Mitochondrion as a Selective Target for the Treatment of Atherosclerosis: Role of Mitochondrial DNA Mutations and Defective Mitophagy in the Pathogenesis of Atherosclerosis and Chronic Inflammation

Abstract

Background: Atherosclerosis is a chronic inflammatory condition that affects different arteries in the human body and often leads to severe neurological complications, such as stroke and its sequelae. Affected blood vessels develop atherosclerotic lesions in the form of focal thickening of the intimal layer, so called atherosclerotic plaques. Objectives: Despite the high priority of atherosclerosis research for global health and the numerous preclinical and clinical studies conducted, currently there is no effective pharmacological treatment that directly impacts atherosclerotic plaques. Many knowledge gaps exist in our understanding of the mechanisms of plaque formation. In this Review, we discuss the role of mitochondria in different cell types involved in atherogenesis and provide information about mtDNA mutations associated with the disease. Results: Mitochondria of blood and arterial wall cells appear to be one of the important factors in the disease initiation and development. Significant experimental evidence connects oxidative stress associated with mitochondrial dysfunction and vascular disease. Moreover, mitochondrial DNA (mtDNA) deletions and mutations are being considered as potential disease markers. Further study of mtDNA damage and associated dysfunction may open new perspectives for atherosclerosis treatment. Conclusion: Mitochondria can be considered as important disease-modifying factors in several chronic pathologies. Deletions and mutations of mtDNA may be used as potential disease markers. Mitochondria-targeting antioxidant therapies appear to be promising for the development of treatment of atherosclerosis and other diseases associated with oxidative stress and chronic inflammation.

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

“…According to the revised hypothesis, the proinflammatory response could be an inductor of the intracellular lipid accumulation (Figure 3) [57]. This hypothesis involves not only lipid accumulation and proinflammatory response, but also underlines the crucial role of phagocytosis in the aforementioned relation.…”

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

“…Such mutations could be homoplasmic (absence or presence of the mutation) or heteroplasmic (different proportions of mutant allele). Another recent study identified variants of mtDNA that uncoupled oxidative phosphorylation: m.del562G, m.1555A>G, m.14459G>A, and m.14846G>A. Variants of mtDNA that sustained ATP synthase activity were m.3256C>T, m.12315G>A, and m.13513G>A [110]. The m.14459G>A mtDNA variant was associated with a higher basal rate of oxygen consumption.…”

“…A recent study conducted by our group has reported a relationship between mitochondrial functions and atherosclerosis-associated mtDNA mutations investigated on cybrid cell lines carrying various variants of the mitochondrial genome obtained from atherosclerotic patients [110]. Earlier studies of mtDNA obtained from the leukocytes of atherosclerotic patients revealed a correlation between certain mtDNA mutations and atherosclerosis [111][112][113].…”

“…The relationship between mitochondrial functions and atherosclerosis-associated mitochondrial mutations was investigated on cybrid cell lines carrying various variants of the mtDNA obtained from atherosclerotic patients. The identified mtDNA variants associated with increased mitophagy (as assessed by LAMP gene expression) were: m.3336T>C, m.3256C>T, m.5178C>A, m.3336T>C, m.3256C>T, and m.5178C>A [110].…”

11-amino acid peptide imitating the structure of erythropoietin α-helix b improves endothelial function, but stimulates thrombosis in rats.

“…При этом опыт, накопленный, начиная с первых работ Н.Н. Аничкова [3], демонстрирует, что атеросклеротическое повреждение сосудистой стенки является длительным многофакторным процессом [4]. В соответствии с современным пониманием патогенеза сердечно-сосудистых заболеваний, интеграль-ную роль в развитии атеросклероза и связанных с ним осложнений играет эндотелиальная дисфункция (ЭД) [5][6][7].…”