Relationship between Cellular Oxygen Consumption and Atherosclerosis-Associated Mitochondrial Mutations (Variants of the Mitochondrial Genome).

ABSTRACT

BACKGROUND: Mitochondria are the main sites of cellular aerobic energy production through conjugation of respiration and oxidative phosphorylation. We have recently discovered mutations (genome variants) of mitochondrial DNA (mtDNA) associated with atherosclerosis. We have then investigated the possible mechanisms underlying such association and the role of mitochondrial mutations in atherogenesis. Mitochondrial dysfunction is a known component of the pathogenesis of chronic human diseases, including atherosclerosis. OBJECTIVE: The aim of the study was to explore whether there is a relationship between cellular oxygen consumption and atherosclerosis-associated mitochondrial mutations. The study of mitochondrial respiration abnormalities can help to understand the role of mtDNA mutations in pathology. METHOD: By using the polarographic method with Clark electrode, we tested the possibility of respiration impairment in permeabilized cells carrying the tested mtDNA variants using the cybrid (cytoplasmic hybrid) lines. Mitochondria introduced in the cybrid lines were obtained from atherosclerotic patients that differed in the profile of mtDNA mutations, which made it possible to compare the degree of mtDNA mutation load with the rate of oxygen consumption by cybrid cells. RESULTS: It was found that three of the studied mutations were individually associated with impaired respiration. Besides, some combinations of two specific mutations have a high probability of being associated with altered oxygen consumption. As a result, eight mutations were identified, individually or paired combinations of which were associated with high or low rates of cellular respiration, significantly different from control cells. CONCLUSION: The observed effect may be involved in the pathogenesis of atherosclerosis. The study of mtDNA mutations associated with atherosclerosis can help reveal pharmacological targets for the development of novel therapies.