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

Nature Cell Biology volume 5, pages 1051–1061 (2003)Cite this article

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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Author notes

  1. Darren Boehning and Randen L. Patterson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, 21205, Maryland, USA

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

  2. Departments of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, 21205, Maryland, USA

    Solomon H. Snyder

  3. Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, 21205, Maryland, USA

    Solomon H. Snyder

  4. Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, and Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Moriguchi, 570-8506, Japan

    Tomohiro Kurosaki

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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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