Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain

Yusuke Kageyama, Masahiko Hoshijima, Kinya Seo, Djahida Bedja, Polina Sysa-Shah, Shaida A. Andrabi, Weiran Chen, Ahmet Hoke, Valina Dawson, Ted M Dawson, Kathleen L Gabrielson, David A Kass, Miho Iijima, Hiromi Sesaki

Research output: Contribution to journalArticle

Abstract

Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's disease-associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals. Synopsis In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease-associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain. Mitochondria divide in cardiomyocytes. Drp1 deficiency causes mitochondrial dysfunction, lethal heart failure and neurodegeneration due to defects in mitophagy. Mitochondria enlarge and accumulate ubiquitinated outer membrane proteins and mitophagy adaptor protein p62 independently of parkin. Parkin is dispensable for mitochondrial respiration, heart function and neuronal survival in the presence of Drp1-regulated mitophagy. Simultaneous loss of Drp1 and parkin increases mitophagy defects. In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease-associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.

Original languageEnglish (US)
Pages (from-to)2798-2813
Number of pages16
JournalThe EMBO journal
Volume33
Issue number23
DOIs
StatePublished - Dec 1 2014

Fingerprint

Mitochondrial Degradation
Mitochondria
Brain
Ubiquitination
Mitochondrial Dynamics
Mitochondrial Proteins
Parkinson Disease
Heart Mitochondria
Defects
Ligases
Cardiac Myocytes
Degradation
Respiration
Homeostasis
Ubiquitinated Proteins
Dynamins
Neurodegenerative diseases
Ubiquitin-Protein Ligases
Proteins
Mammals

Keywords

  • mice
  • mitochondria
  • organelle division
  • respiration

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. / Kageyama, Yusuke; Hoshijima, Masahiko; Seo, Kinya; Bedja, Djahida; Sysa-Shah, Polina; Andrabi, Shaida A.; Chen, Weiran; Hoke, Ahmet; Dawson, Valina; Dawson, Ted M; Gabrielson, Kathleen L; Kass, David A; Iijima, Miho; Sesaki, Hiromi.

In: The EMBO journal, Vol. 33, No. 23, 01.12.2014, p. 2798-2813.

Research output: Contribution to journalArticle

Kageyama Y, Hoshijima M, Seo K, Bedja D, Sysa-Shah P, Andrabi SA et al. Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. The EMBO journal. 2014 Dec 1;33(23):2798-2813. https://doi.org/10.15252/embj.201488658
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abstract = "Mitochondrial dynamics and mitophagy have been linked to cardiovascular and neurodegenerative diseases. Here, we demonstrate that the mitochondrial division dynamin Drp1 and the Parkinson's disease-associated E3 ubiquitin ligase parkin synergistically maintain the integrity of mitochondrial structure and function in mouse heart and brain. Mice lacking cardiac Drp1 exhibited lethal heart defects. In Drp1KO cardiomyocytes, mitochondria increased their connectivity, accumulated ubiquitinated proteins, and decreased their respiration. In contrast to the current views of the role of parkin in ubiquitination of mitochondrial proteins, mitochondrial ubiquitination was independent of parkin in Drp1KO hearts, and simultaneous loss of Drp1 and parkin worsened cardiac defects. Drp1 and parkin also play synergistic roles in neuronal mitochondrial homeostasis and survival. Mitochondrial degradation was further decreased by combination of Drp1 and parkin deficiency, compared with their single loss. Thus, the physiological importance of parkin in mitochondrial homeostasis is revealed in the absence of mitochondrial division in mammals. Synopsis In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease-associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain. Mitochondria divide in cardiomyocytes. Drp1 deficiency causes mitochondrial dysfunction, lethal heart failure and neurodegeneration due to defects in mitophagy. Mitochondria enlarge and accumulate ubiquitinated outer membrane proteins and mitophagy adaptor protein p62 independently of parkin. Parkin is dispensable for mitochondrial respiration, heart function and neuronal survival in the presence of Drp1-regulated mitophagy. Simultaneous loss of Drp1 and parkin increases mitophagy defects. In vivo analysis reveals a synergistic role of mitochondrial fission protein Drp1 and Parkinson's disease-associated ligase parkin in the regulation of ubiquitination and degradation of mitochondria in the heart and brain.",
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AU - Sysa-Shah, Polina

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AU - Chen, Weiran

AU - Hoke, Ahmet

AU - Dawson, Valina

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