Apoptosis driven by IP 3 -linked mitochondrial calcium signals

Increases of mitochondrial matrix [Ca 2+ ] ([Ca 2+ ] 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 Ca 2+ ‐induced opening of the mitochondrial permeability transition pore (PTP). Thus [Ca 2+ ] m signals evoked by addition of large Ca 2+ pulses or, unexpectedly, by IP 3 ‐mediated cytosolic [Ca 2+ ] spikes trigger mitochondrial permeability transition and, in turn, cytochrome c release. IP 3 ‐induced opening of PTP is dependent on a privileged Ca 2+ signal transmission from IP 3 receptors to mitochondria. After the decay of Ca 2+ 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.