PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death
Open accessAbstract
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.
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Knockdown of PINK1 expression in primary neurons and neuroblastoma cells causes increased oxidative stress and a 50% reduction of NADH levels.
“Knockdown of PINK1 expression in primary neurons and neuroblastoma cells causes increased oxidative stress and 50% reduction of NADH levels (Gandhi et al., 2009).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Gandhi et al., 2009
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References 42 · Cited by 682
- Authors
- Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., Downward, J., Latchman, D. S., Tabrizi, S. J., Wood, N. W., Duchen, M. R., & Abramov, A. Y.
- Affiliations
- National Hospital for Neurology and Neurosurgery (GB)
- Cancer Research UK (GB)
- Birkbeck, University of London (GB)
- University College London (GB)
- Corresponding author
- Abramov, Andrey Y.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 33
- Issue
- 5
- Pages
- 627-638
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2724101
- OpenAlex
- W1495978914
- Cited by
- 682
- References
- 42
- Citations by year
- 2026: 24 · 2025: 29 · 2024: 25 · 2023: 28 · 2022: 36 · 2021: 52 · 2020: 45 · 2019: 36 · 2018: 31 · 2017: 35 · 2016: 47 · 2015: 37 · 2014: 48 · 2013: 44 · 2012: 48
- FWCI
- 35.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BIROn (Birkbeck, University of London) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Parkinson's UK (F-0806)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- PINK1, autosomal recessive Parkinson's disease, mitochondrial calcium overload, mitochondrial Na+/Ca2+ exchanger, reactive oxygen species, NADPH oxidase, glucose transporters, mitochondrial respiration, mitochondrial complex I, succinate dehydrogenase, mitochondrial permeability transition pore, neuronal vulnerability, mitochondrial dysfunction
- MeSH terms
- Mitochondrial Permeability Transition Pore, PTEN-Induced Putative Kinase, Animals, Calcium, Cells, Cultured, Cytosol, Energy Metabolism, Homeostasis, Humans, Mesencephalon, Mitochondria, Neurons, Oxidation-Reduction, Protein Kinases, Time Factors, Ultraviolet Rays, Apoptosis, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Sodium-Calcium Exchanger, Parkinsonian Disorders, Mitochondrial Membrane Transport Proteins, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Glucose Transport Proteins, Facilitative, Mice, Membrane Potential, Mitochondrial, Fetal Stem Cells
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