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Spare Respiratory Capacity Rather Than Oxidative Stress Regulates Glutamate Excitotoxicity after Partial Respiratory Inhibition of Mitochondrial Complex I with Rotenone
Open accessAbstract
Partial inhibition of mitochondrial respiratory complex I by rotenone reproduces aspects of Parkinson's disease in rodents. The hypothesis that rotenone enhancement of neuronal cell death is attributable to oxidative stress was tested in an acute glutamate excitotoxicity model using primary cultures of rat cerebellar granule neurons. As little as 5 n m rotenone increased mitochondrial superoxide (O 2·−) levels and potentiated glutamate-induced cytoplasmic Ca 2+deregulation, the first irreversible stage of necrotic cell death. However, the potent cell-permeant O 2·−trap manganese tetrakis (N-ethylpyridinium-2yl) porphyrin failed to prevent the effects of the inhibitor. The bioenergetic consequences of rotenone addition were quantified by monitoring cell respiration. Glutamate activation of NMDA receptors used the full respiratory capacity of the in situ mitochondria, and >80% of the glutamate-stimulated respiration was attributable to increased cellular ATP demand. Rotenone at 20 n m inhibited basal and carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated cell respiration and caused respiratory failure in the presence of glutamate. ATP synthase inhibition by oligomycin was also toxic in the presence of glutamate. We conclude that the cell vulnerability in the rotenone model of partial complex I deficiency under these specific conditions is primarily determined by spare respiratory capacity rather than oxidative stress.
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Metadata
- Authors
- Yadava, N., & Nicholls, D. G.
- Affiliations
- Buck Institute for Research on Aging (US)
- Corresponding author
- Nicholls, David G.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-07-04
- Volume
- 27
- Issue
- 27
- Pages
- 7310-7317
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6794596
- OpenAlex
- W2061113435
- Cited by
- 272
- References
- 39
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 14 · 2021: 11 · 2020: 23 · 2019: 15 · 2018: 17 · 2017: 22 · 2016: 22 · 2015: 15 · 2014: 15 · 2013: 17 · 2012: 24
- FWCI
- 5.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01 AG2 1440, R01AG021440)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- rotenone, mitochondrial complex I deficiency, Parkinson's disease model, glutamate excitotoxicity, oxidative stress, spare respiratory capacity, mitochondrial superoxide, manganese porphyrin, necrosis, NMDA receptor, ATP demand, mitochondrial respiration, oligomycin, ATP synthase inhibition, cerebellar granule cells
- MeSH terms
- Animals, Mitochondria, Rotenone, Cell Death, Rats, Wistar, Oxidative Stress, Excitatory Amino Acid Agonists, Glutamic Acid, Cell Respiration, Electron Transport Complex I, Rats
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