Abstract
Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects depending on the tissue energy status. Arterial wall cells are among the most vulnerable to mitochondrial dysfunction due to their barrier and metabolic functions. In atherosclerosis, mitochondria cause alteration of cellular metabolism and respiration and are known to produce excessive amounts of reactive oxygen species (ROS) resulting in oxidative stress. These processes are involved in vascular disease and chronic inflammation associated with atherosclerosis. Currently, the list of known mtDNA mutations associated with human pathologies is growing, and many of the identified mtDNA variants are being tested as disease markers. Alleviation of oxidative stress and inflammation appears to be promising for atherosclerosis treatment. In this review, we discuss the role of mitochondrial dysfunction in atherosclerosis development, focusing on the key cell types of the arterial wall involved in the pathological processes. Accumulation of mtDNA mutations in isolated arterial wall cells, such as endothelial cells, may contribute to the development of local inflammatory process that helps explaining the focal distribution of atherosclerotic plaques on the arterial wall surface. We also discuss antioxidant and anti-inflammatory approaches that can potentially reduce the impact of mitochondrial dysfunction.
Highlights
Atherosclerosis with related cardiovascular diseases is still the leading cause of mortality worldwide
Mitochondrial dysfunction is currently recognized as an important therapeutic target for treatment of chronic human disorders, including atherosclerosis
Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutation which can be inherited or spontaneously acquired and accumulated during lifespan in different organs and tissues
Summary
Atherosclerosis with related cardiovascular diseases is still the leading cause of mortality worldwide. Macroscopic examination of post-mortem aortic wall specimens allows distinguishing areas, unaffected by atherosclerosis or developing diffuse intimal thickening, and areas containing atherosclerotic plaques at different development stages Microscopic study of such samples demonstrated that atherosclerotic plaque development may possibly be explained by the course of local inflammatory response. The mtDNA, which is located close to the mitochondrial membranes where the reactions take place, is exposed to elevated ROS levels Questionable, such exposure is generally believed to be one of the possible explanations of increased mutagenesis rate in the mtDNA as compared to genomic DNA. As mitochondria are inherited through the maternal line, so do known inherited mitochondrial diseases, such as MIDD (maternally inherited diabetes and deafness) or MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) [10] These conditions are associated with increased risk of stroke and cardiovascular events, their link to atherosclerosis remains elusive. Restoration of mitochondrial function using different strategies is considered as attractive therapeutic approach, and such strategies are being actively developed [14]
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