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Biochim Biophys Acta Mol Cell Res. 2017 Jul;1864(7):1308-1317. doi: 10.1016/j.bbamcr.2017.04.009. Epub 2017 Apr 19.

p62-Mediated mitochondrial clustering attenuates apoptosis induced by mitochondrial depolarization.

Author information

1
Department of Neurology, National Neuroscience Institute, Singapore; Department of Neurology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China.
2
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
3
Department of research, National Neuroscience Institute, Singapore.
4
Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore; Department of Physiology, National University of Singapore, Singapore; Duke-NUS Graduate Medical School, National University of Singapore, Singapore.
5
Department of Neurology, National Neuroscience Institute, Singapore; Department of Neurology, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, National University of Singapore, Singapore. Electronic address: tan.eng.king@sgh.com.sg.

Abstract

Parkin/PINK1-mediated mitophagy is implicated in the pathogenesis of Parkinson's disease (PD). Prior to elimination of damaged mitochondria, Parkin translocates to mitochondria and induces mitochondrial clustering. While the mechanism of PINK1-dependent Parkin redistribution to mitochondria is now becoming clear, the role of mitochondrial clustering has been less well understood. In our study, we found that loss of p62 disrupted mitochondrial aggregation and specifically sensitized Parkin-expressing cells to apoptosis induced by mitochondrial depolarization. Notably, altering mitochondrial aggregation through regulating p62 or other methods was sufficient to affect such apoptosis. Moreover, disruption of mitochondrial aggregation promoted proteasome-dependent degradation of outer mitochondrial membrane (OMM) proteins. The accelerated degradation in turn facilitated cytochrome c release from mitochondria, leading to apoptosis. Together, our study demonstrates a protective role of mitochondrial clustering in mitophagy and helps in understanding how aggregation defends cells against stress.

KEYWORDS:

Apoptosis; Mitochondrial clustering; Mitophagy; p62

PMID:
28433685
DOI:
10.1016/j.bbamcr.2017.04.009
[Indexed for MEDLINE]
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