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

TY - JOUR

T1 - Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

AU - Boehning, Darren

AU - Patterson, Randen L.

AU - Sedaghat, Leela

AU - Glebova, Natalia O.

AU - Kurosaki, Tomohiro

AU - Snyder, Solomon H.

N1 - Funding Information: The authors thank D.B. Murphy for valuable comments and FRET instrumentation. We also thank S.K. Joseph for an initial supply of anti-InsP3R-I antibody and InsP3R expression constructs. We appreciate the support and useful discussion of D. Van Rossum, R.E. Rothe and P. Stankovic. This work was supported by USPHS grants MH-18501 and DA-000266 and Research Scientist Award DA-00074 (SHS), and National Research Service Awards NS-043850 (D.B.) and NH65090 (R.L.P.).

PY - 2003/12

Y1 - 2003/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/0344825875

UR - https://www.scopus.com/pages/publications/0344825875#tab=citedBy

U2 - 10.1038/ncb1063

DO - 10.1038/ncb1063

M3 - Article

C2 - 14608362

SN - 1465-7392

VL - 5

SP - 1051

EP - 1061

JO - Nature cell biology

JF - Nature cell biology

IS - 12

ER -