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.

Original languageEnglish (US)
JournalCell Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Mitochondrial Degradation
Ubiquitination
Liver
Mitochondria
Cullin Proteins
Mitochondrial Dynamics
Mitochondrial Size
Dynamins
Ubiquitin-Protein Ligases
Liver Mitochondrion
GTP Phosphohydrolases
Autophagy
Diet
Non-alcoholic Fatty Liver Disease
Proteins

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Mitochondrial Stasis Reveals p62-Mediated Ubiquitination in Parkin-Independent Mitophagy and Mitigates Nonalcoholic Fatty Liver Disease. / Yamada, Tatsuya; Murata, Daisuke; Adachi, Yoshihiro; Itoh, Kie; Kameoka, Shoichiro; Igarashi, Atsushi; Kato, Takashi; Araki, Yoichi; Huganir, Richard L; Dawson, Ted M; Yanagawa, Toru; Okamoto, Koji; Iijima, Miho; Sesaki, Hiromi.

In: Cell Metabolism, 01.01.2018.

Research output: Contribution to journalArticle

Yamada, Tatsuya ; Murata, Daisuke ; Adachi, Yoshihiro ; Itoh, Kie ; Kameoka, Shoichiro ; Igarashi, Atsushi ; Kato, Takashi ; Araki, Yoichi ; Huganir, Richard L ; Dawson, Ted M ; Yanagawa, Toru ; Okamoto, Koji ; Iijima, Miho ; Sesaki, Hiromi. / Mitochondrial Stasis Reveals p62-Mediated Ubiquitination in Parkin-Independent Mitophagy and Mitigates Nonalcoholic Fatty Liver Disease. In: Cell Metabolism. 2018.
@article{0a4a6f688702475e898af5a2721aba1d,
title = "Mitochondrial Stasis Reveals p62-Mediated Ubiquitination in Parkin-Independent Mitophagy and Mitigates Nonalcoholic Fatty Liver Disease",
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.",
keywords = "Drp1, dynamin-related GTPase, fatty liver, mitochondria, mitochondrial division, mitochondrial fission, mitochondrial fusion, mitophagy, nonalcoholic steatohepatitis, Opa1",
author = "Tatsuya Yamada and Daisuke Murata and Yoshihiro Adachi and Kie Itoh and Shoichiro Kameoka and Atsushi Igarashi and Takashi Kato and Yoichi Araki and Huganir, {Richard L} and Dawson, {Ted M} and Toru Yanagawa and Koji Okamoto and Miho Iijima and Hiromi Sesaki",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.cmet.2018.06.014",
language = "English (US)",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",

}

TY - JOUR

T1 - Mitochondrial Stasis Reveals p62-Mediated Ubiquitination in Parkin-Independent Mitophagy and Mitigates Nonalcoholic Fatty Liver Disease

AU - Yamada, Tatsuya

AU - Murata, Daisuke

AU - Adachi, Yoshihiro

AU - Itoh, Kie

AU - Kameoka, Shoichiro

AU - Igarashi, Atsushi

AU - Kato, Takashi

AU - Araki, Yoichi

AU - Huganir, Richard L

AU - Dawson, Ted M

AU - Yanagawa, Toru

AU - Okamoto, Koji

AU - Iijima, Miho

AU - Sesaki, Hiromi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Drp1

KW - dynamin-related GTPase

KW - fatty liver

KW - mitochondria

KW - mitochondrial division

KW - mitochondrial fission

KW - mitochondrial fusion

KW - mitophagy

KW - nonalcoholic steatohepatitis

KW - Opa1

UR - http://www.scopus.com/inward/record.url?scp=85049309449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049309449&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2018.06.014

DO - 10.1016/j.cmet.2018.06.014

M3 - Article

C2 - 30017357

AN - SCOPUS:85049309449

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

ER -