Role of Mitochondrial Genome Mutations in Pathogenesis of Carotid Atherosclerosis

Abstract

Mutations of mtDNA, due to their higher frequency of occurrence compared to nuclear DNA mutations, are the most promising biomarkers for assessing predisposition of the occurrence and development of atherogenesis. The aim of the present article was an analysis of correlation of several mitochondrial genome mutations with carotid atherosclerosis. Leukocytes from blood of study participants from Moscow polyclinics were used as research material. The sample size was 700 people. The sample members were diagnosed with “atherosclerosis” on the basis of ultrasonographic examination and biochemical and molecular cell tests. DNA was isolated from blood leukocyte samples of the study participants. PCR fragments of DNA, containing the region of 11 investigated mutations, were pyrosequenced. The heteroplasmy level of these mutations was detected. Statistical analysis of the obtained results was performed using the software package SPSS 22.0. According to the obtained results, an association of mutations m.652delG, m.3336C>T, m.12315G>A, m.14459G>A m.15059G>A with carotid atherosclerosis was found. These mutations can be biomarkers for assessing predisposition to this disease. Additionally, two single nucleotide substitutions (m.13513G>A and m.14846G>A), negatively correlating with atherosclerotic lesions, were detected. These mutations may be potential candidates for gene therapy of atherosclerosis and its risk factors.

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

“…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]. Such mutations could be homoplasmic (absence or presence of the mutation) or heteroplasmic (different proportions of mutant allele).…”

MtDNA mutations linked with left ventricular hypertrophy

“…This age difference between samples of patients with left ventricular hypertrophy and conventionally healthy participants was not statistically significant. The linkage of mtDNA mutations 652insG, m.5178C>A, m.3336T>C, m.14459G>A, 652delG, m.14846G>A, m.1555A>G, m.15059G>A, m.3256C>T, m.12315G>A and m.13513G>A with atherosclerosis was described earlier by our laboratory researchers [24,[28][29][30][31] . Since LVH has common risk factors with atherosclerosis, it was decided to analyze the relationship of these mutations to mtDNA with left ventricular hypertrophy.…”

“…At the same time, two other mutations (m.3336T>C and m.14459G>A) of this enzyme seem to have a protective, stabilizing effect and positively affect mitochondria and cardiac muscle cells. In our preliminary studies, it was found that mutation m.12315G>A, localized in the transfer RNA-Leucine gene (recognition codon CUN), was associated with atherosclerosis [29] . However, in the present study it was found that this mutation has a protective effect on left ventricular hypertrophy.…”

“…This was necessary for the analysis of the biotinylated DNA chain of the investigated amplificate using the pyrosequencing [35][36][37] . PCR primer sequences, taken for the present reseach [24,26,[28][29][30] Annealing temperature for the PCR is shown in Table 3.…”

“…For pyrosequencing the following primer sequences were used [24,26,[28][29][30] : 1. For m.652insG The heteroplasmy level of mtDNA mutations was analyzed using a quantitative method developed on the basis of pyrosequencing technology by our laboratory [24][25][26]38,39] .…”