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Citation
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, Z. (2020). PINK1 phosphorylates Drp1S616 to regulate mitophagy-independent mitochondrial dynamics.  EMBO Rep. 21(8): e48686.
FlyBase ID
FBrf0247465
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC7403662 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    EMBO Rep.
    Title
    EMBO Reports
    Publication Year
    2000-
    ISBN/ISSN
    1469-221X 1469-3178
    Data From Reference
    Alleles (7)
    Genes (4)
    Human Disease Models (1)
    Natural transposons (1)
    Experimental Tools (3)
    Transgenic Constructs (4)