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EMBO J. 2014 Dec 1;33(23):2798-813. doi: 10.15252/embj.201488658. Epub 2014 Oct 27.

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

Author information

  • 1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2Center for Research in Biological Systems and Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 3Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 4Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering Johns Hopkins University School of Medicine, Baltimore, MD, USA Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
  • 6Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 7Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA hsesaki@jhmi.edu.

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.

© 2014 The Authors.

KEYWORDS:

mice; mitochondria; organelle division; respiration

PMID:
25349190
[PubMed - indexed for MEDLINE]
PMCID:
PMC4282557
Free PMC Article
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