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

By S. Gandhi, A. Wood‐Kaczmar, Zhi Yao, H. Plun-Favreau, E. Deas, Kristina Klupsch, Julian Downward, D. Latchman, Sarah J. Tabrizi, N. Wood and 2 more. Molecules and Cells, 2009

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Summary 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.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/299409407bcdb10a40e27529c8dd77e46c039a4f

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Citations in the corpus

Neuronal calcium signaling: function and dysfunction (2014, background): “However, even if a disturbance in mitochondrial Ca2+ handling is involved, it is still not known whether it is due to the altered activity of the mitochondrial Ca2+ uniporter [219], of the mitochondrial Na/Ca2+ exchanger [220], or of the mPTP [221].”
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “PINK1 can increase the resistance to diverse cellular stressors in a kinase-dependent manner (Petit et al , 2005; Haque et al , 2008; Wood-Kaczmar et al , 2008; Gandhi et al , 2009; Morais et al , 2009; Sandebring et al , 2009; Klinkenberg et al , 2010; Murata et al , 2011; Wang et al , 2011b).”
NCLX is an essential component of mitochondrial Na+/Ca2+ exchange (2009, background): “Finally, the profound change in mitochondrial Ca exchange activity observed for example in a neuronal Parkinson model (34) underscores the pathophysiological relevance of NCLX regulation.”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, neutral): “death (Akundi et al., 2011; Gandhi et al., 2009; Heeman et al., 2011; Marongiu et al., 2009).”
Mechanism of Oxidative Stress in Neurodegeneration (2012, background): “Mutations in α-synuclein gene cause a familial form of autosomal dominant PD. Expression of mutant α-synuclein in mouse models or neurons results in mitochondrial dysfunction and increased ROS production [33, 34].”
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin (2010, background): “Although some of these abnormalities may be a reversible consequence of others—for instance, mitochondrial fragmentation may be due to low membrane potential [34], and ETC dysfunction and decreased membrane potential may be, in part, a functional consequence of calcium dysregulation [51]—other abnor”
Role of Oxidative Stress in Parkinson's Disease (2013, background): “Mutations in PINK1 induce mitochondrial dysfunction including excess free radical formation [30].”
Metals, oxidative stress and neurodegenerative disorders (2010, neutral): “substrate delivery and respiration [116].”
Role of mitochondrial ROS in the brain: from physiology to neurodegeneration (2018, background): “Excessive ROS production in mitochondrial of PINK1 knockout neurons can be an inductor of inhibition of mitochondrial Na 2+ /Ca 2+ exchanger or glucose transporter and can be rescued by antioxidants [57]; [61]; [62] (Figure 1).”
The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “Mitochondria isolated from the striatum or whole brain of aged PINK1-KO mice display defects in complex I (Gautier et al., 2008; Morais et al., 2009), and mitochondria derived from the brains of PINK1-KO mice have reduced calcium-buffering capacity (Akundi et al., 2011).”