Mitochondrial calcium function and dysfunction in the central nervous system - PubMed (original) (raw)

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Mitochondrial calcium function and dysfunction in the central nervous system

David G Nicholls. Biochim Biophys Acta. 2009 Nov.

Abstract

The ability of isolated brain mitochondria to accumulate, store and release calcium has been extensively characterized. Extrapolation to the intact neuron led to predictions that the in situ mitochondria would reversibly accumulate Ca(2+) when the concentration of the cation in the vicinity of the mitochondria rose above the 'set-point' at which uptake and efflux were in balance, storing Ca(2+) as a complex with phosphate, and slowly releasing the cation when plasma membrane ion pumps lowered the cytoplasmic free Ca(2+). Excessive accumulation of the cation was predicted to lead to activation of the permeability transition, with catastrophic consequences for the neuron. Each of these predictions has been confirmed with intact neurons, and there is convincing evidence for the permeability transition in cellular Ca(2+) overload associated with glutamate excitotoxicity and stroke, while the neurodegenerative disease in which possible defects in mitochondrial Ca(2+) handling have been most intensively investigated is Huntington's Disease. In this brief review evidence that mitochondrial Ca(2+) transport is relevant to neuronal survival in these conditions will be discussed.

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Figures

Fig. 1

Fig. 1

Ca2+ transport by isolated mitochondrial. (a) Kinetics of Ca2+ uptake via the Ca2+ uniporter in rat liver mitochondria as a function of external free Ca2+ concentration. (b) Kinetics of Ca2+ release via the Ca2+/2H+ exchanger in rat liver mitochondria as a function of matrix Ca2+ load; Ac, phosphate depleted mitochondria in the presence of 5mM acetate, Pi, mitochondria in the presence of 3.3mM phosphate. The efflux rate in Pi is independent of total matrix Ca2+ because free matrix Ca2+ is buffered by the Ca2+-phosphate complex. (c) Rat liver mitochondrial matrix free Ca2+ concentration as a function of matrix Ca2+ load. Note the transition from varying to buffered free Ca2+ at 10nmol Ca2+/mg when the Ca2+ phosphate complex starts to form. (d) Rat brain mitochondria buffer the external free Ca2+ concentration close to 0.25μM in Mg2+-free media. For experimental details see [2,8,11]

References

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