Mitochondrial Ca2+ and cell death

Abstract

It has been known for a long time that cellular Ca2+ overload, occurring in excitotoxicity and various genetic or acquired diseases, leads to energy wasting and cell death, mostly by necrosis. The analysis of the effects of the oncogene Bcl-2 on cellular Ca2+ handling has led to a series of discoveries that suggest another, more specific, role of Ca2+ in cell death, i.e. that of modulating cellular sensitivity to apoptosis. Indeed, mitochondrial Ca2+ loading synergizes with toxic or signalling inputs in favouring the opening of a large-conductance mitochondrial channel, the permeability transition pore (PTP), thus altering mitochondrial structure and causing the release of caspase cofactors, such as cytochrome c, into the cytosol. The antiapoptotic protein Bcl-2 counteracts this effect by partially depleting the endoplasmic reticulum (ER) Ca2+ store (thus reducing mitochondrial Ca2+ loading), whereas the proapoptotic gene products Bax and Bak exert the opposite effect. In this contribution, we review (i) the data on the effect of pro- and antiapoptotic gene products of the Bcl-2 family on cellular Ca2+ homeostasis, (ii) the functional significance of the Ca2+ signalling alteration and (iii) the recent insights into the mechanism of this effect that may account for the apparent discrepancies between the data obtained in different studies.