Parkin‐independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain
- 27 October 2014
- journal article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 33 (23), 2798-2813
- https://doi.org/10.15252/embj.201488658
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. ![][1] 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. [1]: pending:yesKeywords
Funding Information
- NIH (GM084015, GM089853, NS084154, HL107153, HL59480, HL077180, NS38377)
- AHA (0840013N, 12GRANT1173006)
This publication has 40 references indexed in Scilit:
- Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell?Frontiers in Physiology, 2013
- Mitochondrial division: molecular machinery and physiological functionsCurrent Opinion in Cell Biology, 2011
- SnapShot: Mitochondrial DynamicsCell, 2011
- Parkin Ubiquitinates Drp1 for Proteasome-dependent DegradationJournal of Biological Chemistry, 2011
- PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson's DiseaseCell, 2011
- Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by ParkinThe Journal of cell biology, 2010
- Genetic Animal Models of Parkinson's DiseaseNeuron, 2010
- Parkin is recruited selectively to impaired mitochondria and promotes their autophagyThe Journal of cell biology, 2008
- Fission and selective fusion govern mitochondrial segregation and elimination by autophagyThe EMBO Journal, 2008
- Computer Visualization of Three-Dimensional Image Data Using IMODJournal of Structural Biology, 1996