Apoptosis driven by IP3-linked mitochondrial calcium signals

Increases of mitochondrial matrix [Ca2+] ([Ca2+](m)) evoked by calcium mobi lizing agonists play a fundamental role in the physiological control of cel lular energy metabolism. Here, we report that apoptotic stimuli induce a sw itch in mitochondrial calcium signalling at the beginning of the apoptotic process by facilitating Ca2+-induced opening of the mitochondrial permeabil ity transition pore (PTP). Thus [Ca2+](m) signals evoked by addition of lar ge Ca2+ pulses or, unexpectedly, by IP3-mediated cytosolic [Ca2+] spikes tr igger mitochondrial permeability transition and, in turn, cytochrome c rele ase. IP3-induced opening of PTP is dependent on a privileged Ca2+ signal tr ansmission from IP3 receptors to mitochondria. After the decay of Ca2+ spik es, resealing of PTP occurs allowing mitochondrial metabolism to recover, w hereas activation of caspases is triggered by cytochrome c released to the cytosol. This organization provides an efficient mechanism to establish cas pase activation while mitochondrial metabolism is maintained to meet ATP re quirements of apoptotic cell death.