Orekhov Alexander N, Sinyov Vasily V, Vyssokikh Mikhail Y, Manukhova Ludmila, Marey Maria V, Angelova Plamena R, Omelchenko Andrey V, Vinokurov Andrey Y, Khasanova Zukhra B, Sobenin Igor A
Institute for Atherosclerosis Research, Moscow, Russsia.
Institute for Atherosclerosis Research / Institute of General Pathology and Pathophysiology, Moscow, Russsia.
Curr Med Chem. 2024 Jun 14. doi: 10.2174/0109298673302002240605092523.
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.
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.
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.
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.
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.
线粒体是通过呼吸作用与氧化磷酸化作用结合进行细胞有氧能量产生的主要场所。我们最近发现了与动脉粥样硬化相关的线粒体DNA（mtDNA）突变（基因组变异）。随后，我们研究了这种关联背后的可能机制以及线粒体突变在动脉粥样硬化发生中的作用。线粒体功能障碍是包括动脉粥样硬化在内的慢性人类疾病发病机制中的一个已知组成部分。
本研究的目的是探讨细胞耗氧量与动脉粥样硬化相关线粒体突变之间是否存在关联。对线粒体呼吸异常的研究有助于了解mtDNA突变在病理学中的作用。
通过使用带有克拉克电极的极谱法，我们利用胞质杂种（细胞质杂交）细胞系测试了携带测试mtDNA变体的通透细胞呼吸受损的可能性。胞质杂种细胞系中引入的线粒体取自mtDNA突变谱不同的动脉粥样硬化患者，这使得我们能够将mtDNA突变负荷程度与胞质杂种细胞的耗氧率进行比较。
发现所研究的三个突变各自与呼吸受损相关。此外，两个特定突变的某些组合很可能与耗氧量改变有关。结果，鉴定出八个突变，其中单个或成对组合与细胞呼吸的高或低速率相关，与对照细胞有显著差异。
观察到的效应可能参与动脉粥样硬化的发病机制。对与动脉粥样硬化相关的mtDNA突变的研究有助于揭示开发新疗法的药理学靶点。
