Apoptosis driven by IP3-linked mitochondrial calcium signals

Increases of mitochondrial matrix [Ca2+] ([Ca2+](m)) evoked by calcium mobilizing agonists play a fundamental role in the physiological control of cellular energy metabolism. Here, we report that apoptotic stimuli induce a switch in mitochondrial calcium signalling at the beginning of the apoptotic process by facilitating Ca2+-induced opening of the mitochondrial permeability transition pore (PTP). Thus [Ca2+](m) signals evoked by addition of large Ca2+ pulses or, unexpectedly, by IP3-mediated cytosolic [Ca2+] spikes trigger mitochondrial permeability transition and, in turn, cytochrome c release. IP3-induced opening of PTP is dependent on a privileged Ca2+ signal transmission from IP3 receptors to mitochondria. After the decay of Ca2+ spikes, resealing of PTP occurs allowing mitochondrial metabolism to recover, whereas activation of caspases is triggered by cytochrome c released to the cytosol. This organization provides an efficient mechanism to establish caspase activation while mitochondrial metabolism is maintained to meet ATP requirements of apoptotic cell death.