Apoptosis driven by IP3-linked mitochondrial calcium signals

doi:10.1093/emboj/18.22.6349

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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 physiologicalcontrol of cellular energy metabolism. Here, we report that apoptoticstimuli induce a switch in mitochondrial calcium signalling atthe beginning of the apoptotic process by facilitating Ca²⁺-induced opening of the mitochondrial permeability transitionpore (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, inturn, cytochrome c release. IP₃-induced opening of PTP is dependenton a privileged Ca²⁺ signal transmission from IP₃ receptors to mitochondria. Afterthe decay of Ca²⁺ spikes, resealing of PTP occurs allowing mitochondrial metabolismto recover, whereas activation of caspases is triggered by cytochromec released to the cytosol. This organization provides an efficientmechanism to establish caspase activation while mitochondrialmetabolism is maintained to meet ATP requirements of apoptoticcell death.