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PINK1 and Parkin regulate IP3R-mediated ER calcium release

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  • Su Jin Ham

    (Seoul National University
    Seoul National University
    Seoul National University)

  • Heesuk Yoo

    (Seoul National University
    Seoul National University
    Seoul National University)

  • Daihn Woo

    (Seoul National University)

  • Da Hyun Lee

    (Seoul National University
    Seoul National University)

  • Kyu-Sang Park

    (Yonsei University Wonju College of Medicine
    Yonsei University Wonju College of Medicine)

  • Jongkyeong Chung

    (Seoul National University
    Seoul National University
    Seoul National University)

Abstract

Although defects in intracellular calcium homeostasis are known to play a role in the pathogenesis of Parkinson’s disease (PD), the underlying molecular mechanisms remain unclear. Here, we show that loss of PTEN-induced kinase 1 (PINK1) and Parkin leads to dysregulation of inositol 1,4,5-trisphosphate receptor (IP3R) activity, robustly increasing ER calcium release. In addition, we identify that CDGSH iron sulfur domain 1 (CISD1, also known as mitoNEET) functions downstream of Parkin to directly control IP3R. Both genetic and pharmacologic suppression of CISD1 and its Drosophila homolog CISD (also known as Dosmit) restore the increased ER calcium release in PINK1 and Parkin null mammalian cells and flies, respectively, demonstrating the evolutionarily conserved regulatory mechanism of intracellular calcium homeostasis by the PINK1-Parkin pathway. More importantly, suppression of CISD in PINK1 and Parkin null flies rescues PD-related phenotypes including defective locomotor activity and dopaminergic neuronal degeneration. Based on these data, we propose that the regulation of ER calcium release by PINK1 and Parkin through CISD1 and IP3R is a feasible target for treating PD pathogenesis.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40929-z
    DOI: 10.1038/s41467-023-40929-z
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