Atherosclerosis is a complex disease which can be described as an excessive fibrofatty, proliferative, inflammatory response to damage to the artery wall involving several cell types such as smooth muscle cells, monocyte-derived macrophages, lymphocytes, dendritic cells and platelets. On the other hand, atherosclerosis is a typical age-related degenerative pathology, which is characterized by signs of cell senescence in the arterial wall including reduced cell proliferation, irreversible growth arrest and apoptosis, increased DNA damage, the presence of epigenetic modifications, shortening of telomere length and mitochondrial dysfunction. The most prominent characteristics of mitochondrial aging are their structural alterations and mitochondrial DNA damage. The mechanisms of mitochondrial genome damage in the development of chronic age-related diseases such as atherosclerosis are not yet well understood. This review focuses on the latest findings from studies of those mutations of the mitochondrial genome which may play an important role in the development of atherosclerosis and which are, at the same time, also markers of mitochondrial aging and cell senescence.

1.
Schwartz CJ, Valente AJ, Sprague EA: A modern view of atherogenesis. Am J Cardiol 1993;71:9B-14B.
2.
Libby P, Ridker PM, Hansson GK: Progress and challenges in translating the biology of atherosclerosis. Nature 2011;473:317-325.
3.
Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyörälä K: Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis 1998;140:199-270.
4.
Orekhov AN, Tertov VV, Novikov ID, Krushinsky AV, Andreeva ER, Lankin VZ, Smirnov VN: Lipids in cells of atherosclerotic and uninvolved human aorta. 1. Lipid composition of aortic tissue and enzyme-isolated and cultured cells. Exp Mol Pathol 1985;42:117-137.
5.
Miller YI, Choi SH, Fang L, Tsimikas S: Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis. Subcell Biochem 2010;51:229-251.
6.
Tertov VV, Orekhov AN, Ryong LH, Smirnov VN: Intracellular cholesterol accumulation is accompanied by enhanced proliferative activity of human aortic intimal cells. Tissue Cell 1988;20:849-854.
7.
Orekhov AN, Tertov VV, Kudryashov SA, Smirnov VN: Triggerlike stimulation of cholesterol accumulation and DNA and extracellular matrix synthesis induced by atherogenic serum or low density lipoprotein in cultured cells. Circ Res 1990;66:311-320.
8.
Bobryshev YV, Andreeva ER, Mikhailova IA, Andrianova IV, Moisenovich MM, Khapchaev S, Agapov II, Sobenin IA, Lusta KA, Orekhov AN: Correlation between lipid deposition, immune-inflammatory cell content and MHC class II expression in diffuse intimal thickening of the human aorta. Atherosclerosis 2011;219:171-183.
9.
Wang C, Bennett M: Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 2012;111:245-259.
10.
Stemerman M, Weinstein R, Rowe J, Maciag T, Fuhro R, Gardner R: Vascular smooth muscle cell growth kinetics in vivo in aged rats. Proc Natl Acad Sci USA 1982;79:3863-3866.
11.
Hariri RJ, Hajjar DP, Coletti D, Alonso DR, Weksler ME, Rabellino E: Aging and arteriosclerosis: cell cycle kinetics of young and old arterial smooth muscle cells. Am J Pathol 1988;131:132-136.
12.
Chung HY, Sung B, Jung KJ, Zou Y, Yu BP: The molecular inflammatory process in aging. Antioxid Redox Signal 2006;8:572-581.
13.
Gerhard M, Roddy MA, Creager SJ, Creager MA: Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension 1996;27:849-853.
14.
Horan MP, Cooper DN: The emergence of the mitochondrial genome as a partial regulator of nuclear function is providing new insights into the genetic mechanisms underlying age-related complex disease. Hum Genet 2014;133:435-458.
15.
Damas J, Samuels DC, Carneiro J, Amorim A, Pereira F: Mitochondrial DNA rearrangements in health and disease - a comprehensive study. Hum Mutat 2014;35:1-14.
16.
Lee HC, Wei YH: Mitochondria and aging. Adv Exp Med Biol 2012;942:311-327.
17.
Wei YH: Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med 1998;217:53-63.
18.
Lenaz G, Baracca A, Fato R, Genova ML, Solaini G: New insights into structure and function of mitochondria and their role in aging and disease. Antioxid Redox Signal 2006;8:417-437.
19.
Yao YG, Kajigaya S, Feng X, Samsel L, McCoy JP Jr, Torelli G, Young NS: Accumulation of mtDNA variations in human single CD34+ cells from maternally related individuals: effects of aging and family genetic background. Stem Cell Res 2013;10:361-370.
20.
Andreassi MG: Coronary atherosclerosis and somatic mutations: an overview of the contributive factors for oxidative DNA damage. Mutat Res 2003;543:67-86.
21.
Nomiyama T, Tanaka Y, Piao L, Hattori N, Uchino H, Watada H, Kawamori R, Ohta S: Accumulation of somatic mutation in mitochondrial DNA and atherosclerosis in diabetic patients. Ann NY Acad Sci 2004;1011:193-204.
22.
Botto N, Berti S, Manfredi S, Al-Jabri A, Federici C, Clerico A, Ciofini E, Biagini A, Andreassi MG: Detection of mtDNA with 4977 bp deletion in blood cells and atherosclerotic lesions of patients with coronary artery disease. Mutat Res 2005;570:81-88.
23.
Marian AJ: Mitochondrial genetics and human systemic hypertension. Circ Res 2011;108:784-786.
24.
Ding Y, Xia B, Yu J, Leng J, Huang J: Mitochondrial DNA mutations and essential hypertension. Int J Mol Med 2013;32:768-774.
25.
Avital G, Buchshtav M, Zhidkov I, Tuval Feder J, Dadon S, Rubin E, Glass D, Spector TD, Mishmar D: Mitochondrial DNA heteroplasmy in diabetes and normal adults: role of acquired and inherited mutational patterns in twins. Hum Mol Genet 2012;21:4214-4224.
26.
Bhopal RS, Rafnsson SB: Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular diseases in South Asian populations? Int J Epidemiol 2009;38:1072-1081.
27.
Wallace DC: Colloquium paper: bioenergetics, the origins of complexity, and the ascent of man. Proc Natl Acad Sci USA 2011;107 (suppl 2):8947-8953.
28.
Wallace DC: Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 2010;51:440-450.
29.
John PA, Ioannidis MD: Prediction of cardiovascular disease outcomes and established cardiovascular risk factors by genome-wide association markers. Circ Cardiovasc Genet 2009;2:7-15.
30.
Sobenin IA, Chistiakov DA, Bobryshev YV, Postnov AY, Orekhov AN: Mitochondrial mutations in atherosclerosis: new solutions in research and possible clinical applications. Curr Pharm Des 2013;19:5942-5953.
31.
Davidson SM, Duchen MR: Endothelial mitochondria: contributing to vascular function and disease. Circ Res 2007;100:1128-1141.
32.
Wu LL, Chiou CC, Chang PY, Wu JT: Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin Chim Acta 2004;339:1-9.
33.
Wang YC, Lee WC, Liao SC, Lee LC, Su YJ, Lee CT, Chen JB: Mitochondrial DNA copy number correlates with oxidative stress and predicts mortality in nondiabetic hemodialysis patients. J Nephrol 2011;24:351-358.
34.
Liu CS, Kuo CL, Cheng WL, Huang CS, Lee CF, Wei YH: Alteration of the copy number of mitochondrial DNA in leukocytes of patients with hyperlipidemia. Ann NY Acad Sci 2005;1042:70-75.
35.
Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV: Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res Int 2014;2014:238463.
36.
Kennedy SR, Salk JJ, Schmitt MW, Loeb LA: Ultra-sensitive sequencing reveals an age- related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet 2013;9:e1003794.
37.
Rizza S, Copetti M, Rossi C, Cianfarani MA, Zucchelli M, Luzi A, Pecchioli C, Porzio O, Di Cola G, Urbani A, Pellegrini F, Federici M: Metabolomics signature improves the prediction of cardiovascular events in elderly subjects. Atherosclerosis 2014;232:260-264.
38.
Mercer JR, Cheng KK, Figg N, Gorenne I, Mahmoudi M, Griffin J, Vidal-Puig A, Logan A, Murphy MP, Bennett M: DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome. Circ Res 2010;107:1021-1031.
39.
Harrison CM, Pompilius M, Pinkerton KE, Ballinger SW: Mitochondrial oxidative stress significantly influences atherogenic risk and cytokine-induced oxidant production. Environ Health Perspect 2011;119:676-681.
40.
Ding Z, Liu S, Wang X, Khaidakov M, Dai Y, Mehta JL: Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis. Sci Rep 2013;3:1077.
41.
Wang Y, Wang GZ, Rabinovitch PS, Tabas I: Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-κB-mediated inflammation in macrophages. Circ Res 2014;114:421-433.
42.
Yu E, Calvert PA, Mercer JR, Harrison J, Baker L, Figg NL, Kumar S, Wang JC, Hurst LA, Obaid DR, Logan A, West NE, Clarke MC, Vidal-Puig A, Murphy MP, Bennett MR: Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans. Circulation 2013;128:702-712.
43.
Ding Z, Liu S, Wang X, Dai Y, Khaidakov M, Deng X, Fan Y, Xiang D, Mehta JL: LOX-1, mtDNA damage, and NLRP3 inflammasome activation in macrophages: implications in atherogenesis. Cardiovasc Res 2014;103:619-628.
44.
Lee HY, Chung U, Park MJ, Yoo JE, Han GR, Shin KJ: Differential distribution of human mitochondrial DNA in somatic tissues and hairs. Ann Hum Genet 2006;70(pt 1):59-65.
45.
Kroenke CH, Pletcher MJ, Lin J, Blackburn E, Adler N, Matthews K, Epel E: Telomerase, telomere length, and coronary artery calcium in black and white men in the CARDIA study. Atherosclerosis 2012;220:506-512.
46.
Raschenberger J, Kollerits B, Hammerer- Lercher A, Rantner B, Stadler M, Haun M, Klein-Weigel P, Fraedrich G, Kronenberg F: The association of relative telomere length with symptomatic peripheral arterial disease: results from the CAVASIC study. Atherosclerosis 2013;229:469-474.
47.
Moslehi J, DePinho RA, Sahin E: Telomeres and mitochondria in the aging heart. Circ Res 2012;110:1226-1237.
48.
Chung IM, Schwartz SM, Murry CE: Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development. Am J Pathol 1998;152:913-923.
49.
Schwartz SM, Murry CE: Proliferation and the monoclonal origins of atherosclerotic lesions. Ann Rev Med 1998;49:437-460.
50.
Bogliolo M, Izzotti A, De Flora S, Carli C, Abbondandolo A, Degan P: Detection of the ‘4,977 bp' mitochondrial DNA deletion in human atherosclerotic lesions. Mutagenesis 1999;14:77-82.
51.
Mueller EE, Eder W, Ebner S, Schwaiger E, Santic D, Kreindl T, Stanger O, Paulweber B, Iglseder B, Oberkofler H, Maier R, Mayr JA, Krempler F, Weitgasser R, Patsch W, Sperl W, Kofler B: The mitochondrial T16189C polymorphism is associated with coronary artery disease in Middle European populations. PLoS One 2011;6:e16455.
52.
Sazonova M, Budnikov E, Khasanova Z, Sobenin I, Postnov A, Orekhov A: Studies of the human aortic intima by a direct quantitative assay of mutant alleles in the mitochondrial genome. Atherosclerosis 2009;204:184-190.
53.
Sobenin IA, Sazonova MA, Postnov AY, Bobryshev YV, Orekhov AN: Mitochondrial mutations are associated with atherosclerotic lesions in the human aorta. Clin Dev Immunol 2012;2012:832464.
54.
Sobenin IA, Sazonova MA, Postnov AY, Bobryshev YV, Orekhov AN: Changes of mitochondria in atherosclerosis: possible determinant in the pathogenesis of the disease. Atherosclerosis 2013;227:283-288.
55.
Sobenin IA, Sazonova MA, Ivanova MM, Zhelankin AV, Myasoedova VA, Postnov AY, Nurbaev SD, Bobryshev YV, Orekhov AN: Mutation C3256T of mitochondrial genome in white blood cells: novel genetic marker of atherosclerosis and coronary heart disease. PLoS One 2012;7:e46573.
56.
Sobenin IA, Sazonova MA, Postnov AY, Salonen JT, Bobryshev YV, Orekhov AN: Association of mitochondrial genetic variation with carotid atherosclerosis. PLoS One 2013;8:e68070.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.