Mitochondrial Quality Control in Macrophages During Cardiovascular Disease

Macrophages are key cells of the innate immune system. Within the cardiovascular system, macrophages exhibit marked phenotypic plasticity, which enables them to sense local cues and regulate vascular inflammation, myocardial injury, and tissue remodelling. Mitochondria serve as multifunctional organelles in macrophages and integrate cellular metabolism with the production of immunogenic signals that shape inflammatory responses. In cardiovascular disease (CVD), mitochondrial dysfunction in macrophages drives maladaptive inflammatory responses that when unresolved, lead to chronic inflammation and tissue injury underlying adverse cardiovascular outcomes. To preserve mitochondrial integrity in diverse conditions, cells engage an interconnected network of mitochondrial quality control (MQC) mechanisms, namely mitochondrial biogenesis, maintenance of mitochondrial DNA, remodelling by fission and fusion, mitophagy, and the mitochondrial unfolded protein response. In this review, how these MQC systems govern macrophage polarization, inflammatory signalling, and survival in CVD are examined, with a focus on atherosclerosis, myocardial infarction, and heart failure. Evidence demonstrating that the dysregulation of these mechanisms in macrophages contributes to cardiovascular impairment is discussed, with particular emphasis on how dysregulated mitochondrial dynamics, heightened mitochondrial oxidative stress, and mitochondrial DNA release converge to amplify inflammation in CVD. We further highlight clinical evidence that suggests that current therapies, such as statins, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists enhance macrophage MQC to alleviate stress, improve metabolic function, and dampen inflammation, which might contribute to their cardiovascular benefit. By examining the role of MQC in macrophages within the cardiovascular system, this review establishes the mechanisms governing mitochondrial homeostasis and dysfunction as a critical immunometabolic axis and potential therapeutic avenue underlying CVD.