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

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.

• Authors: Yusuke Kageyama, Masahiko Hoshijima, Kinya Seo, Djahida Bedja, Polina Sysa-Shah, Shaida A Andrabi, Weiran Chen, Ahmet Höke, Valina L Dawson, Ted M Dawson, Kathleen Gabrielson, David A Kass, Miho Iijima, Hiromi Sesaki
• Journal: The EMBO journal (EMBO J) Vol. 33 Issue 23 Pg. 2798-813 (Dec 01 2014) ISSN: 1460-2075 [Electronic] England
• PMID: 25349190 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors.

Chemical References

• Myh6 protein, mouse
• Ubiquitin-Protein Ligases
• parkin protein
• Myosin Heavy Chains
• Dnm1l protein, mouse
• Dynamins

Topics

• Animals
• Brain (metabolism)
• Dynamins (genetics, metabolism)
• Electron Microscope Tomography
• Mice
• Mice, Knockout
• Microscopy, Fluorescence
• Mitochondria (metabolism)
• Mitophagy (physiology)
• Myocytes, Cardiac (metabolism)
• Myosin Heavy Chains (genetics)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination