Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis

Abstract

There is a growing consensus that the various forms of cell death (necrosis, apoptosis and autophagy) are not separated by strict boundaries, but rather share molecular effectors and signaling routes. Among the latter, a clear role is played by calcium (Ca(2+)), the ubiquitous second messenger involved in the control of a broad variety of physiological events. Fine tuning of intracellular Ca(2+) homeostasis by anti- and proapoptotic proteins shapes the Ca(2+) signal to which mitochondria and other cellular effectors are exposed, and hence the efficiency of various cell death inducers. Here, we will review: (i) the evidence linking calcium homeostasis to the regulation of apoptotic, and more recently autophagic cell death, (ii) the discussion of mitochondria as a critical, although not unique checkpoint and (iii) the molecular and functional elucidation of ER/mitochondria contacts, corresponding to the mitochondria-associated membrane (MAM) subfraction and proposed to be a specialized signaling microdomain.

Figure 1

Differential decoding of Ca²⁺-linked stimuli evoking the activation of cell metabolism or apoptosis.

Figure 2

Mitochondria-associated membrane (MAM) machinery in cell survival and cell death: proteins involved in mitochondrial and reticular Ca²⁺ homeostasis and in MAM structure. SERCA: sarco–endoplasmic reticulum Ca²⁺ ATPase; IP3R-1: inositol 3 phosphate receptor type 1; IP3R-1: inositol 3 phosphate receptor type 3; Sig1R: σ1 receptor (reticular chaperone); GRP75: glucose-regulated protein 75 (mitochondrial chaperone); PACS-2: molecular chaperone that links ER-mitochondrial axis; p66: 66-kDa isoform of the growth factor adapter Shc.