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.
Szalai
G
G
Department of Pathology, Anatomy and Cell Biology, Room 253 JAH, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Krishnamurthy
R
R
Hajnóczky
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002463:Cell Membrane Permeability; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007425:Intracellular Membranes / Q000502:physiology; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology*; D010539:Permeability; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D020169:Caspases; D002118:Calcium