BIROn - Birkbeck Institutional Research Online

    PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death

    Gandhi, S. and Wood-Kaczmar, A. and Yao, Z. and Plun-Favreau, H. and Deas, E. and Klupsch, K. and Downward, J. and Latchman, David S. and Tabrizi, S.J. and Wood, N.W. and Duchen, M.R. and Abramov, A.Y. (2009) PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death. Molecular Cell 33 (5), pp. 627-638. ISSN 1097-2765.

    3898.pdf - Published Version of Record
    Available under License Creative Commons Attribution.

    Download (1MB) | Preview


    Mutations in PINK1 cause autosomal recessive Parkinson's disease. PINK1 is a mitochondrial kinase of unknown function. We investigated calcium homeostasis and mitochondrial function in PINK1-deficient mammalian neurons. We demonstrate physiologically that PINK1 regulates calcium efflux from the mitochondria via the mitochondrial Na+/Ca2+ exchanger. PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload. We show that calcium overload stimulates reactive oxygen species (ROS) production via NADPH oxidase. ROS production inhibits the glucose transporter, reducing substrate delivery and causing impaired respiration. We demonstrate that impaired respiration may be restored by provision of mitochondrial complex I and II substrates. Taken together, reduced mitochondrial calcium capacity and increased ROS lower the threshold of opening of the mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells. Our findings propose a mechanism by which PINK1 dysfunction renders neurons vulnerable to cell death.


    Item Type: Article
    Keyword(s) / Subject(s): cellbio, cellcycle
    School: Birkbeck Professional Services > Vice-Chancellor's Office
    Depositing User: Administrator
    Date Deposited: 28 Jul 2011 09:48
    Last Modified: 02 Aug 2023 16:55


    Activity Overview
    6 month trend
    6 month trend

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item