damage was associated with abnormal mitochondrial fission and hepatocyte EMT. The reactive oxygen species (ROS) scavengers apocynin and mito-tempo effectively attenuated carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced abnormal mitochondrial fission and liver fibrosis. Restoring mitochondrial biogenesis attenuated hepatocyte EMT. Oxidative stress-induced abnormal hepatocyte mitochondrial fission events by a mechanism that involved the down regulation of PGC-1\u03b1. PGC-1\u03b1 knockout mice challenged with CCl<jats:sub>4<\/jats:sub> had increased abnormal mitochondrial fission and more severe liver fibrosis than wild type mice. These results indicate that PGC-1\u03b1 has a protective role in oxidative stress-induced-hepatocyte EMT and liver fibrosis.<\/jats:p>","DOI":"10.1038\/s41419-020-2429-9","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T13:03:24Z","timestamp":1586351004000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Imbalance in mitochondrial dynamics induced by low PGC-1\u03b1 expression contributes to hepatocyte EMT and liver fibrosis"],"prefix":"10.1038","volume":"11","author":[{"given":"Linzhong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanghao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxiang","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,8]]},"reference":[{"key":"2429_CR1","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.stem.2016.05.005","volume":"18","author":"M Rezvani","year":"2016","unstructured":"Rezvani, M. et al. In vivo hepatic reprogramming of myofibroblasts with AAV vectors as a therapeutic strategy for liver fibrosis. Cell Stem Cell 18, 809\u2013816 (2016).","journal-title":"Cell Stem Cell"},{"key":"2429_CR2","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9630175","author":"R Shah","year":"2018","unstructured":"Shah, R. et al. Thymosin \u03b24 prevents oxidative stress, inflammation, and fibrosis in Ethanol- and LPS-Induced liver injury in mice. Oxid. Med. Cell. Longev. https:\/\/doi.org\/10.1155\/2018\/9630175 (2018).","journal-title":"Oxid. Med. Cell. Longev."},{"key":"2429_CR3","doi-asserted-by":"publisher","first-page":"S60","DOI":"10.1016\/j.clinre.2015.06.015","volume":"39","author":"M Sun","year":"2015","unstructured":"Sun, M. & Kisseleva, T. Reversibility of liver fibrosis. Clin. Res. Hepatol. Gas. 39, S60\u2013S63 (2015).","journal-title":"Clin. Res. Hepatol. Gas."},{"key":"2429_CR4","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.gene.2018.06.053","volume":"674","author":"J Wang","year":"2018","unstructured":"Wang, J. et al. Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis. Gene 674, 57\u201369 (2018).","journal-title":"Gene"},{"key":"2429_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.355","volume":"5","author":"S Srivastava","year":"2014","unstructured":"Srivastava, S., Sinha, D., Saha, P. P., Marthala, H. & D\u2019Silva, P. Magmas functions as a ROS regulator and provides cytoprotection against oxidative stress-mediated damages. Cell Death Dis. 5, e1394 (2014).","journal-title":"Cell Death Dis."},{"key":"2429_CR6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004972","volume":"11","author":"CE Schaar","year":"2015","unstructured":"Schaar, C. E. et al. Mitochondrial and cytoplasmic ROS have opposing effects on lifespan. Plos Genet. 11, e1004972 (2015).","journal-title":"Plos Genet."},{"key":"2429_CR7","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1111\/liv.13436","volume":"37","author":"M Vilaseca","year":"2017","unstructured":"Vilaseca, M. et al. Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats. Liver Int. 37, 1002\u20131012 (2017).","journal-title":"Liver Int."},{"key":"2429_CR8","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1042\/BCJ20160503C","volume":"473","author":"P Newsholme","year":"2016","unstructured":"Newsholme, P., Cruzat, V. F., Keane, K. N., Carlessi, R. & de Bittencourt, P. I. Jr Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem. J. 473, 4527\u20134550 (2016).","journal-title":"Biochem. J."},{"key":"2429_CR9","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.stem.2010.11.028","volume":"8","author":"JE Le Belle","year":"2011","unstructured":"Le Belle, J. E. et al. Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K\/Akt-dependant manner. Cell Stem Cell 8, 59\u201371 (2011).","journal-title":"Cell Stem Cell"},{"key":"2429_CR10","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.1093\/ndt\/gfw469","volume":"32","author":"S Zhang","year":"2017","unstructured":"Zhang, S., Tan, X., Chen, Y. & Zhang, X. Postconditioning protects renal fibrosis by attenuating oxidative stress-induced mitochondrial injury. Nephrol. Dial. Transplant. 32, 1628\u20131636 (2017).","journal-title":"Nephrol. Dial. Transplant."},{"key":"2429_CR11","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.cmet.2015.08.006","volume":"22","author":"D Jacobi","year":"2015","unstructured":"Jacobi, D. et al. Hepatic Bmal1 regulates rhythmic mitochondrial dynamics and promotes metabolic fitness. Cell Metab. 22, 709\u2013720 (2015).","journal-title":"Cell Metab."},{"key":"2429_CR12","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.neuint.2017.04.009","volume":"109","author":"A Aouacheria","year":"2017","unstructured":"Aouacheria, A. et al. Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins. Neurochem. Int. 109, 141\u2013161 (2017).","journal-title":"Neurochem. Int."},{"key":"2429_CR13","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1007\/s00018-016-2451-3","volume":"74","author":"AP Trotta","year":"2017","unstructured":"Trotta, A. P. & Chipuk, J. E. Mitochondrial dynamics as regulators of cancer biology. Cell Mol. Life Sci. 74, 1999\u20132017 (2017).","journal-title":"Cell Mol. Life Sci."},{"key":"2429_CR14","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1126\/science.1219855","volume":"337","author":"RJ Youle","year":"2012","unstructured":"Youle, R. J. & van der Bliek, A. M. Mitochondrial fission, fusion, and stress. Science 337, 1062\u20131065 (2012).","journal-title":"Science"},{"key":"2429_CR15","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.redox.2018.10.012","volume":"20","author":"H Li","year":"2019","unstructured":"Li, H. et al. Mst1 deletion attenuates renal ischaemia-reperfusion injury: the role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3beta-p53 signalling pathway. Redox Biol. 20, 261\u2013274 (2019).","journal-title":"Redox Biol."},{"key":"2429_CR16","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1126\/science.1207385","volume":"334","author":"JR Friedman","year":"2011","unstructured":"Friedman, J. R. et al. ER tubules mark sites of mitochondrial division. Science 334, 358\u2013362 (2011).","journal-title":"Science"},{"key":"2429_CR17","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1038\/s41418-018-0197-1","volume":"26","author":"R Bravo-Sagua","year":"2019","unstructured":"Bravo-Sagua, R. et al. Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER-mitochondria communication during the early phase of ER stress. Cell Death Differ. 26, 1195\u20131212 (2019).","journal-title":"Cell Death Differ."},{"key":"2429_CR18","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/nm.3983","volume":"22","author":"W Wang","year":"2016","unstructured":"Wang, W. et al. Parkinson\u2019s disease-associated mutant VPS35 causes mitochondrial dysfuntion by recycling DLP complexes. Nat. Med. 22, 54\u201363 (2016).","journal-title":"Nat. Med."},{"key":"2429_CR19","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1007\/s12035-014-8893-4","volume":"52","author":"D Santos","year":"2015","unstructured":"Santos, D., Esteves, A. R., Silva, D. F., Januario, C. & Cardoso, S. M. The impact of mitochondrial fusion and fission modulation in sporadic Parkinson\u2019s disease. Mol. Neurobiol. 52, 573\u2013586 (2015).","journal-title":"Mol. Neurobiol."},{"key":"2429_CR20","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1038\/nm.2439","volume":"17","author":"G Haemmerle","year":"2011","unstructured":"Haemmerle, G. et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-\u03b1 and PGC-1. Nat. Med. 17, 1076\u20131085 (2011).","journal-title":"Nat. Med."},{"key":"2429_CR21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0125176","volume":"10","author":"K Guo","year":"2015","unstructured":"Guo, K. et al. Protective role of PGC-1alpha in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling. Plos ONE 10, e0125176 (2015).","journal-title":"Plos ONE"},{"key":"2429_CR22","doi-asserted-by":"publisher","first-page":"C1176","DOI":"10.1152\/ajpcell.00017.2014","volume":"306","author":"S Iqbal","year":"2014","unstructured":"Iqbal, S. & Hood, D. A. Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts. Am. J. Physiol. Cell Physiol. 306, C1176\u2013C1183 (2014).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"2429_CR23","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.tox.2011.01.017","volume":"282","author":"HY Kim","year":"2011","unstructured":"Kim, H. Y. et al. Ferulic acid protects against carbon tetrachloride-induced liver injury in mice. Toxicology 282, 104\u2013111 (2011).","journal-title":"Toxicology"},{"key":"2429_CR24","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.freeradbiomed.2015.12.016","volume":"91","author":"MA Abdelmegeed","year":"2016","unstructured":"Abdelmegeed, M. A., Choi, Y., Ha, S. & Song, B. Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress. Free Radic. Biol. Med. 91, 188\u2013202 (2016).","journal-title":"Free Radic. Biol. Med."},{"key":"2429_CR25","doi-asserted-by":"publisher","first-page":"4850","DOI":"10.2174\/092986712803341520","volume":"19","author":"V Sanchez-Valle","year":"2012","unstructured":"Sanchez-Valle, V., Chavez-Tapia, N. C., Uribe, M. & Mendez-Sanchez, N. Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr. Med. Chem. 19, 4850\u20134860 (2012).","journal-title":"Curr. Med. Chem."},{"key":"2429_CR26","doi-asserted-by":"publisher","first-page":"44464","DOI":"10.1074\/jbc.M112.422626","volume":"287","author":"R CAI","year":"2012","unstructured":"CAI, R. et al. SUMO-specific protease 1 regulates mitochondrial biogenesis through PGC-1\u03b1. J. Biol. Chem. 287, 44464\u201344470 (2012).","journal-title":"J. Biol. Chem."},{"key":"2429_CR27","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.mam.2018.09.002","volume":"65","author":"M Parola","year":"2019","unstructured":"Parola, M. & Pinzani, M. Liver fibrosis: pathophysiology, pathogenetic targets and clinical issues. Mol. Asp. Med. 65, 37\u201355 (2019).","journal-title":"Mol. Asp. Med."},{"key":"2429_CR28","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1007\/s00204-015-1525-6","volume":"89","author":"R Chen","year":"2015","unstructured":"Chen, R., Wu, H. & Wang, Y. Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch. Toxicol. 89, 1727\u20131750 (2015).","journal-title":"Arch. Toxicol."},{"key":"2429_CR29","doi-asserted-by":"publisher","first-page":"E3297","DOI":"10.1073\/pnas.1400062111","volume":"111","author":"K Iwaisako","year":"2014","unstructured":"Iwaisako, K. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl Acad. Sci. USA 111, E3297\u2013E3305 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2429_CR30","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.jaut.2018.05.001","volume":"91","author":"E Hintermann","year":"2018","unstructured":"Hintermann, E. et al. Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice. J. Autoimmun. 91, 83\u201396 (2018).","journal-title":"J. Autoimmun."},{"key":"2429_CR31","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1111\/liv.12577","volume":"35","author":"C Cicchini","year":"2015","unstructured":"Cicchini, C. et al. Molecular mechanisms controlling the phenotype and the EMT\/MET dynamics of hepatocyte. Liver Int. 35, 302\u2013310 (2015).","journal-title":"Liver Int."},{"key":"2429_CR32","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.omtn.2017.06.022","volume":"8","author":"JY Kim","year":"2017","unstructured":"Kim, J. Y. et al. Anti-fibrotic effects of synthetic oligodeoxynucleotide for TGF-\u03b21 and Smad in an animal model of liver cirrhosis. Mol. Ther. Nucleic Acids 8, 250\u2013263 (2017).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"2429_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/s40635-018-0197-y","volume":"6","author":"P Eyenga","year":"2018","unstructured":"Eyenga, P. et al. Time course of liver mitochondrial function and intrinsic changes in oxidative phosphorylation in a rat model of sepsis. Intensive Care Med. Exp. 6, 31 (2018).","journal-title":"Intensive Care Med. Exp."},{"key":"2429_CR34","doi-asserted-by":"publisher","first-page":"R453","DOI":"10.1016\/j.cub.2014.03.034","volume":"24","author":"M Schieber","year":"2014","unstructured":"Schieber, M. & Chandel, N. S. ROS function in redox signaling and oxidative stress. Curr. Biol. 24, R453\u2013R462 (2014).","journal-title":"Curr. Biol."},{"key":"2429_CR35","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9547613","author":"M Masarone","year":"2018","unstructured":"Masarone, M. et al. Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxid. Med. Cell Longev. https:\/\/doi.org\/10.1155\/2018\/9547613 (2018).","journal-title":"Oxid. Med. Cell Longev."},{"key":"2429_CR36","doi-asserted-by":"publisher","unstructured":"Das, N. et al. Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. J. Pineal Res. 62, https:\/\/doi.org\/10.1111\/jpi.12404 (2017).","DOI":"10.1111\/jpi.12404"},{"key":"2429_CR37","first-page":"127","volume":"62","author":"H Otera","year":"2016","unstructured":"Otera, H., Ishihara, N. & Mihara, K. New insights into the function and regulation of mitochondrial fission. Biochim. Biophys. Acta 62, 127\u2013137 (2016).","journal-title":"Biochim. Biophys. Acta"},{"key":"2429_CR38","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1111\/jpi.12310","volume":"60","author":"S Xu","year":"2016","unstructured":"Xu, S. et al. Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria. J. Pineal Res. 60, 291\u2013302 (2016).","journal-title":"J. Pineal Res."},{"key":"2429_CR39","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/s12192-017-0841-6","volume":"23","author":"J Cui","year":"2018","unstructured":"Cui, J. et al. Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca2+-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK\/SERCA2a pathway. Cell Stress Chaperones. 23, 281\u2013293 (2018).","journal-title":"Cell Stress Chaperones."},{"key":"2429_CR40","doi-asserted-by":"publisher","first-page":"34074","DOI":"10.1074\/jbc.M114.588616","volume":"289","author":"Z Yu","year":"2014","unstructured":"Yu, Z. et al. Decreasing mitochondrial fission prevents cholestatic liver injury. J. Biol. Chem. 289, 34074\u201334088 (2014).","journal-title":"J. Biol. Chem."},{"key":"2429_CR41","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.tem.2012.06.006","volume":"23","author":"RC Scarpulla","year":"2012","unstructured":"Scarpulla, R. C., Vega, R. B. & Kelly, D. P. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459\u2013466 (2012).","journal-title":"Trends Endocrinol. Metab."},{"key":"2429_CR42","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1172\/JCI27794","volume":"116","author":"BN Finck","year":"2006","unstructured":"Finck, B. N. & Kelly, D. P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615\u2013622 (2006).","journal-title":"J. Clin. Invest."},{"key":"2429_CR43","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1111\/jpi.12319","volume":"60","author":"J Kang","year":"2016","unstructured":"Kang, J., Hong, J. & Lee, S. M. Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis. J. Pineal Res. 60, 383\u2013393 (2016).","journal-title":"J. Pineal Res."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2429-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2429-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2429-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T14:53:51Z","timestamp":1670252031000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2429-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,8]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["2429"],"URL":"https:\/\/doi.org\/10.1038\/s41419-020-2429-9","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,8]]},"assertion":[{"value":"11 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 March 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 April 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"226"}}