PINK 1 phosphorylates Drp1 S616 to regulate mitophagy‐independent mitochondrial dynamics
- 2 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Reports
- Vol. 21 (8), e48686
- https://doi.org/10.15252/embr.201948686
Abstract
Impairment of PINK1/parkin-mediated mitophagy is currently proposed to be the molecular basis of mitochondrial abnormality in Parkinson's disease (PD). We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. Drp1(S616) phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK1, but unaffected by parkin inactivation. PINK1-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 PINK1 deficiency-associated phenotypes in Drosophila. Moreover, Drp1 restores PINK1-dependent mitochondrial fission in ATG5-null cells and ATG7-null Drosophila. Reduced Drp1(S616) phosphorylation is detected in fibroblasts derived from 4 PD patients harboring PINK1 mutations and in 4 out of 7 sporadic PD cases. Taken together, we have identified Drp1 as a substrate of PINK1 and a novel mechanism how PINK1 regulates mitochondrial fission independent of parkin and autophagy. Our results further link impaired PINK1-mediated Drp1(S616) phosphorylation with the pathogenesis of both familial and sporadic PD.Keywords
Funding Information
- National Natural Science Foundation of China (31730036, 81861138012, 81161120498, 81429002, 31330031)
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