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

An Erratum to this article was published on 01 January 2004

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.

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Figure 1: Cytochrome c interacts with InsP3R.
Figure 2: Cytochrome c translocates to the endoplasmic-reticulum-binding InsP3R during apoptosis in HeLa cells.
Figure 3: Cytochrome c translocates to the endoplasmic-reticulum-binding InsP3R during apoptosis in PC12 cells.
Figure 4: Translocation of cytochrome c to the endoplasmic reticulum is upstream of caspase activation.
Figure 5: Cytochrome c translocation to endoplasmic reticulum is blocked in the absence of InsP3R.
Figure 6: Cytochrome c–InsP3R interaction during apoptosis demonstrated by FRET.
Figure 7: Changes in cytosolic calcium coincide with the coordinate release of cytochrome c from mitochondria.
Figure 8: Cytochrome c binding to InsP3R is required for STS-induced calcium oscillations and coordinate release of cytochrome c.

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Acknowledgements

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.).

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Correspondence to Solomon H. Snyder.

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Boehning, D., Patterson, R., Sedaghat, L. et al. Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5, 1051–1061 (2003). https://doi.org/10.1038/ncb1063

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