Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver

• Published in: iScience Vol. 25; no. 4; p. 103996
• Main Authors: Yamada, Tatsuya, Murata, Daisuke, Kleiner, David E., Anders, Robert, Rosenberg, Avi Z., Kaplan, Jeffrey, Hamilton, James P., Aghajan, Mariam, Levi, Moshe, Wang, Nae-Yuh, Dawson, Ted M., Yanagawa, Toru, Powers, Andrew F., Iijima, Miho, Sesaki, Hiromi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.04.2022; Elsevier
• Subjects: Cell biology; Hepatology; Cell biology; Hepatology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.103996

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. [Display omitted] •A NASH mouse model induced by the MCD diet produces megamitochondria in hepatocytes•Megamitochondria decrease mitophagy•Blocking mitochondrial fusion by targeting OPA1 mitigates NASH pathologies•Targeting OPA1 improves the SDH activity in the MCD model Hepatology; Cell biology