Dual Role of Mitochondria in Life and Death

Science's STKE  23 Nov 1999:
Vol. 1999, Issue 9, pp. tw1
DOI: 10.1126/stke.1999.9.tw1

Mitochondria play an important role in apoptosis by releasing apoptosis-inducing factors such as cytochrome c, an activator of the caspase enzymes. Cytochrome c is released through the mitochondrial permeability transition pore (PTP), which itself is controlled in part by calcium in the mitochondria. It is also known that calcium released from other intracellular stores in an IP3-dependent manner is taken up by mitochondria. In healthy cells, mitochondrial uptake of calcium stimulates ATP production. Szalai et al. show that in cells stimulated to undergo programmed cell death by exposure to the apoptosis-inducing agents ceramide or staurosporin, an "apoptotic switch" occurs in the mitochondria such that IP3-linked calcium signals cause PTPs to open, releasing cytochrome c and inducing nuclear apoptosis. When the calcium concentration in mitochondria decreased, PTPs closed and mitochondrial metabolism was restored. This event occurred with rapid and transient mobilization of submicromolar concentrations of calcium, indicating that small calcium spikes are effective to induce this response. Hence, IP3-linked calcium signals appear to regulate cell survival and apoptosis.

Szalai, G., Krishnamurthy, R., and Hajnóczky, G. (1999) Apoptosis driven by IP3-linked mitochondrial calcium signals. EMBO J. 18: 6349-6361. [Abstract] [Full Text]