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

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...

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Bibliographic Details
Published in:Molecular cell 2009-03, Vol.33 (5), p.627-638
Main Authors: Gandhi, Sonia, Wood-Kaczmar, Alison, Yao, Zhi, Plun-Favreau, Helene, Deas, Emma, Klupsch, Kristina, Downward, Julian, Latchman, David S., Tabrizi, Sarah J., Wood, Nicholas W., Duchen, Michael R., Abramov, Andrey Y.
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Apoptosis - radiation effects
Calcium - metabolism
Cell Line, Tumor
CELLBIO
CELLCYCLE
Cells, Cultured
Cytosol - metabolism
Energy Metabolism
Fetal Stem Cells - drug effects
Fetal Stem Cells - enzymology
Fetal Stem Cells - pathology
Fetal Stem Cells - radiation effects
Glucose Transport Proteins, Facilitative - metabolism
Homeostasis
Humans
Membrane Potential, Mitochondrial
Mesencephalon - embryology
Mesencephalon - enzymology
Mice
Mice, Knockout
Mitochondria - drug effects
Mitochondria - enzymology
Mitochondria - pathology
Mitochondria - radiation effects
Mitochondrial Membrane Transport Proteins - metabolism
Mitochondrial Permeability Transition Pore
NADPH Oxidases - metabolism
Neurons - drug effects
Neurons - enzymology
Neurons - pathology
Neurons - radiation effects
Oxidation-Reduction
Oxidative Stress
Parkinsonian Disorders - enzymology
Parkinsonian Disorders - genetics
Parkinsonian Disorders - pathology
Protein Kinases - deficiency
Protein Kinases - genetics
Protein Kinases - metabolism
Reactive Oxygen Species - metabolism
RNA Interference
RNA, Small Interfering - metabolism
Sodium-Calcium Exchanger - metabolism
Time Factors
Ultraviolet Rays
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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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2009.02.013