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The principal PINK1 and Parkin cellular events triggered in response to dissipation of mitochondrial membrane potential occur in primary neurons
Author(s) -
Koyano Fumika,
Okatsu Kei,
Ishigaki Shinsuke,
Fujioka Yusuke,
Kimura Mayumi,
Sobue Gen,
Tanaka Keiji,
Matsuda Noriyuki
Publication year - 2013
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12066
Subject(s) - pink1 , biology , parkin , mitochondrion , membrane potential , microbiology and biotechnology , mitophagy , neuroscience , genetics , apoptosis , autophagy , parkinson's disease , medicine , disease , pathology
PINK1 and PARKIN are causal genes for hereditary Parkinsonism. Recent studies have shown that PINK1 and Parkin play a pivotal role in the quality control of mitochondria, and dysfunction of either protein likely results in the accumulation of low‐quality mitochondria that triggers early‐onset familial Parkinsonism. As neurons are destined to degenerate in PINK1 /Parkin‐associated Parkinsonism, it is imperative to investigate the function of PINK1 and Parkin in neurons. However, most studies investigating PINK1 /Parkin have used non‐neuronal cell lines. Here we show that the principal PINK1 and Parkin cellular events that have been documented in non‐neuronal lines in response to mitochondrial damage also occur in primary neurons. We found that dissipation of the mitochondrial membrane potential triggers phosphorylation of both PINK1 and Parkin and that, in response, Parkin translocates to depolarized mitochondria. Furthermore, Parkin's E3 activity is re‐established concomitant with ubiquitin–ester formation at Cys431 of Parkin. As a result, mitochondrial substrates in neurons become ubiquitylated. These results underscore the relevance of the PINK1 /Parkin‐mediated mitochondrial quality control pathway in primary neurons and shed further light on the underlying mechanisms of the PINK1 and Parkin pathogenic mutations that predispose Parkinsonism in vivo .