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18 (22): 6349-6361

Copyright © 1999 by the European Molecular Biology Organization.

The EMBO Journal Vol. 18,pp. 6349-6361, 1999, Copyright © European Molecular Biology Organization

Apoptosis driven by IP3-linked mitochondrial calcium signals

Gábor Szalai, Rajeshwari Krishnamurthy and György Hajnóczky

Department of Pathology, Anatomy and Cell Biology, Room 253 JAH, Thomas Jefferson University, Philadelphia, PA 19107, USA
1   Corresponding author
   e-mail: Gyorgy.Hajnoczky{at}mail.tju.edu

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.

Keywords: apoptosis/Ca2+/IP3/local signalling/mitochondria

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