@article{6f1c6cd0395b4f1cb01da4e039a71a31,
title = "Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver",
abstract = "Non-alcoholic steatohepatitis (NASH) is a most common chronic liver disease that is manifested by steatosis, inflammation, fibrosis, and tissue damage. Hepatocytes produce giant mitochondria termed megamitochondria in patients with NASH. It has been shown that gene knockout of OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, prevents megamitochondria formation and liver damage in a NASH mouse model induced by a methionine-choline-deficient (MCD) diet. However, it is unknown whether blocking mitochondrial fusion mitigates NASH pathologies. Here, we acutely depleted OPA1 using antisense oligonucleotides in the NASH mouse model before or after megamitochondria formation. When OPA1 ASOs were applied at the disease onset, they effectively prevented megamitochondria formation and liver pathologies in the MCD model. Notably, even when applied after mice robustly developed NASH pathologies, OPA1 targeting effectively regressed megamitochondria and the disease phenotypes. Thus, our data show the efficacy of mitochondrial dynamics as a unique therapy for megamitochondria-associated liver disease.",
keywords = "Cell biology, Hepatology",
author = "Tatsuya Yamada and Daisuke Murata and Kleiner, {David E.} and Robert Anders and Rosenberg, {Avi Z.} and Jeffrey Kaplan and Hamilton, {James P.} and Mariam Aghajan and Moshe Levi and Wang, {Nae Yuh} and Dawson, {Ted M.} and Toru Yanagawa and Powers, {Andrew F.} and Miho Iijima and Hiromi Sesaki",
note = "Funding Information: We thank past and present members of the Iijima and Sesaki labs for helpful discussions and technical assistance. We are grateful to Dr. Alexander M. van der Bliek for the anti-MFF antibody. This work was supported by grants from NIH to MI ( GM131768) and HS (GM130695 and GM144103 ), the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation to HS (Medical Research Grant), and the Hopkins Conte Digestive Diseases Basic and Translational Research Core Center to T. Yamada (Pilot/Feasibility Project). Funding Information: We thank past and present members of the Iijima and Sesaki labs for helpful discussions and technical assistance. We are grateful to Dr. Alexander M. van der Bliek for the anti-MFF antibody. This work was supported by grants from NIH to MI (GM131768) and HS (GM130695 and GM144103), the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation to HS (Medical Research Grant), and the Hopkins Conte Digestive Diseases Basic and Translational Research Core Center to T. Yamada (Pilot/Feasibility Project). T. Yamada, MI, and HS conceived the project. T. Yamada, DM, and DEK performed the experiments. T. Yamada, DM, DEK, and RA analyzed the data. MA, AZR, JK, ML, TMD, T. Yanagawa, and AFP provided critical materials and reagents. T. Yamada, DM, DEK, MA, AZR, JK, JPH, ML, NYW, TMD, T. Yanagawa, AFP, MI, and HS contributed to discussions. T. Yamada, JK, MI, and HS wrote the manuscript. T. Yamada, DM, DEK, RA, AZR, JK, JPH, ML, NYW, TMD, T. Yanagawa, MI, and HS declare that they have no competing interests. AFP and MA are employees and shareholders of Ionis Pharmaceuticals. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
day = "15",
doi = "10.1016/j.isci.2022.103996",
language = "English (US)",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "4",
}