Mitochondria, glutamate neurotoxicity and the death cascade.
This review focuses on two questions: the role of mitochondria in excitotoxic neuronal death and the connection of mitochondria with the apoptotic death cascade. The goal is to highlight the regulatory role of mitochondrial channels on the mitochondrial membrane potential, Deltapsi, and their involvement in determining neuronal survival or death. A hypothesis is developed centered on the notion that protein-protein interactions between members of the Bcl-2 family of death suppressor and promoter proteins lead to the selective elimination of depolarizing currents that, in turn, collapse Deltapsi and set in motion the irreversible pathway of cell death. The model considers the remarkable propensity of Bcl-2 family proteins to dimerize or oligomerize and thereby restrict the localization of partner molecules to mitochondrial membrane contact sites. The fundamental principle invoked here is that through a concerted set of protein-protein interactions, information is exchanged by specific heterodimers, one of the partners acting as a toxic protein and the second as its antidote. The review concludes with the elaboration of a speculative model about cellular mechanisms for the prevention of cell destruction as triggered by extracellular signals which may be conserved in its molecular design from bacteria to eukaryotes.
Department of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0366, USA. montal@biomail.ucsd.edu
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015220:Calcium Channels / Q000378:metabolism; D016923:Cell Death; D018698:Glutamic Acid / Q000494:pharmacology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D015398:Signal Transduction
D015220:Calcium Channels; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid