Open AccessPINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress
Author(s) -
Emma Huang,
Dianbo Qu,
Tianwen Huang,
Nicoletta Rizzi,
Wassamon Boonying,
Dorothy Krolak,
Paolo Ciana,
John Woulfe,
Christine Klein,
Ruth S. Slack,
Daniel Figeys,
David Park
Publication year - 2017
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-017-01435-1
Subject(s) - pink1 , mitochondrion , microbiology and biotechnology , phosphorylation , calcium , kinase , biology , chemistry , biochemistry , mitophagy , apoptosis , autophagy , organic chemistry
Mutations in PTEN-induced kinase 1 (PINK1) result in a recessive familial form of Parkinson’s disease (PD). PINK1 loss is associated with mitochondrial Ca 2+ 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 Ca 2+ level through LETM1 and suggest a model by which PINK1 loss leads to deficient phosphorylation of LETM1 and impaired mitochondrial Ca 2+ transport..