p66Shc is an apoptotic rheostat whose targeted ROS inhibition improves MI outcomes

Haslem, L.; Hays, J. M.; Schmitz, H.; Matsuzaki, S.; Sjoelund, V.; Byrum, S. D.; Humphries, K. M. A.; Frazer, J. K.; Demeler, B.; Benbrook, D. M.; Tierney, R. M.; Duggan, K. D.; Hays, F. A.

doi:10.1101/2022.04.14.487897

bioRxiv · 10.1101/2022.04.14.487897

p66Shc is an apoptotic rheostat whose targeted ROS inhibition improves MI outcomes

Haslem, L.·Hays, J. M.·Schmitz, H.·Matsuzaki, S.·Sjoelund, V.·Byrum, S. D.·Humphries, K. M. A.·Frazer, J. K.·Demeler, B.·Benbrook, D. M.·Tierney, R. M.·Duggan, K. D.·Hays, F. A.

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Abstract

p66Shc is an oxidoreductase that responds to cell stress by translocating to mitochondria, where p66Shc produces pro-apoptotic reactive oxygen species (ROS). This study identifies ROS-active p66Shc as a monomer that produces superoxide anion independent of metal ions, inhibits cytochrome c peroxidase, and is regulated by environmental condition-induced structural changes. p66Shc anti-apoptotic functions, including: cytochrome c reduction, increased electron transport chain activity, and caspase cascade inhibition were also discovered. This study also demonstrates that p66Shc is a stress-dependent rheostat of apoptosis, regulated by p66Shc-mortalin complexes. These complexes decrease pro-apoptotic ROS production, without blocking p66Shc-mediated cytochrome c reduction. However, stress disrupts p66Shc-mortalin interactions, promoting apoptosis. Tipping p66Shcs apoptotic balance toward anti-apoptotic functions by genetic knockdown or p66Shc-selective ROS inhibition decreased pro-apoptotic effects and improved outcomes in zebrafish myocardial infarction models, representing a potential new myocardial infarction treatment with promising results.

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Haslem, L., Hays, J. M., Schmitz, H., Matsuzaki, S., Sjoelund, V., Byrum, S. D., Humphries, K. M. A., Frazer, J. K., Demeler, B., Benbrook, D. M., Tierney, R. M., Duggan, K. D., Hays, F. A.. 2022-04-14. p66Shc is an apoptotic rheostat whose targeted ROS inhibition improves MI outcomes. https://doi.org/10.1101/2022.04.14.487897

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