Metformin, a “Wonder Drug”, Targets METC for Pulmonary Protection

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Metformin, a widely used antidiabetic drug, possesses other beneficial activities, including cardiovascular protection, anti-tumorigenesis, antiaging, and weight control. This Cutting-Edge Research Highlights outlines some latest basic research discoveries on metformin’s suppression of mitochondrial electron transport chain (METC) in the intervention of pulmonary inflammatory disorders, including tuberculosis and acute respiratory distress syndrome in animal models. These novel discoveries further support metformin as a pleiotropic drug for treating diverse diseases. (First online: February 19, 2023) REFERENCES Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab 2014; 20(6):953–66. doi: https://dx.doi.org/10.1016/j.cmet.2014.09.018 Vasan K, Werner M, Chandel NS. Mitochondrial metabolism as a target for cancer therapy. Cell Metab 2020; 32(3):341–52. doi: https://dx.doi.org/10.1016/j.cmet.2020.06.019 Kulkarni AS, Gubbi S, Barzilai N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab 2020; 32(1):15–30. doi: https://dx.doi.org/10.1016/j.cmet.2020.04.001 Day EA, Ford RJ, Smith BK, Mohammadi-Shemirani P, Morrow MR, Gutgesell RM, et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat Metab 2019; 1(12):1202–8. doi: https://dx.doi.org/10.1038/s42255-019-0146-4 Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 2020; 578(7795):444–8. doi: https://dx.doi.org/10.1038/s41586-019-1911-y Roca FJ, Whitworth LJ, Prag HA, Murphy MP, Ramakrishnan L. Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport. Science 2022; 376(6600):eabh2841. doi: https://dx.doi.org/10.1126/science.abh2841 Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother TR, Tourtellotte WG, et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 2021; 54(7):1463–77 e11. doi: https://dx.doi.org/10.1016/j.immuni.2021.05.004 Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin XJ, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 2018; 560(7717):198–203. doi: https://dx.doi.org/10.1038/s41586-018-0372-z Billingham LK, Stoolman JS, Vasan K, Rodriguez AE, Poor TA, Szibor M, et al. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation. Nat Immunol 2022; 23(5):692–704. doi: https://dx.doi.org/10.1038/s41590-022-01185-3 Guo H, Wang Q, Ghneim K, Wang L, Rampanelli E, Holley-Guthrie E, et al. Multi-omics analyses reveal that HIV-1 alters CD4+ T cell immunometabolism to fuel virus replication. Nat Immunol 2021; 22(4):423–33. doi: https://dx.doi.org/10.1038/s41590-021-00898-1