Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

• DOI: 10.1038/ncb1063
• Publication Date: 2003-11-09T18:18:17Z
• Authors: Darren Boehning; Randen L. Patterson; Leela Sedaghat; Natalia O. Glebova; Tomohiro Kurosaki; Solomon H. Snyder
• Keywords: Feedback, Physiological; 0301 basic medicine; 0303 health sciences; Binding Sites; Cytochromes c; Receptors, Cytoplasmic and Nuclear; Apoptosis; Endoplasmic Reticulum; Mitochondria; Rats; 03 medical and health sciences; Cytosol; Biological Clocks; Animals; Humans; Inositol 1,4,5-Trisphosphate Receptors; Calcium; Calcium Channels; Calcium Signaling; HeLa Cells; Signal Transduction

Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InsP(3)R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP(3)R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InsP(3)R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP(3)R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP(3)R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.