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The Journal of Neuroscience, October 1, 2000, 20(19):7208-7219
Mitochondrial Membrane Potential and Glutamate Excitotoxicity in
Cultured Cerebellar Granule Cells
Manus W.
Ward,
A. Cristina
Rego,
Bruno G.
Frenguelli, and
David G.
Nicholls
Neurosciences Institute, Department of Pharmacology and
Neuroscience, University of Dundee, Dundee DD1 9SY, Scotland, United
Kingdom
The relationship between changes in mitochondrial membrane
potential (  m) and the failure of cytoplasmic
Ca2+ homeostasis, delayed
Ca2+deregulation (DCD), is investigated for cultured
rat cerebellar granule cells exposed to glutamate. To interpret the
single-cell fluorescence response of cells loaded with
tetramethylrhodamine methyl ester (TMRM+) or
rhodamine-123, we devised and validated a mathematical
simulation with well characterized effectors of m and
plasma membrane potential (P). Glutamate
usually caused an immediate decrease in m of <10 mV,
attributable to Ca2+ accumulation rather than
enhanced ATP demand, and these cells continued to generate ATP by
oxidative phosphorylation until DCD. Cells for which the mitochondria
showed a larger initial depolarization deregulated more rapidly. The
mitochondria in a subpopulation of glutamate-exposed cells that failed
to extrude Ca2+ that was released from the matrix
after protonophore addition were bioenergetically competent. The onset
of DCD during continuous glutamate exposure in the presence or absence
of oligomycin was associated with a slowly developing mitochondrial
depolarization, but cause and effect could not be established
readily. In contrast, the slowly developing mitochondrial
depolarization after transient NMDA receptor activation occurs before
cytoplasmic free Ca2+
([Ca2+]c) has risen to the set
point at which mitochondria retain Ca2+. In the
presence of oligomycin no increase in
[Ca2+]c occurs during this
depolarization. We conclude that transient Ca2+
loading of mitochondria as a consequence of NMDA receptor activation initiates oxidative damage to both plasma membrane
Ca2+ extrusion pathways and the inhibition of
mitochondrial respiration. Depending on experimental conditions, one of
these factors becomes rate-limiting and precipitates DCD.
Key words:
glutamate excitotoxicity; mitochondrial membrane
potential; delayed calcium deregulation; glutamate receptors; TMRM; rhodamine-123
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197208-12$05.00/0
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