Atherosclerosis is a complex inflammatory process associated with high-mortality cardiovascular diseases. Today, there is a growing body of evidence linking atherosclerosis to mutations of mitochondrial DNA (mtDNA). But the mechanism of this link is insufficiently studied. Atherosclerosis progression involves different cell types and macrophages are one of the most important. Due to their high plasticity, macrophages can demonstrate pro-inflammatory and pro-atherogenic (macrophage type M1) or anti-inflammatory and anti-atherogenic (macrophage type M2) effects. These two cell types, formed as a result of external stimuli, differ significantly in their metabolic profile, which suggests the central role of mitochondria in the implementation of the macrophage polarization route. According to this, we assume that mtDNA mutations causing mitochondrial disturbances can play the role of an internal trigger, leading to the formation of macrophage M1 or M2. This review provides a comparative analysis of the characteristics of mitochondrial function in different types of macrophages and their possible associations with mtDNA mutations linked with inflammation-based pathologies including atherosclerosis.

Sukhorukov VN, et al. J Lipid Atheroscler. 2024 May;13(2):166-183. https://doi.org/10.12997/jla.2024.13.2.166

Background: Atherosclerosis is a complex cardiovascular disease often associated with mitochondrial dysfunction, which can lead to various cellular and metabolic abnormalities. Within the mitochondrial genome, specific mutations have been implicated in contributing to mitochondrial dysfunction. Atherosclerosis-associated m.15059G>A mutation has been of particular interest due to its potential role in altering mitochondrial function and cellular health. Objective: This study aims to investigate the role of the atherosclerosis-associated m.15059G>A mutation in the development of mitochondrial dysfunction in monocyte-- like cells. Methods: Monocyte-like cytoplasmic hybrid cell line TC-HSMAM1, which contains the m.15059G>A mutation in mtDNA, was used. The MitoCas9 vector was utilized to eliminate mtDNA copies carrying the m.15059G>A mutation from TC-HSMAM1 cybrids. Mitochondrial membrane potential, generation of reactive oxygen species, and lipid peroxidation levels were assessed using flow cytometry. Cellular reduced glutathione levels were assessed using the confocal microscopy. The oxygen consumption rate was measured using polarographic oxygen respirometry. Results: The elimination of the m.15059G>A mutation resulted in a significant increase in mitochondrial membrane potential and improved mitochondrial efficiency while also causing a decrease in the generation of reactive oxygen species, lipid peroxidation, as well as cellular bioenergetic parameters, such as proton leak and non-mitochondrial oxygen consumption. At the same time, no changes were found in the intracellular antioxidant system after the mitochondrial genome editing. Conclusions: The presence of the m.15059G>A mutation contributes to mitochondrial dysfunction by reducing mitochondrial membrane potential, increasing the generation of reactive oxygen species and lipid peroxidation, and altering mitochondrial bioenergetics. Elimination of the mtDNA containing atherogenic mutation leads to an improvement in mitochondrial function.

Macrophage metabolic plasticity providing their polarization towards classically (M1) or alternatively (M2) activated cells is an important element of the initiation, development, and resolving or inflammation-linked pathologies. The prevalence of M1 or M2 types of macrophages during different stages of diseases supports increased inflammation and phagocytosis or tissue repair, respectively. An imbalance leading to a shift toward an M1- or M2-dominant state is associated with a chronic pathological process. This characterizes the regulation of macrophage phenotypes as a prospective strategy in the treatment of various diseases and makes it relevant to a deep understanding of the mechanisms defining cell polarization. According to the central role of calcium signaling in cell metabolism, changes in calcium homeostasis are closely linked to the regulation of polarization. The exact balance between calcium flows across plasma and intracellular membranes provided by a number of receptors and channels, as well as the differences in the calcium-buffering capability of endoplasmic reticulum and mitochondria, are able to influence macrophage polarization towards an M1 or M2 phenotype. This review focuses on the role of the calcium homeostasis system in macrophage functionality and calcium-induced changes in macrophage metabolism that forms the basis of target disease therapy.