Mitochondrial permeability transition in Ca2+-dependent apoptosis and necrosis

A variety of stimuli utilize an increase of cytosolic free Ca2+ concentration as a second messenger to transmit signals, through Ca2+ release from the endoplasmic reticulum or opening of plasma membrane Ca2+ channels. Mitochondria contribute to the tight spatiotemporal control of this process by accumulating Ca2+, thus shaping the return of cytosolic Ca2+ to resting levels. The rise of mitochondrial matrix free Ca2+ concentration stimulates oxidative metabolism; yet, in the presence of a variety of sensitizing factors of pathophysiological relevance, the matrix Ca2+ increase can also lead to opening of the permeability transition pore (PTP), a high conductance inner membrane channel. While transient openings may serve the purpose of providing a fast Ca2+ release mechanism, persistent PTP opening is followed by deregulated release of matrix Ca2+, termination of oxidative phosphorylation, matrix swelling with inner membrane unfolding and eventually outer membrane rupture with release of apoptogenic proteins and cell death. Thus, a rise in mitochondrial Ca2+ can convey both apoptotic and necrotic death signals by inducing opening of the PTP. Understanding the signalling networks that govern changes in mitochondrial free Ca2+ concentration, their interplay with Ca2+ signalling in other subcellular compartments, and regulation of PTP has important implications in the fine comprehension of the main biological routines of the cell and in disease pathogenesis.