Mitochondria and calcium: from cell signalling to cell death

Abstract

While a pathway for Ca 2+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 Ca 2+during physiological Ca 2+signalling in a variety of cell types leads to four questions: (i) ‘What is the impact of mitochondrial Ca 2+uptake on mitochondrial function?’ (ii) ‘What is the impact of mitochondrial Ca 2+uptake on Ca 2+signalling?’ (iii) ‘What are the consequences of impaired mitochondrial Ca 2+uptake for cell function?’ and finally (iv) ‘What are the consequences of pathological [Ca 2+]c signalling for mitochondrial function?’ These will be addressed in turn. Thus: (i) accumulation of Ca 2+into mitochondria regulates mitochondrial metabolism and causes a transient depolarisation of mitochondrial membrane potential. (ii) Mitochondria may act as a spatial Ca 2+buffer in many cells, regulating the local Ca 2+concentration in cellular microdomains. This process regulates processes dependent on local cytoplasmic Ca 2+concentration ([Ca 2+]c), particularly the flux of Ca 2+through IP 3‐gated channels of the endoplasmic reticulum (ER) and the channels mediating capacitative Ca 2+influx through the plasma membrane. Consequently, mitochondrial Ca 2+uptake plays a substantial role in shaping [Ca 2+]c signals in many cell types. (iii) Impaired mitochondrial Ca 2+uptake alters the spatiotemporal characteristics of cellular [Ca 2+]c signalling and downregulates mitochondrial metabolism. (iv) Under pathological conditions of cellular [Ca 2+]c overload, particularly in association with oxidative stress, mitochondrial Ca 2+uptake may trigger pathological states that lead to cell death. In the model of glutamate excitotoxicity, microdomains of [Ca 2+]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 Ca 2+uptake in combination with NO production triggers the collapse of mitochondrial membrane potential, culminating in delayed cell death.