Mitochondrial Control of Acute Glutamate Excitotoxicity in Cultured Cerebellar Granule Cells
Open accessAbstract
Mitochondria within cultured rat cerebellar granule cells have a complex influence on cytoplasmic free Ca 2+([Ca 2+]c) responses to glutamate. A decreased initial [Ca 2+]c elevation in cells whose mitochondria are depolarized by inhibition of the ATP synthase and respiratory chain (conditions which avoid ATP depletion) was attributed to enhanced Ca 2+extrusion from the cell rather than inhibited Ca 2+entry via the NMDA receptor. Even in the presence of elevated extracellular Ca 2+, when [Ca 2+]c responses were restored to control values, such cells showed resistance to acute excitotoxicity, defined as a delayed cytoplasmic Ca 2+deregulation (DCD) during glutamate exposure. DCD was a function of the duration of mitochondrial polarization in the presence of glutamate rather than the total period of glutamate exposure. Once initiated, DCD could not be reversed by NMDA receptor inhibition. In the absence of ATP synthase inhibition, respiratory chain inhibitors produced an immediate Ca 2+deregulation (ICD), ascribed to an ATP deficit. In contrast to DCD, ICD could be reversed by subsequent ATP synthase inhibition with or without additional NMDA receptor blockade. DCD could not be ascribed to the failure of an ATP yielding metabolic pathway. It is concluded that mitochondria can control Ca 2+extrusion from glutamate-exposed granule cells by the plasma membrane in three ways: by competing with efflux pathways for Ca 2+, by restricting ATP supply, and by inducing a delayed failure of Ca 2+extrusion. Inhibitors of the mitochondrial permeability transition only marginally delayed the onset of DCD.
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1 μg/mL oligomycin causes a minor nonspecific effect on mitochondrial and cellular function.
“the use of this oligomycin concentration is common in the literature and causes a minor nonspecific effect on mitochondrial and cellular function [15,25,26,27].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [27]
The Figure 1 caption reports that oligomycin at 2.5 μg/mL did not affect one glutamate-induced calcium transient in cultured cerebellar granule cells. The paper also identifies oligomycin as an ATP-synthase inhibitor. It does not establish that 1 μg/mL is commonly used or that its effects on mitochondrial and cellular function are minor and nonspecific. (LLM, conf=0.79)
Experimental — accuracy not yet measured1 μg/mL oligomycin (10 times more than 0.1 μg/mL) elicits minor nonspecific effects and is common in the literature.
“However, we used 10 times more oligomycin in our experiments since this oligomycin concentration elicits minor nonspecific effects and it is common in the literature [15,25,26,27].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [27]
Figure 1 reports using 2.5 μg/mL oligomycin and finding no effect on one glutamate-induced calcium transient; other figures use higher concentrations. This supports the use of oligomycin at concentrations above 0.1 μg/mL, but the paper does not establish that 1 μg/mL has only minor nonspecific effects or that this specific concentration is common in the literature. Page numbers are unavailable in our copy. (LLM, conf=0.82)
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Research works printed but not linked: 2
- Beal M F, Howell N, Bodis-Wollner I (1997) Mitochondria and free radicals in neurodegenerative disease. New York: Wiley-Liss.
- Henneberry RC (1997) E xcitotoxicity as a consequence of impairment of energy metabolism: the energy-linked excitotoxic hypothesis. In: Mitochondria and free radicals in neurodegenerative disease (Beal MF, Howell N, Bodis-Wollner I, eds), pp 111-143. New York: Wiley-Liss.
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Mattiasson, G., Shamloo, M., Gido, G., Mathi, K., Tomasevic, G., Yi, S., Warden, C. H., Castilho, R. F., Melcher, T., Gonzalez-Zulueta, M., et al. (2003) · Nature Medicine · doi:10.1038/nm903 · Cited by 515 · see citing works
Self-citationHansson, O., Petersén, Å., Leist, M., Nicotera, P., Castilho, R. F., & Brundin, P. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.15.8727 · Cited by 228 · see citing works
Self-citationSpare respiratory capacity, oxidative stress and excitotoxicity
Nicholls, D. G. (2009) · Biochemical Society Transactions · doi:10.1042/bst0371385 · Cited by 161 · see citing works
Self-citationConnolly, N. M. C., Dussmann, H., Anilkumar, U., Huber, H. J., & Prehn, J. H. M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3127-13.2014 · Cited by 62 · see citing works
Storozhevykh, T. P., Tukhbatova, G. R., Senilova, Y. E., Pinelis, V. G., Andreeva, L. A., & Myasoyedov, N. F. (2007) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-007-0192-x · Cited by 41 · see citing works
Vander Jagt, T. A., Connor, J. A., & Shuttleworth, C. W. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.5069-07.2008 · Cited by 38 · see citing works
Silva, E. A., Dalla Costa, A. P., Ruas, J. S., Siqueira-Santos, E. S., Francisco, A., & Castilho, R. F. (2023) · Cells · doi:10.3390/cells12050683 · Cited by 5 · see citing works
Self-citation
- Authors
- Castilho, R. F., Hansson, O., Ward, M. W., Budd, S. L., & Nicholls, D. G.
- Affiliations
- University of Dundee (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1998-12-15
- Volume
- 18
- Issue
- 24
- Pages
- 10277-10286
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6793348
- OpenAlex
- W1598578622
- Cited by
- 197
- References
- 0
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 2 · 2014: 7 · 2013: 3 · 2012: 8
- FWCI
- 4.52
- 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
- Wellcome Trust (040237)
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- mitochondrial depolarization, glutamate excitotoxicity, cerebellar granule cells, calcium efflux, NMDA receptor, ATP synthase inhibition, respiratory chain inhibitors, ATP depletion, mitochondrial permeability transition, calcium homeostasis
- MeSH terms
- Adenosine Triphosphate, Animals, Calcium, Cells, Cultured, Cerebellum, Cytoplasm, Intracellular Membranes, Ketamine, Mitochondria, Oligomycins, Permeability, Rotenone, Time Factors, Uncoupling Agents, Rats, Wistar, Excitatory Amino Acid Antagonists, Glutamic Acid, Rats
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