A Deadly Feedback

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Science  19 Dec 2003:
Vol. 302, Issue 5653, pp. 2035
DOI: 10.1126/science.302.5653.2035b

Both mitochondria and the endoplasmic reticulum (ER) are involved in apoptosis, and release of cytochrome c from the mitochondria and calcium from the ER contribute to cell death. Calcium release is also involved in many nonpathological signaling processes, and Boehning et al. show that the interaction of cytochrome c with the inositol trisphosphate receptors (IP3Rs) of the ER may drive calcium release to pathological levels. An interaction between these two proteins was identified in a yeast two-hybrid screen, and they were coprecipitated from cells treated with a broad-spectrum kinase inhibitor that induced apoptosis. Furthermore, fractionation of apoptotic cells showed that cytochrome c had accumulated in the ER fraction and had been depleted from the mitochondrial fraction. Normally, nanomolar cytoplasmic calcium stimulates IP3Rs to open, thus releasing ER stores of calcium. In contrast, at micromolar concentrations, calcium inhibits IP3R-mediated calcium release. Therefore, cytochrome c, released from the mitochondria in small amounts, would bind to the IP3R and prevent calcium inhibition of ER calcium release; the resulting global increase in calcium would trigger a massive release of cytochrome c in a positive feedback loop. — NG

Nat. Cell. Biol. 5, 1051 (2003).

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