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Mitochondria and calcium: from cell signalling to cell death

Michael R. Duchen

While a pathway for Ca²⁺ accumulation into mitochondria has long been established, its functional significance is only now becoming clear in relation to cell physiology and pathophysiology. The observation that mitochondria take up Ca²⁺ during physiological Ca²⁺ signalling in a variety of cell types leads to four questions: (i) 'What is the impact of mitochondrial Ca²⁺ uptake on mitochondrial function?' (ii) 'What is the impact of mitochondrial Ca²⁺ uptake on Ca²⁺ signalling?' (iii) 'What are the consequences of impaired mitochondrial Ca²⁺ uptake for cell function?' and finally (iv) 'What are the consequences of pathological [Ca²⁺]_c signalling for mitochondrial function?' These will be addressed in turn. Thus: (i) accumulation of Ca²⁺ into mitochondria regulates mitochondrial metabolism and causes a transient depolarisation of mitochondrial membrane potential. (ii) Mitochondria may act as a spatial Ca²⁺ buffer in many cells, regulating the local Ca²⁺ concentration in cellular microdomains. This process regulates processes dependent on local cytoplasmic Ca²⁺ concentration ([Ca²⁺]_c), particularly the flux of Ca²⁺ through IP₃-gated channels of the endoplasmic reticulum (ER) and the channels mediating capacitative Ca²⁺ influx through the plasma membrane. Consequently, mitochondrial Ca²⁺ uptake plays a substantial role in shaping [Ca²⁺]_c signals in many cell types. (iii) Impaired mitochondrial Ca²⁺ uptake alters the spatiotemporal characteristics of cellular [Ca²⁺]_c signalling and downregulates mitochondrial metabolism. (iv) Under pathological conditions of cellular [Ca²⁺]_c overload, particularly in association with oxidative stress, mitochondrial Ca²⁺ uptake may trigger pathological states that lead to cell death. In the model of glutamate excitotoxicity, microdomains of [Ca²⁺]_c are apparently central, as the pathway to cell death seems to require the local activation of neuronal nitric oxide synthase (nNOS), itself held by scaffolding proteins in close association with the NMDA receptor. Mitochondrial Ca²⁺ uptake in combination with NO production triggers the collapse of mitochondrial membrane potential, culminating in delayed cell death.

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