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

Darren Boehning, Randen L. Patterson, Leela Sedaghat, Natalia O. Glebova, Tomohiro Kurosaki, Solomon H. Snyder

Research output: Contribution to journalArticle

479 Scopus citations

Abstract

Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InSp3R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP3R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InSP3R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP3R, 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 InsP3R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.

Original languageEnglish (US)
Pages (from-to)1051-1061
Number of pages11
JournalNature Cell Biology
Volume5
Issue number12
DOIs
StatePublished - Dec 2003
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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    Boehning, D., Patterson, R. L., Sedaghat, L., Glebova, N. O., Kurosaki, T., & Snyder, S. H. (2003). Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nature Cell Biology, 5(12), 1051-1061. https://doi.org/10.1038/ncb1063