title: PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death.
abstract: 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(+)/Ca(2+) 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.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK.
authors.forename: Sonia
authors.initials: S
authors.lastname: Gandhi
authors.forename: Alison
authors.initials: A
authors.lastname: Wood-Kaczmar
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Helene
authors.initials: H
authors.lastname: Plun-Favreau
authors.forename: Emma
authors.initials: E
authors.lastname: Deas
authors.forename: Kristina
authors.initials: K
authors.lastname: Klupsch
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004734:Energy Metabolism; D053686:Fetal Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008636:Mesencephalon / Q000196:embryology / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000528:radiation effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020734:Parkinsonian Disorders / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013997:Time Factors; D014466:Ultraviolet Rays; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002118:Calcium; D051246:Glucose Transport Proteins, Facilitative; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019255:NADPH Oxidases; D011494:Protein Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019831:Sodium-Calcium Exchanger; D000099202:PTEN-Induced Putative Kinase