Impact of Mitochondrial DNA Mutations on Carotid Intima-Media Thickness in the Novosibirsk Region

Abstract

The search for markers of predisposition to atherosclerosis development is very important for early identification of individuals with a high risk of cardiovascular disease. The aim of the present study was to investigate the association of mitochondrial DNA mutations with carotid intima-media thickness and to determine the impact of mitochondrial heteroplasmy measurements in the prognosis of atherosclerosis development. This cross-sectional, population-based study was conducted in 468 subjects from the Novosibirsk region. It was shown that the mean (carotid intima-media thickness) cIMT correlated with the following mtDNA mutations: m.15059G>A (r = 0.159, p = 0.001), m.12315G>A (r = 0.119; p = 0.011), m.5178C>A (r = 0.114, p = 0.014), and m.3256C>T (r = 0.130, p = 0.011); a negative correlation with mtDNA mutations m.14846G>A (r = −0.111, p = 0.042) and m.13513G>A (r = −0.133, p = 0.004) was observed. In the linear regression analysis, the addition of the set of mtDNA mutations to the conventional cardiovascular risk factors increased the ability to predict the cIMT variability from 17 to 27%. Multi-step linear regression analysis revealed the most important predictors of mean cIMT variability: age, systolic blood pressure, blood levels of total cholesterol, LDL and triglycerides, as well as the mtDNA mutations m.13513G>A, m.15059G>A, m.12315G>A, and m.3256C>T. Thus, a high predictive value of mtDNA mutations for cIMT variability was demonstrated. The association of mutation m.13513G>A and m.14846G>A with a low value of cIMT, demonstrated in several studies, represents a potential for the development of anti-atherosclerotic gene therapy.

Challenges of mitochondrial DNA editing in mammalian cells: focus on treatment of cardiovascular disease

“…Numerous studies have associated mtDNA mutations with the development of atherosclerosis [7,14,59,67,68] . Their prevalence is affected by various factors, such as sex and regional location [64,[69][70][71] . Whole blood cells and buccal epithelial cells are used as biomarkers of mitochondrial mutations associated with atherosclerosis [72][73][74] .…”

The Reactive Species Interactome - Mitochondria Axis

“…The MELAS disease (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) is another well-known mitochondrial disease, which is a myopathy caused by mutations in the mitochondrial tRNALeu (UUR) gene in more than 80% of MELAS patients [112,116,118]. Mitochondrial DNA mutations are also associated with carotid intima-media thickness, atherosclerosis, and cardiovascular diseases [112,119]. In a non-exhaustive manner, mtDNA rearrangement mutations, mutations in mitochondrial DNA polymerase POLG, mtDNA maintenance protein twinkle, mitochondrial thymidine kinase 2 (TK2), mitochondrial deoxyguanosine kinase (DGUOK), mitochondrial malate dehydrogenase 2 (MDH2), and mitochondrial GTPase optic atrophy protein 1 (OPA1) lead to mtDNA deletion and depletion that affect muscle, pancreas with type II diabetes, the heart, and brain, including with neurodegeneration [9,114,116,120,121].…”

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

“…For example, activation of apoptosis and proliferation genes may begin, and the level of cytokine expression may increase. In addition, somatic DNA mutations and cytotoxicity may occur [ 35 , 36 , 37 , 38 , 39 ].…”

“…This ROS is formed using enzyme NO synthase, which is found in macrophages. Its expression occurs with the development of inflammation, in response to bacterial endotoxins and cytokines [ 33 , 34 , 35 , 36 , 37 ].…”