Thursday, 18 October 2018

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, James M. Walter, Ching-I Chen,  Monica Chi, Stephen Chiu, Francisco J. Gonzalez-Gonzalez, Matthew Antalek, Hiam Adbala-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, Go¨ khan M. Mutlu  and G.R. Scott Budinger.

Intro: a word on macrophages.
Macrophages (big eaters, from Greek μακρός and φαγείν) are a type of white blood cell, of the immune system, that engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the type of proteins specific to healthy body cells on its surface, in a process called phagocytosis. They are large phagocytes found essentially in every tissue, where they patrol for potential pathogens.

An alveolar macrophage (or dust cell) is a type of macrophage found in the pulmonary alveolus, near the pneumocytes, but separated from the wall.

The study
While air pollution exposure is associated with a variety of poor health outcomes, the major driver of mortality is an increased risk of death attributable to ischemic cardiovascular events, primarily heart attacks and ischemic/thrombotic strokes.

Urban PM air pollution induces the release of pro-inflammatory cytokines, including interleukin-6 (IL-6) from alveolar macrophages. Alveolar macrophage-produced IL-6 enters the circulation to induce the transcription of several coagulation factors in the liver, and augments the tendency toward arterial thrombosis in a murine model of stroke. This phenomenon was not observed in mice lacking IL-6.

Key findings of this model were recently confirmed in humans in an interventional trial of filtered air compared with ambient air conducted in a region of China with high levels of ambient PM.

Accordingly, molecules that can attenuate IL-6 release in response to PM predicted to lower the risk of arterial thrombosis in exposed populations.

Soberanes et al., find that metformin can attenuate PM-induced IL-6 release from alveolar macrophages in mice and reduce the resulting increase in the risk of arterial thrombosis.

The link to mitochondria
In alveolar macrophages from mice and humans, PM-induced mitochondrial ROS generation caused endoplasmic reticulum calcium store depletion, and the opening of store-operated calcium channels, which augmented IL-6 release.

Metformin acted as a complex I inhibitor in alveolar macrophages to reduce mitochondrial ROS from complex III of the mitochondrial electron transport chain in response to PM. That’s the mechanism behind his effectiveness in limiting IL-6 release in from alveolar macrophages.

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