2. Academic Validation
  3. PINK1 phosphorylates Drp1S616 to regulate mitophagy-independent mitochondrial dynamics

PINK1 phosphorylates Drp1S616 to regulate mitophagy-independent mitochondrial dynamics

  • EMBO Rep. 2020 Aug 5;21(8):e48686. doi: 10.15252/embr.201948686.
Hailong Han 1 2,  Jieqiong Tan 1 2,  Ruoxi Wang 1 2,  Huida Wan 3,  Yaohui He 4,  Xinxiang Yan 2,  Jifeng Guo 2,  Qingtao Gao 1 2,  Jie Li 1 2,  Shuai Shang 1 2,  Fang Chen 1 2,  Runyi Tian 1 2,  Wen Liu 4,  Lujian Liao 3,  Beisha Tang 2,  Zhuohua Zhang 1 2 5
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Precision Medicine of Hunan Province and Center for Medical Genetics, Institute of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, China.
  • 2 Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
  • 4 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
  • 5 Department of Neurosciences, University of South China Medical School, Hengyang, China.
PMID: 32484300 DOI: 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. 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.

Keywords

Parkinson’s disease; autophagy; human dermal fibroblasts; mitochondrial dynamics; parkin.

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