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Humanin peptide suppresses apoptosis by interfering with Bax activation

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Abstract

Bax (Bcl2-associated X protein) is an apoptosis-inducing protein that participates in cell death during normal development and in various diseases1. Bax resides in an inactive state in the cytosol of many cells. In response to death stimuli, Bax protein undergoes conformational changes that expose membrane-targeting domains, resulting in its translocation to mitochondrial membranes, where Bax inserts and causes release of cytochrome c and other apoptogenic proteins2. It is unknown what controls conversion of Bax from the inactive to active conformation. Here we show that Bax interacts with humanin (HN), an anti-apoptotic peptide of 24 amino acids encoded in mammalian genomes3,4. HN prevents the translocation of Bax from cytosol to mitochondria. Conversely, reducing HN expression by small interfering RNAs sensitizes cells to Bax and increases Bax translocation to membranes. HN peptides also block Bax association with isolated mitochondria, and suppress cytochrome c release in vitro. Notably, the mitochondrial genome contains an identical open reading frame, and the mitochondrial version of HN can also bind and suppress Bax. We speculate therefore that HN arose from mitochondria and transferred to the nuclear genome, providing a mechanism for protecting these organelles from Bax.

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Figure 1: HN interacts with Bax.
Figure 2: HN inhibits cell death induced by Bax.
Figure 3: HN blocks Bax translocation to mitochondria.
Figure 4: Comparison of nuclear (N)- and mitochondria (M)-encoded HN.

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Acknowledgements

We wish to thank the NIH and the Department of Defense for its generous support. We also thank R. Cornell and A. Sawyer for manuscript preparation, and B. Vogelstein, D. Bredesen, R. Youle and I. Nishimoto for reagents.

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  1. The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California, 92037, USA

    Bin Guo, Dayong Zhai, Edelmira Cabezas, Kate Welsh, Shahrzad Nouraini, Arnold C. Satterthwait & John C. Reed

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  1. Bin Guo
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  2. Dayong Zhai
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Correspondence to John C. Reed.

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Guo, B., Zhai, D., Cabezas, E. et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423, 456–461 (2003). https://doi.org/10.1038/nature01627

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