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Haem oxygenase-1 prevents cell death by regulating cellular iron

Nature Cell Biology volume 1, pages 152–157 (1999)Cite this article

Abstract

Haem oxygenase-1 (HO1) is a heat-shock protein that is induced by stressful stimuli. Here we demonstrate a cytoprotective role for HO1: cell death produced by serum deprivation, staurosporine or etoposide is markedly accentuated in cells from mice with a targeted deletion of the HO1 gene, and greatly reduced in cells that overexpress HO1. Iron efflux from cells is augmented by HO1 transfection and reduced in HO1-deficient fibroblasts. Iron accumulation in HO1-deficient cells explains their death: iron chelators protect HO1-deficient fibroblasts from cell death. Thus, cytoprotection by HO1 is attributable to its augmentation of iron efflux, reflecting a role for HO1 in modulating intracellular iron levels and regulating cell viability.

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Figure 1: Increased apoptosis in HO1-/- fibroblasts following serum deprivation.
Figure 2: Transfection of HO1 into HEK-293 cells protects against serum-deprivation-induced apoptosis.
Figure 3: HO1 transfection regulates 55Fe uptake and release in HEK-293 cells.
Figure 4: Genetic deletion of HO1 regulates 55Fe uptake and release in primary fibroblasts.
Figure 5: Iron chelation, but not incubation with cGMP or bilirubin, blocks serum-deprivation-induced apoptosis in HO1-/- fibroblasts.

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Acknowledgements

We thank R. Seaforth for providing [55Fe]haemin, D. C. Dodson for secretarial assistance, and S. Tonegawa for initial supplies of HO1−/− mice. This work was supported by USPHS grant MH-18501 and Research Scientist Award DA-00074 to S.H.S., and a National Research Service Award (DA-05900) to D.E.B. C.D.F. has a Howard Hughes Fellowship for Physicians and H.W. is a Pew Fellow.

Correspondence and requests for materials should be addressed to S.H.S. or C.D.F.

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Authors and Affiliations

  1. Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Christopher D. Ferris, Samie R. Jaffrey, Akira Sawa, Masaaki Takahashi, Stephen D. Brady, Roxanne K. Barrow, Herman Wolosker, David E. Barañano, Sylvain Doré & Solomon H. Snyder

  2. Department of Medicine (Division of Gastroenterology), The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Christopher D. Ferris

  3. Department of Chemistry and Physics, Skidmore College, Saratoga Springs, 12866, New York, USA

    Steven A. Tysoe

  4. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Kenneth D. Poss

  5. Departments of Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Solomon H. Snyder

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Correspondence to Solomon H. Snyder.

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Ferris, C., Jaffrey, S., Sawa, A. et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol 1, 152–157 (1999). https://doi.org/10.1038/11072

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