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

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

Author information

1
University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada, K1H 8M5.
2
Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133, Milan, Italy.
3
Center of Excellence on Neurodegenerative Diseases, Department of Oncology and Hemato-Oncology, University of Milan, Via Balzaretti 9, 20133, Milan, Italy.
4
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada, K1H 8M5.
5
Institute of Neurogenetics, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
6
Department of Biochemistry, Microbiology and Immunology, Department of Chemistry and Biomolecular Sciences, and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada, K1H 8M5.
7
University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada, K1H 8M5. dpark@uottawa.ca.

Abstract

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..

PMID:
29123128
PMCID:
PMC5680261
DOI:
10.1038/s41467-017-01435-1
[Indexed for MEDLINE]
Free PMC Article

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