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Cell Metab. 2019 Feb 5;29(2):335-347.e5. doi: 10.1016/j.cmet.2018.09.019. Epub 2018 Oct 11.

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

Author information

1
Department of Medicine and Pulmonary and Critical Care Medicine, Northwestern University, 240 E Huron Street, M300, Chicago, IL 60611, USA.
2
Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA.
3
Department of Medicine, University of Chicago, 5841 S Maryland Avenue, MC6026, Chicago, IL 60637, USA.
4
Department of Surgery, Northwestern University, Chicago, IL 60611, USA.
5
Rice Institute for Biomedical Research, Department of Molecular Biosciences, Northwestern University, Evanston, IL 60201, USA.
6
United States Environmental Protections Agency, Chapel Hill, NC 27599, USA.
7
Scripps Research, Department of Molecular Medicine, La Jolla, CA 92037, USA.
8
Department of Medicine and Pulmonary and Critical Care Medicine, Northwestern University, 240 E Huron Street, M300, Chicago, IL 60611, USA; Department of Medicine, University of Chicago, 5841 S Maryland Avenue, MC6026, Chicago, IL 60637, USA. Electronic address: gmutlu@medicine.bsd.uchicago.edu.
9
Department of Medicine and Pulmonary and Critical Care Medicine, Northwestern University, 240 E Huron Street, M300, Chicago, IL 60611, USA. Electronic address: s-buding@northwestern.edu.

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.

KEYWORDS:

air pollution; calcium channels; electron transport chain; mitochondria; proteostasis; reactive oxygen species; signaling; thrombosis

PMID:
30318339
PMCID:
PMC6365216
[Available on 2020-02-05]
DOI:
10.1016/j.cmet.2018.09.019

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