Premium
PINK 1 phosphorylates Drp1 S616 to regulate mitophagy‐independent mitochondrial dynamics
Author(s) -
Han Hailong,
Tan Jieqiong,
Wang Ruoxi,
Wan Huida,
He Yaohui,
Yan Xinxiang,
Guo Jifeng,
Gao Qingtao,
Li Jie,
Shang Shuai,
Chen Fang,
Tian Runyi,
Liu Wen,
Liao Lujian,
Tang Beisha,
Zhang Zhuohua
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948686
Subject(s) - pink1 , mitophagy , parkin , mitochondrial fission , phosphorylation , microbiology and biotechnology , biology , mitochondrion , autophagy , genetics , parkinson's disease , apoptosis , medicine , disease , pathology
Impairment of PINK 1/parkin‐mediated mitophagy is currently proposed to be the molecular basis of mitochondrial abnormality in Parkinson's disease ( PD ). We here demonstrate that PINK 1 directly phosphorylates Drp1 on S616. Drp1 S616 phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK 1, but unaffected by parkin inactivation. PINK 1‐mediated mitochondrial fission is Drp1 S616 phosphorylation dependent. Overexpression of either wild‐type Drp1 or of the phosphomimetic mutant Drp1 S616D , but not a dephosphorylation‐mimic mutant Drp1 S616A , rescues PINK 1 deficiency‐associated phenotypes in Drosophila . Moreover, Drp1 restores PINK 1‐dependent mitochondrial fission in ATG 5‐null cells and ATG 7‐null Drosophila . Reduced Drp1 S616 phosphorylation is detected in fibroblasts derived from 4 PD patients harboring PINK 1 mutations and in 4 out of 7 sporadic PD cases. Taken together, we have identified Drp1 as a substrate of PINK 1 and a novel mechanism how PINK 1 regulates mitochondrial fission independent of parkin and autophagy. Our results further link impaired PINK 1‐mediated Drp1 S616 phosphorylation with the pathogenesis of both familial and sporadic PD .