PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria

Dysfunction of PINK1, a mitochondrial Ser/Thr kinase, causes familial Parkinson's disease (PD). Recent studies have revealed that PINK1 is rapidly degraded in healthy mitochondria but accumulates on the membrane potential (ΔΨm)-deficient mitochondria, where it recruits another familial PD gene product, Parkin, to ubiquitylate the damaged mitochondria. Despite extensive study, the mechanism underlying the homeostatic control of PINK1 remains unknown. Here we report that PINK1 is autophosphorylated following a decrease in ΔΨm and that most disease-relevant mutations hinder this event. Mass spectrometric and mutational analyses demonstrate that PINK1 autophosphorylation occurs at Ser228 and Ser402, residues that…

• TS
  Takeda Science Foundation

  Award: 21000012
• MO
  Ministry of Education, Culture, Sports, Science and Technology

  Award: 24111557
• JS
  Japan Society for the Promotion of Science

  Awards: 21000012, 23687018