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

Tatsuya Yamada; Daisuke Murata; David E Kleiner; Robert Anders; Avi Z Rosenberg; Jeffrey Kaplan; James P Hamilton; Mariam Aghajan; Moshe Levi; Nae-Yuh Wang; Ted M Dawson; Toru Yanagawa; Andrew F Powers; Miho Iijima; Hiromi Sesaki

doi:10.1016/j.isci.2022.103996

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

iScience. 2022 Feb 26;25(4):103996. doi: 10.1016/j.isci.2022.103996. eCollection 2022 Apr 15.

Authors

Tatsuya Yamada¹, Daisuke Murata¹, David E Kleiner², Robert Anders³, Avi Z Rosenberg³, Jeffrey Kaplan⁴, James P Hamilton⁵, Mariam Aghajan⁶, Moshe Levi⁷, Nae-Yuh Wang^{5

8}, Ted M Dawson^{9

10}, Toru Yanagawa¹¹, Andrew F Powers⁶, Miho Iijima¹, Hiromi Sesaki¹

Affiliations

¹ Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
⁵ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Ionis Pharmaceuticals, Carlsbad, CA, USA.
⁷ Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA.
⁸ Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
⁹ Departments of Neurology and Neuroscience and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

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.

Abstract

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