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 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.
Gandhi
Sonia
S
Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK.
Wood-Kaczmar
Alison
A
Yao
Zhi
Z
Plun-Favreau
Helene
H
Deas
Emma
E
Klupsch
Kristina
K
Downward
Julian
J
Latchman
David S
DS
Tabrizi
Sarah J
SJ
Wood
Nicholas W
NW
Duchen
Michael R
MR
Abramov
Andrey Y
AY
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
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