Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis

Saul Soberanes, Alexander V Misharin, Amit Jairaman, Luisa Morales-Nebreda, Alexandra C McQuattie-Pimentel, Takugo Cho, Robert B Hamanaka, Angelo Y Meliton, Paul A Reyfman, James M Walter, Ching-I Chen, Monica Chi, Stephen Chiu, Francisco J Gonzalez-Gonzalez, Matthew Antalek, Hiam Abdala-Valencia, Sergio E Chiarella, Kaitlyn A Sun, Parker S Woods, Andrew J GhioManu Jain, Harris Perlman, Karen M Ridge, Richard I Morimoto, Jacob I Sznajder, William E Balch, Sangeeta M Bhorade, Ankit Bharat, Murali Prakriya, Navdeep S Chandel, Gökhan M Mutlu, G R Scott Budinger

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Urban particulate matter air pollution induces the release of pro-inflammatory cytokines including interleukin-6 (IL-6) from alveolar macrophages, resulting in an increase in thrombosis. Here, we report that metformin provides protection in this murine model. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevented the particulate matter-induced generation of complex III mitochondrial reactive oxygen species, which were necessary for the opening of calcium release-activated channels (CRAC) and release of IL-6. Targeted genetic deletion of electron transport or CRAC channels in alveolar macrophages in mice prevented particulate matter-induced acceleration of arterial thrombosis. These findings suggest metformin as a potential therapy to prevent some of the premature deaths attributable to air pollution exposure worldwide.

Original languageEnglish (US)
JournalCell Metabolism
DOIs
StateE-pub ahead of print - Oct 11 2018

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    Soberanes, S., Misharin, A. V., Jairaman, A., Morales-Nebreda, L., McQuattie-Pimentel, A. C., Cho, T., Hamanaka, R. B., Meliton, A. Y., Reyfman, P. A., Walter, J. M., Chen, C-I., Chi, M., Chiu, S., Gonzalez-Gonzalez, F. J., Antalek, M., Abdala-Valencia, H., Chiarella, S. E., Sun, K. A., Woods, P. S., ... Budinger, G. R. S. (2018). Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis. Cell Metabolism. https://doi.org/10.1016/j.cmet.2018.09.019