MtDNA mutations linked with left ventricular hypertrophy

Aim: In left ventricular hypertrophy (LVH), the heart muscle thickens. One third of individuals with LVH never complain of heart problems. However, such patients have a high risk of sudden death. LVH can be caused by arterial atherosclerotic lesions. 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. The aim of the study was to analyze the linkage of these mtDNA mutations with LVH.Methods: DNA from white blood cells was isolated using a phenol-chloroform method. PCR-fragments of DNA contained the region of the investigated mutations. The heteroplasmy level of mtDNA mutations was analyzed using a pyrosequencing-based method developed by our laboratory.Results: We investigated two groups of individuals. One hundred and ninety-four patients with LVH. Two hundred and ten were conventionally healthy. It was found that mtDNA mutation m.5178C>A was significantly associated with LVH. Single nucleotide replacement m.1555A>G was associated with LVH at the level of significance P ≤ 0.1. At the same time m.12315G>A and m.3336T>C were significantly associated with the absence of this pathology. Single nucleotide replacement m.14459G>A was associated with the absence of LVH at the significance level P ≤ 0.1.Conclusion: MtDNA mutations m.5178C>A and m.1555A>G can be used for molecular genetic assessment of the predisposition of individuals to the occurrence of left ventricular hypertrophy. They can also be used for the family analysis of this pathology. Mutations m.12315G>A, m.3336T>C and m.14459G>A can be used in the development of LVH gene therapy methods

Carotid atherosclerosis-related mutations of mitochondrial DNA do not explain the phenotype of metabolic syndrome

Aim: This study was undertaken to explore the relationship between metabolic syndrome (MetS) and atherosclerosis-related mitochondrial DNA (mtDNA) mutations, since MetS shares conventional and genetic risk factors with atherosclerosis.Methods: The study involved 220 participants; the carotid ultrasonography followed by intima-media thickness (cIMT) measurement was used for quantitative diagnostics of carotid atherosclerosis. The diagnosis of MetS was set according to International Diabetes Federation criteria (IDF-2009). The level of mtDNA heteroplasmy in leukocytes was determined by qPCR. The severity of MetS was estimated on combination of serum HDL cholesterol, triglycerides and fasting glucose, systolic and diastolic blood pressure, and waist circumference measurements.Results: MetS was present in 44 study participants. Ten mtDNA mutations were tested, and m.3336T>C and m.652delG heteroplasmy levels correlated with the clusterization of MetS symptoms, in particular the cardiovascular and metabolic risk factors, of triglyceride and fasting glucose levels. The other mtDNA mutations each only correlated with one symptom (i.e., m.652delG and m.12315G>A-with triglycerides; m.3256C>T, m.1555A>G, and m.15059G>A-with systolic blood pressure; m.14846G>A-with fasting glucose). There was no correlation between integral severity of MetS and cIMT.Conclusion: In this study, the MetS phenotype was not explained directly by atherosclerosis-related mtDNA variants. It is possible to hypothesize that mtDNA-related mechanisms in atherosclerosis and MetS may be different, in spite of the similarity of several phenotypic characteristics

Dataset of mitochondrial genome variants associated with asymptomatic atherosclerosis

This dataset report is dedicated to mitochondrial genome variants associated with asymptomatic atherosclerosis. These data were obtained using the method of next generation pyrosequencing (NGPS). The whole mitochondrial genome of the sample of patients from the Moscow region was analyzed. In this article the dataset including anthropometric, biochemical and clinical parameters along with detected mtDNA variants in patients with carotid atherosclerosis and healthy individuals was presented. Among 58 of the most common homoplasmic mtDNA variants found in the observed sample, 7 variants occurred more often in patients with atherosclerosis and 16 variants occurred more often in healthy individuals. Keywords: mtDNA variant, Mitochondrial genome, Homoplasmic, Asymptomatic atherosclerosi

Role of Mitochondrial Genome Mutations in Pathogenesis of Carotid Atherosclerosis

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

Profiling of risk of subclinical atherosclerosis: possible interplay of genetic and environmental factors as the update of conventional approach

Aim: To explore whether geographical location, genetic and environmental factors are associated with carotid atherosclerosis in high-risk individuals.Methods: In Moscow 470 apparently healthy, asymptomatic volunteer subjects with a high cardiovascular disease risk were recruited to participate in a cross-sectional study. Carotid intima-media thickness (cIMT), a validated biomarker for present and future cardiovascular disease risk, was assessed by means of high resolution ultrasound scans in subjects.Results: The total burden of conventional cardiovascular risk factors explained 21% of the cIMT variability; the mutational burden of mitochondrial genome defined by heteroplasmic mutations m.652delG, m.3256C>T, m.13513G>A, m.14459G>A, and m.15059G>A independently explained 23% variability; the combination of conventional and genetic risk factors increased explanatory level to 36%. Further exploratory statistical analyses showed air pollution as an independent risk factor for cIMT.Conclusion: In our study we confirmed and expanded the existence of a European geographic gradient of atherosclerosis risk and its association with cardiovascular disease risk. Geographical, environmental (particularly, air pollution) - and genetic risk factors (particularly, mutant variants of mitochondrial genome) may interplay in the formation of susceptibility to atherosclerosis

Mutations of mitochondrial genome in carotid atherosclerosis

With aim of detection the spectrum of mitochondrial DNA mutations in patients with carotid atherosclerosis from Moscow Region, we used a Roche 454 high-throughput sequencing of the whole mitochondrial genome. We have found that the presence of a number of homoplasmic mitochondrial DNA mutations in genes of 16S ribosomal RNA, subunits 2, 4, and 5 NADH dehydrogenase, subunits 1 and 2 cytochrome C oxidase, subunit 6 ATP-synthase, tRNA-Leu 2 and cytochrome B differed between conventionally healthy participants of the study and patients with carotid atherosclerosis. We also found heteroplasmic mutations, including insertions one or several nucleotides, that occurred more frequently in mitochondrial DNA of conventionally healthy participants of the study or patients with atherosclerotic lesions

Data on association of mitochondrial heteroplasmy and cardiovascular risk factors: Comparison of samples from Russian and Mexican populations

Despite the fact that the role of mitochondrial genome mutations in a number of human diseases is widely studied, the effect of mitochondrial heteroplasmy in the development of cardiovascular disease has not been adequately investigated. In this study, we compared the heteroplasmy levels of mtDNA from leukocytes for m.3256C>T, m.3336T>C, m.12315G>A, m.5178C>A, m.13513G>A, m.14459G>A, m.14846G>A, m.15059G>A, m.652insG and m.1555A>G mutations in CVD-free subjects and CVD patients in samples derived from Russian and Mexican populations. It was demonstrated that heteroplasmy level of m.5178C>A was associated with CVD in Russian men, and m.14459G>A – in Russian women. Mitochondrial heteroplasmy level of m.13513G>A and m.652insG were associated with CVD in Mexican men, and only m.652insG– in Mexican women. The levels of heteroplasmy for mitochondrial mutations m.3336T>C, m.5178C>A, m.14459G>A, m.14846G>A and m.1555A>G were significantly higher in CVD-free Mexican men, and for m.3256C>T, m.3336T>C, and m.14459G>A – in CVD-free Mexican women. Keywords: Mitochondrial mutations, Heteroplasmy, Atherosclerosis, Cardiovascular risk factors, Coronary heart diseas

Some Molecular and Cellular Stress Mechanisms Associated with Neurodegenerative Diseases and Atherosclerosis

Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress

Some Molecular and Cellular Stress Mechanisms Associated with Neurodegenerative Diseases and Atherosclerosis

Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress