The Role of mtDNA Mutations in Atherosclerosis: The Influence of Mitochondrial Dysfunction on Macrophage Polarization

Abstract

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.

Keywords: atherosclerosis; inflammation; macrophages; mtDNA; mutations; polarization.

Figure 1

The role of macrophages in atherosclerosis plaque progression.

Figure 2

Macrophage plasticity and its role in atherosclerosis plaque stability. (A) External stimuli-based macrophage polarization with the formation of M1 and M2 cell types with differences in the phenotypic profile, including basal metabolic processes, redox balance, calcium homeostasis maintenance, and mitochondrial dynamics. (B) The difference in structure and stability of atherosclerosis plaques with the predominance of M1 or M2 macrophages (LPS—lipopolysaccharide; FAO—fatty acid oxidation; FAS—fatty acid synthesis; MCU—mitochondrila calcium uniporter; OXPHOS—oxidative phosphorylation; TRPC1—transient receptor potential canonical channel 1; SOCE—store-operated calcium entry; SOD—superoxide dismutase; and Orai1—calcium release-activated calcium channel protein 1).

Figure 3

The base of mtDNA mutations influences mitochondrial function. mtDNA encodes subunits of complexes I, III, IV, and V of mitochondrial ETC as well as the machinery of these proteins’ synthesis (12S and 16S rRNAs and all of the tRNAs).

Figure 4

Possible mechanisms of mtDNA mutations that influence basal metabolic processes. Dysfunction of complexes I, III, IV, and V is associated with defective proteins. Complex II, through global alterations in ETC, prevents some reactions of the TCA cycle due to depletion of NAD or accumulation of succinate, which decreases mitochondrial respiration, ATP synthesis, glutaminolysis, and FAO rate. Increased citrate is used for FAS. Energy depletion enhances the role of glycolysis in ATP production.

Figure 5

mtDNA-associated mitochondrial dysfunction and disturbances of intracellular calcium homeostasis. Mitochondria calcium buffering is primarily supported by MCU transportation of Ca²⁺ into the matrix due to the electrochemical gradient that is mostly formed by the mitochondrial membrane potential (ΔΨm). Efflux of Ca²⁺ from the matrix is provided by the mitochondrial Na⁺-Ca²⁺ exchanger (NCLX) and leucine zipper–EF hand-containing transmembrane protein 1 (LETM1). ETC dysfunction is frequently linked with ΔΨm decrease, which leads to alterations in calcium buffering capability. Complex V dysfunction reduces the energy support role of calcium transport processes. The close relationship of mitochondria with ER (Ryanodine (RyR) and inositol trisphosphate (IP3R) receptors) worsens ER stress due to a decrease in MAM formation.

Figure 6

The relationship between mitochondrial and cytosolic ROS in macrophages. ETC dysfunction leads to an increase in the production of ${}^{·}\mathrm{O}_2^{-}$ in the mitochondrial matrix (by complexes I, II, and III) as well as in the intermembrane space (by complex III). Transmembrane transporting systems and mPTP opening can provide ${}^{·}\mathrm{O}_2^{-}$ release into the cytosol and activation of NOX2.