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Previous Article | Next Article
The Journal of Neuroscience, January 1, 2000, 20(1):103-113
Dual Responses of CNS Mitochondria to Elevated Calcium
Nickolay Brustovetsky and Janet M. Dubinsky Departments of Physiology and Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
Isolated brain mitochondria were examined for their responses to calcium challenges under varying conditions. Mitochondrial membrane potential was monitored by following the distribution of tetraphenylphosphonium ions in the mitochondrial suspension, mitochondrial swelling by observing absorbance changes, calcium accumulation by an external calcium electrode, and oxygen consumption with an oxygen electrode. Both the extent and rate of calcium-induced mitochondrial swelling and depolarization varied greatly depending on the energy source provided to the mitochondria. When energized with succinate plus glutamate, after a calcium challenge, CNS mitochondria depolarized transiently, accumulated substantial calcium, and increased in volume, characteristic of a mitochondrial permeability transition. When energized with 3 mM succinate, CNS mitochondria maintained a sustained calcium-induced depolarization without appreciable swelling and were slow to accumulate calcium. Maximal oxygen consumption was also restricted under these conditions, preventing the electron transport chain from compensating for this increased proton permeability. In 3 mM succinate, cyclosporin A and ADP plus oligomycin restored potential and calcium uptake. This low conductance permeability was not effected by bongkrekic acid or carboxyatractylate, suggesting that the adenine nucleotide translocator was not directly involved. Fura-2FF measurements of [Ca2+]i suggest that in cultured hippocampal neurons glutamate-induced increases reached tens of micromolar levels, approaching those used with mitochondria. We propose that in the restricted substrate environment, Ca2+ activated a low-conductance permeability pathway responsible for the sustained mitochondrial depolarization.
Key words: permeability transition; mitochondria; fura-2FF; tetraphenylphosphonium; calcium; neurodegeneration
Copyright © 2000 Society for Neuroscience 0270-6474/0/201103-11$05.00/0
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