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Cardiovascular Disease I
Cardiovascular Disease I
iConcept Press

Chapter 8

Cardiovascular Disease I

Mutations of Mitochondrial Genome and Atherosclerosis: Possible Mechanistic Relationship

by Igor A. Sobenin, Yuri V. Bobryshev, Elena B. Romanenko and Alexander N. Orekhov

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In human pathology, several diseases have been associated with mutations in the mitochondrial genome. Atherosclerosis underlies the development of most cardiovascular diseases, which are the leading cause of death in the 21st century. Somatic mutations within the mitochondrial genome may be a probable cause of atherosclerosis development in humans. Studying associations between mitochondrial mutations and focal development of atherosclerotic lesions human arteries is of high theoretical and practical impact. Such mutations may result in defects in the protein chains of respiratory enzymes and tRNAs that are synthesized directly in mitochondria, therefore producing oxidative stress and increasing the probability of plaque formation. The penetrance and expression of mitochondrial mutations vary greatly between relatives and depend mainly on a genotype and the level of heteroplasmy (a mixture of mutant and normal molecules of DNA). Therefore, both a qualitative and a quantitative evaluation of a mutant allele of mitochondrial genome are necessary for studying the association of mitochondrial mutations with human diseases. A mutant allele quantitative assay has been developed to study mitochondrial mutations associated with atherosclerotic lesions of the aortic intima. Fourty mitochondrial mutations previously identified in several pathological conditions were analyzed. Among them, 10 mutations associated with lipofibrosis plaques have been found in mitochondrial genes that encode rRNA12S, tRNA-Leu (UUR recognition codon), tRNA-Leu (CUN recognition codon), subunits of 1, 2, 5, and 6 NADH-dehydrogenase, and cytochromeB. From 29% up to 86% aortic samples had a significant difference between atherosclerotic plaques and unaffected tissue, with the respect to the level of heteroplasmy for each mutation. Further, the homogenates of affected and normal intimae of 10 aortas were compared to reveal the average level of heteroplasmy for these 10 mutations. For five mutations, the mean level of heteroplasmy was higher in atherosclerotic intimal homogenates in comparison with the unaffected tissue. The integral mutation burden of mtDNA in intimal tissue independently explained not less than 14% variability of atherosclerosis. In a pilot study which was undertaken in order to see if any ultrastructural peculiarities in leukocytes in the blood of patients with atherosclerosis might exist, a marked variability in structural appearance of mitochondria in leukocytes obtained from the blood of patients with atherosclerosis was observed. Then the cross-sectional clinical study was undertaken to examine the association between the level of heteroplasmy for the mutation C3256T in human white blood cells and the extent of carotid atherosclerosis, as well as the presence of coronary heart disease (CHD), the major clinical manifestation of atherosclerosis. The highly significant relationship between C3256T heteroplasmy level and predisposition to atherosclerosis estimated by ultrasonographic examination of carotid arteries was revealed. In individuals with low predisposition to atherosclerosis, the mean level of C3256T heteroplasmy was 16.8%, as compared to 23.8% in moderately predisposed subjects, and further to 25.2% and 28.3% in significantly and highly predisposed subjects, respectively. Further, the association of mitochondrial genetic variation with the severity of carotid atherosclerosis, as assessed by carotid intima-media thickness and the presence of coronary heart disease was analyzed. It has been demonstrated that heteroplasmy levels for several mutations in the mtDNA from leukocytes, including C3256T, T3336C, G12315A, G13513A, G14459A, G14846A, and G15059A mutations, were significantly (p<0.001) associated with both the severity of carotid atherosclerosis and the presence of CHD. Taken together, these findings indicate that mutations of mitochondrial genome play a substantial role in the development of atherosclerosis. They may be considered as biomarkers of mitochondrial dysfunction, novel independent risk factors for atherosclerosis, and informative markers of individual genetic susceptibility to atherosclerosis, coronary heart disease and myocardial infarction.

Author Details

Igor A. Sobenin
Laboratory of Medical Genetics, A.L. Myasnikov Institute of Clinical Cardiology, Russian Cardiology Research and Production Complex, Russia, Russia
Yuri V. Bobryshev
Faculty of Medicine, School of Medical Sciences, University of New South Wales, Australia, Australia
Elena B. Romanenko
A.N. Belozersky Research Institute of Physico-Chemical Biology, M.V. Lomonosov Moscow State University, Russia, Russia
Alexander N. Orekhov
Institute for Atherosclerosis Research, Skolkovo Innovative Center, Russia, Russia


Igor A. Sobenin, Yuri V. Bobryshev, Elena B. Romanenko and Alexander N. Orekhov. Mutations of Mitochondrial Genome and Atherosclerosis: Possible Mechanistic Relationship. In Cardiovascular Disease I. ISBN:978-1-922227-54-6. iConcept Press. 2014.