Mitochondrial Stasis Reveals p62-Mediated Ubiquitination in Parkin-Independent Mitophagy and Mitigates Nonalcoholic Fatty Liver Disease

Tatsuya Yamada, Daisuke Murata, Yoshihiro Adachi, Kie Itoh, Shoichiro Kameoka, Atsushi Igarashi, Takashi Kato, Yoichi Araki, Richard L. Huganir, Ted M. Dawson, Toru Yanagawa, Koji Okamoto, Miho Iijima, Hiromi Sesaki

Research output: Contribution to journalArticle

Abstract

It is unknown what occurs if both mitochondrial division and fusion are completely blocked. Here, we introduced mitochondrial stasis by deleting two dynamin-related GTPases for division (Drp1) and fusion (Opa1) in livers. Mitochondrial stasis rescues liver damage and hypotrophy caused by the single knockout (KO). At the cellular level, mitochondrial stasis re-establishes mitochondrial size and rescues mitophagy defects caused by division deficiency. Using Drp1KO livers, we found that the autophagy adaptor protein p62/sequestosome-1—which is thought to function downstream of ubiquitination—promotes mitochondrial ubiquitination. p62 recruits two subunits of a cullin-RING ubiquitin E3 ligase complex, Keap1 and Rbx1, to mitochondria. Resembling Drp1KO, diet-induced nonalcoholic fatty livers enlarge mitochondria and accumulate mitophagy intermediates. Resembling Drp1Opa1KO, Opa1KO rescues liver damage in this disease model. Our data provide a new concept that mitochondrial stasis leads the spatial dimension of mitochondria to a stationary equilibrium and a new mechanism for mitochondrial ubiquitination in mitophagy. Yamada et al. show that mitochondrial size is antagonistically regulated by division and fusion and that extreme mitochondrial size is deleterious in the liver. They identify a new parkin-independent mitophagy pathway, which is inhibited by megamitochondria present in nonalcoholic liver hepatocytes. Restoring mitophagy could be beneficial in NAFLD.

Original languageEnglish (US)
Pages (from-to)588-604.e5
JournalCell Metabolism
Volume28
Issue number4
DOIs
StatePublished - Oct 2 2018

Keywords

  • Drp1
  • Opa1
  • dynamin-related GTPase
  • fatty liver
  • mitochondria
  • mitochondrial division
  • mitochondrial fission
  • mitochondrial fusion
  • mitophagy
  • nonalcoholic steatohepatitis

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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