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
Affiliations
Tatsuya Yamada
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Daisuke Murata
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
David E. Kleiner
Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
Robert Anders
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Avi Z. Rosenberg
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jeffrey Kaplan
Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA
James P. Hamilton
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Mariam Aghajan
Ionis Pharmaceuticals, Carlsbad, CA, USA
Moshe Levi
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA
Nae-Yuh Wang
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
Ted M. Dawson
Departments of Neurology and Neuroscience and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Toru Yanagawa
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
Andrew F. Powers
Ionis Pharmaceuticals, Carlsbad, CA, USA
Miho Iijima
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author
Hiromi Sesaki
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author
Summary: 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.
