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. Drp1S616 phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK1, but unaffected by parkin inactivation. PINK1-mediated mitochondrial fission is Drp1S616 phosphorylation dependent. Overexpression of either wild-type Drp1 or of the phosphomimetic mutant Drp1S616D , but not a dephosphorylation-mimic mutant Drp1S616A , rescues PINK1 deficiency-associated phenotypes in Drosophila. Moreover, Drp1 restores PINK1-dependent mitochondrial fission in ATG5-null cells and ATG7-null Drosophila. Reduced Drp1S616 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 Drp1S616 phosphorylation with the pathogenesis of both familial and sporadic PD.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
Han H,Tan J,Wang R,Wan H,He Y,Yan X,Guo J,Gao Q,Li J,Shang S,Chen F,Tian R,Liu W,Liao L,Tang B,Zhang Zdoi
10.15252/embr.201948686subject
Has Abstractpub_date
2020-08-05 00:00:00pages
e48686issue
8eissn
1469-221Xissn
1469-3178journal_volume
21pub_type
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