Journal Article

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction

Davis, Jennifer, Zhou, Bo, Tian, Rong, Yoshii, Akira, Bugg, Darrian, Cai, Shanshan, Zhao, Mingyue, Villet, Outi, Sahu, Anita, Olson, Gregory S.

2023

Overview

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3-7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Apoptosis / Biomedical research / Cardiology / Cell death / Cellular control mechanisms / Complications and side effects / Cytokines / Development and progression / Electron transport chain / Electron Transport Complex I - metabolism / Females / Fibroblasts / Gender differences / Gene expression / Genotype & phenotype / Health aspects / Heart / Heart attack / Heart attacks / Inflammation / Inflammation - etiology / Inflammation - metabolism / Macrophages / Macrophages - metabolism / Macrophages - pathology / Medical research / Medicine, Experimental / Metabolism / Mice / Mice, Inbred C57BL / Mitochondria / Mitochondria - metabolism / Mitochondria - pathology / Mortality / Myocardial infarction / Myocardial Infarction - metabolism / Myocardial Infarction - pathology / Myocardium - metabolism / NADH-ubiquinone oxidoreductase / Phagocytosis / Phenotypes / Physiological aspects / Proteins / Roles / Scientific equipment and supplies industry / Tissue engineering / United States