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

En Huang, Dianbo Qu, Tianwen Huang, Nicoletta Rizzi, Wassamon Boonying, Dorothy Krolak, Paolo Ciana, John Woulfe, Christine Klein, Ruth S. Slack, Daniel Figeys and David S. Park ()
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En Huang: University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa
Dianbo Qu: University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa
Tianwen Huang: University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa
Nicoletta Rizzi: University of Milan
Wassamon Boonying: University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa
Dorothy Krolak: University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa
Paolo Ciana: University of Milan
John Woulfe: University of Ottawa
Christine Klein: University of Lübeck
Ruth S. Slack: University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa
Daniel Figeys: University of Ottawa
David S. Park: University of Ottawa Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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..

Date: 2017
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DOI: 10.1038/s41467-017-01435-1

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