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 Ghio; Manu 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

doi:10.1016/j.cmet.2018.09.019

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 journal › Article › peer-review

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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 language	English (US)
Journal	Cell Metabolism
DOIs	https://doi.org/10.1016/j.cmet.2018.09.019
State	E-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

Soberanes, Saul ; Misharin, Alexander V ; Jairaman, Amit ; Morales-Nebreda, Luisa ; McQuattie-Pimentel, Alexandra C ; Cho, Takugo ; Hamanaka, Robert B ; Meliton, Angelo Y ; Reyfman, Paul A ; Walter, James M ; Chen, Ching-I ; Chi, Monica ; Chiu, Stephen ; Gonzalez-Gonzalez, Francisco J ; Antalek, Matthew ; Abdala-Valencia, Hiam ; Chiarella, Sergio E ; Sun, Kaitlyn A ; Woods, Parker S ; Ghio, Andrew J ; Jain, Manu ; Perlman, Harris ; Ridge, Karen M ; Morimoto, Richard I ; Sznajder, Jacob I ; Balch, William E ; Bhorade, Sangeeta M ; Bharat, Ankit ; Prakriya, Murali ; Chandel, Navdeep S ; Mutlu, Gökhan M ; Budinger, G R Scott. / Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis. In: Cell Metabolism. 2018.

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title = "Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis",

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.",

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

year = "2018",

month = oct,

day = "11",

doi = "10.1016/j.cmet.2018.09.019",

language = "English (US)",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

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Soberanes, S, Misharin, AV, Jairaman, A, Morales-Nebreda, L, McQuattie-Pimentel, AC, Cho, T, Hamanaka, RB, Meliton, AY, Reyfman, PA, Walter, JM, Chen, C-I, Chi, M, Chiu, S, Gonzalez-Gonzalez, FJ, Antalek, M, Abdala-Valencia, H, Chiarella, SE, Sun, KA, Woods, PS, Ghio, AJ, Jain, M , Perlman, H , Ridge, KM , Morimoto, RI , Sznajder, JI, Balch, WE, Bhorade, SM, Bharat, A , Prakriya, M , Chandel, NS, Mutlu, GM & Budinger, GRS 2018, 'Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis', Cell Metabolism. https://doi.org/10.1016/j.cmet.2018.09.019

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

In: Cell Metabolism, 11.10.2018.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis

AU - Soberanes, Saul

AU - Misharin, Alexander V

AU - Jairaman, Amit

AU - Morales-Nebreda, Luisa

AU - McQuattie-Pimentel, Alexandra C

AU - Cho, Takugo

AU - Hamanaka, Robert B

AU - Meliton, Angelo Y

AU - Reyfman, Paul A

AU - Walter, James M

AU - Chen, Ching-I

AU - Chi, Monica

AU - Chiu, Stephen

AU - Gonzalez-Gonzalez, Francisco J

AU - Antalek, Matthew

AU - Abdala-Valencia, Hiam

AU - Chiarella, Sergio E

AU - Sun, Kaitlyn A

AU - Woods, Parker S

AU - Ghio, Andrew J

AU - Jain, Manu

AU - Perlman, Harris

AU - Ridge, Karen M

AU - Morimoto, Richard I

AU - Sznajder, Jacob I

AU - Balch, William E

AU - Bhorade, Sangeeta M

AU - Bharat, Ankit

AU - Prakriya, Murali

AU - Chandel, Navdeep S

AU - Mutlu, Gökhan M

AU - Budinger, G R Scott

PY - 2018/10/11

Y1 - 2018/10/11

N2 - 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.

AB - 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.

U2 - 10.1016/j.cmet.2018.09.019

DO - 10.1016/j.cmet.2018.09.019

M3 - Article

C2 - 30318339

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

ER -

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

Abstract

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