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.
PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress / E. Huang, D. Qu, T. Huang, N. Rizzi, W. Boonying, D. Krolak, P. Ciana, J. Woulfe, C. Klein, R.S. Slack, D. Figeys, D.S. Park. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8:1(2017 Nov 09), pp. 1399.1-1399.11.
|Titolo:||PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress|
|Parole Chiave:||Wolf-hirschhorn-syndrome; cyclin-dependent kinase-5; Parkinsons-disease; CA2+/H+ antiporter; oxidative stress; mouse model; cell-death; in-vivo; pink1; MPTP|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||9-nov-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/s41467-017-01435-1|
|Appare nelle tipologie:||01 - Articolo su periodico|