Glutamate excitotoxicity and neuronal energy metabolism

David G. Nicholls*, Samantha L. Budd, Roger F. Castilho, Manus W. Ward

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The bioenergetic properties of the in situ mitochondria play a central role in controlling the susceptibility of neurons to acute or chronic neurodegenerative stress. The mitochondrial membrane potential, Δψ(m), is the parameter that controls three interrelated mitochondrial functions of great relevance to neuronal survival: namely, ATP synthesis, Ca2+ accumulation, and superoxide generation. The in vitro model we study is the rat cerebellar granule cell in primary culture and its susceptibility to NMDA receptor-mediated necrosis, which is preceded by a delayed failure of cytoplasmic Ca2+ homeostasis ('delayed Ca2+ deregulation,' DCD). DCD is not caused by a failure of mitochondrial ATP synthesis since it also occurs in cells maintained purely by glycolysis. The in situ mitochondria maintain a Δψ(m), sufficient for ATP synthesis throughout the exposure of the cells to glutamate until DCD occurs. Even at that stage it appears that mitochondrial depolarization may be an effect of DCD rather than a primary cause. This somewhat unorthodox view resolves a number of apparent paradoxes, such as observations of enhanced superoxide generation by in situ mitochondria during excitotoxic exposure, since isolated mitochondria generate superoxide only under conditions of high Δψ(m). Mitochondrial depolarization by selective inhibitors that do not deplete cellular ATP is acutely neuroprotective.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalAnnals of the New York Academy of Sciences
Volume893
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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