Mitochondrial DNA Damage in Atherosclerosis

Abstract

The defects in the mitochondrial genome are associated with different pathologies, including atherosclerosis. It is generally believed that atherosclerosis leads to premature cell senescence, but there is increasing evidence that cell senescence, the biomarker of which is the mutational load of mitochondrial genome, is itself a mechanistic factor of atherogenesis. The basic scientific problem addressed is an examination of functional consequences of mitochondrial DNA (mtDNA) damage based on the analysis of variability of mitochondrial genome. The paper is devoted to identification of genetic markers of mtDNA mutation burden, molecular and cellular markers of disorders in functional properties of cells arising from mutations in the mitochondrial genome, and identification of combinations of genetic markers that lead to violation of functional properties of human monocyte-macrophages. New data are presented, which resulted from whole genome sequencing of mtDNA from atherosclerotic lesions of arterial intima, the analysis of the relationship of mtDNA damage with the changes in cellular composition of arterial intima and expression of apoptosis-and inflammation-related genes, retrieving the data on mitochondrial genome variability in patients with atherosclerosis, and the study of functional activity of human blood monocytes differing substantially by the degree of mtDNA mutation burden.

Atherogenesis, atherosclerosis and related diseases: unresolved issues

“…Recently we have performed a series of studies on the relationships between (1) mtDNA variability and the changes in cellular composition of arterial atherosclerotic intima and the expression of apoptosis-and inflammation-related genes; (2) mtDNA variants, carotid atherosclerosis and conventional cardiovascular risk factors; and (3) individual mtDNA mutation burden and functional activity of cells in cell culture studies. The results of these studies strongly support the hypothesis on the atherogenic role of mtDNA mutations [26,27] . In further studies, we aimed to create cell models that reproduce the pathological cellular atherosclerotic phenotype with the use of promising approaches such as cytoplasmic hybrids (cybrids).…”

Response to: Comment on “Role of Mitochondrial Genome Mutations in Pathogenesis of Carotid Atherosclerosis”

“…An increase in the degree of heteroplasmy represents some kind of “clonal expansion” of low-level inherited variants, which occurs due to preferential replication of mtDNA carrying certain types of mutations [ 4 ]. However, we have earlier shown that there were no significant differences in the level of heteroplasmy of mtDNA mutations between different types of blood cells (monocytes, neutrophils, lymphocytes, and platelets) from the same individual in 71 study participants [ 5 ]; so, mutations are not accumulated during differentiation of blood cells but more probably are inherent in the progenitor cells in the bone marrow. Additionally, we have shown that in maternal relatives in 2–4 generations (37 families), in whom genotyping was carried out on heteroplasmic variants m.1555A>G, m.5178C>A, m.3256C>T, m.13513G>A, m.12315G>A, m.14846G>A, and m.15059G>A, the probability of hereditary nature of variants varied from 92% to 100%, but the probability of somatic nature arising in any generation varied from 5% to 19% [ 5 ].…”