PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress

Nat Commun. 2017 Nov 9;8(1):1399. doi: 10.1038/s41467-017-01435-1.


Mutations in PTEN-induced kinase 1 (PINK1) result in a recessive familial form of Parkinson's disease (PD). PINK1 loss is associated with mitochondrial Ca2+ mishandling, mitochondrial dysfunction, as well as increased neuronal vulnerability. Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro. Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. Expression of LETM1-T192E but not LETM1-wild type (WT) rescues mitochondrial calcium mishandling in PINK1-deficient neurons. Expression of both LETM1-WT and LETM1-T192E protects neurons against MPP+-MPTP-induced neuronal death in PINK1 WT neurons, whereas only LETM1-T192E protects neurons under conditions of PINK1 loss. Our findings delineate a mechanism by which PINK1 regulates mitochondrial Ca2+ level through LETM1 and suggest a model by which PINK1 loss leads to deficient phosphorylation of LETM1 and impaired mitochondrial Ca2+ transport..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium-Binding Proteins / metabolism*
  • Cation Transport Proteins / metabolism*
  • Cells, Cultured
  • Ion Transport / physiology
  • Liposomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Neurons / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology*
  • Phosphorylation
  • Protein Kinases / genetics*


  • Calcium-Binding Proteins
  • Cation Transport Proteins
  • LETM1 protein, mouse
  • Liposomes
  • Protein Kinases
  • PTEN-induced putative kinase
  • Calcium

Grant support