Mitochondrial Mutations in Atherosclerosis: New Solutions in Research and Possible Clinical Applications

Abstract

Cardiovascular diseases are the leading causes of morbidity and mortality in many industrialized societies. Atherosclerosis is the major risk factor for the development of cardiovascular disease based on arterial endothelial dysfunction caused by the impairment of endothelial-dependent dilation. Atherosclerosis is a complex vascular disease resulted from the harmful interactions between genetic and environmental factors. There is a growing body of evidence in support of a non-redundant role of mitochondrial factors in the pathogenesis of atherosclerosis. Impaired mitochondrial function and structural and qualitative changes in mitochondrial components such as mitochondrial DNA (mtDNA) may be directly involved in the development of multiple atherogenic mechanisms including advanced oxidative stress, abnormalities in glucose and fat metabolism, and altered energy homeostasis. Recent findings showed that the heteroplasmy level of some somatic mtDNA is associated with coronary atherosclerosis. Although this field should further widely elaborated, heteroplasmic mtDNA mutations could represent a new promising molecular biomarker of genetic susceptibility to atherosclerosis and related pathologic conditions. In this review, we critically consider the contribution of mitochondria-related factors to the pathogenesis of the arterial vascular pathology.

Quercetin is a potent anti‐atherosclerotic compound by activation of SIRT1 signaling under oxLDL stimulation

“…In atherosclerotic damage, high ROS concentrations cause multiple types of mitochondrial dysfunction, including injured mitochondrial dynamics and altered oxidative phosphorylation abilities . Mitochondrial dysfunction correlates positively with atherosclerosis progression .…”

Mitochondrial Aging and Age-Related Dysfunction of Mitochondria

“…Premature or accelerated vascular aging and atherosclerosis can be associated with dysfunction of mitochondria [33, 34]. …”

“…Even though mitochondrial dysfunction leads to increased oxidative stress, the role of mitochondrial mutations in atherosclerosis has not received much attention so far [33, 34]. In a recent study we analyzed the association of mitochondrial genetic variation with the severity of carotid atherosclerosis (as assessed by carotid intima-media thickness (cIMT) and the presence of coronary heart disease (CHD)) and found that heteroplasmy for several mutations in the mtDNA in leukocytes, including C3256T, T3336C, G12315A, G13513A, G14459A, G14846A, and G15059A mutations, were significantly associated with both the severity of carotid atherosclerosis and the presence of CHD [37].…”

Quantitative Assessment of Heteroplasmy of Mitochondrial Genome: Perspectives in Diagnostics and Methodological Pitfalls

“…The further important areas of research should include the studies evaluating the mechanistic role of mtDNA mutations in cellular and molecular mechanisms of atherogenesis, the changes in levels of oxidative DNA damage by means of specific drugs as well as chemopreventive agents (i.e., antioxidants), and the effects of such interventions on the initiation and progression of atherosclerosis. This understanding is of direct clinical relevance because increased mtDNA damage can be an important pathogenic factor, an additional prognostic predictor, and a potential target of therapeutic strategies in atherosclerosis [33]. …”