Cited by 272Mitochondrial Function and PathologyParkinson's Disease Mechanisms and TreatmentsCell death mechanisms and regulation

Spare Respiratory Capacity Rather Than Oxidative Stress Regulates Glutamate Excitotoxicity after Partial Respiratory Inhibition of Mitochondrial Complex I with Rotenone

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Yadava, Nagendra, Nicholls, David G.·2007·The Journal of Neuroscience

Abstract

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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Crossref · 10.1523/jneurosci.0212-07.2007

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  • Under increased workload, stress, or nutrient limitation, cells engage spare respiratory capacity to generate more energy and promote viability.

    “Under increased workload, stress, or nutrient limitation, cells engage this reserve capacity to generate more energy and promote cell viability (14, 15).”

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Authors
Yadava, N., & Nicholls, D. G.
Affiliations
Buck Institute for Research on Aging (US)
Corresponding author
Nicholls, David G.
Venue
The Journal of Neuroscience
Published
2007-07-04
Volume
27
Issue
27
Pages
7310-7317
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
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
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 › 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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