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

Author

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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)

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..

Suggested Citation

  • En Huang & Dianbo Qu & Tianwen Huang & Nicoletta Rizzi & Wassamon Boonying & Dorothy Krolak & Paolo Ciana & John Woulfe & Christine Klein & Ruth S. Slack & Daniel Figeys & David S. Park, 2017. "PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01435-1
    DOI: 10.1038/s41467-017-01435-1
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    Cited by:

    1. Su Jin Ham & Heesuk Yoo & Daihn Woo & Da Hyun Lee & Kyu-Sang Park & Jongkyeong Chung, 2023. "PINK1 and Parkin regulate IP3R-mediated ER calcium release," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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