Mitochondrial Dysfunction Associated with mtDNA Mutation: Mitochondrial Genome Editing in Atherosclerosis Research.

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Current medicinal chemistry Pub Date : 2024-10-11 DOI:10.2174/0109298673323639240926095549
Victoria A Khotina, Andrey Y Vinokurov, Vasily V Sinyov, Alexander D Zhuravlev, Daniil Y Popov, Vasily N Sukhorukov, Igor A Sobenin, Alexander N Orekhov
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Abstract

Background: Atherosclerosis is a complex cardiovascular disease often associated with mitochondrial dysfunction, which can lead to various cellular and metabolic abnormalities. Within the mitochondrial genome, specific mutations have been implicated in contributing to mitochondrial dysfunction. Atherosclerosis-associated m.15059G>A mutation has been of particular interest due to its potential role in altering mitochondrial function and cellular health.

Objective: This study aims to investigate the role of the atherosclerosis-associated m.15059G>A mutation in the development of mitochondrial dysfunction in monocyte-- like cells.

Methods: Monocyte-like cytoplasmic hybrid cell line TC-HSMAM1, which contains the m.15059G>A mutation in mtDNA, was used. The MitoCas9 vector was utilized to eliminate mtDNA copies carrying the m.15059G>A mutation from TC-HSMAM1 cybrids. Mitochondrial membrane potential, generation of reactive oxygen species, and lipid peroxidation levels were assessed using flow cytometry. Cellular reduced glutathione levels were assessed using the confocal microscopy. The oxygen consumption rate was measured using polarographic oxygen respirometry.

Results: The elimination of the m.15059G>A mutation resulted in a significant increase in mitochondrial membrane potential and improved mitochondrial efficiency while also causing a decrease in the generation of reactive oxygen species, lipid peroxidation, as well as cellular bioenergetic parameters, such as proton leak and non-mitochondrial oxygen consumption. At the same time, no changes were found in the intracellular antioxidant system after the mitochondrial genome editing.

Conclusions: The presence of the m.15059G>A mutation contributes to mitochondrial dysfunction by reducing mitochondrial membrane potential, increasing the generation of reactive oxygen species and lipid peroxidation, and altering mitochondrial bioenergetics. Elimination of the mtDNA containing atherogenic mutation leads to an improvement in mitochondrial function.

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与 mtDNA 突变有关的线粒体功能障碍:动脉粥样硬化研究中的线粒体基因组编辑。
背景:动脉粥样硬化是一种复杂的心血管疾病,通常与线粒体功能障碍有关,线粒体功能障碍可导致各种细胞和代谢异常。线粒体基因组中的特定突变与线粒体功能障碍有关。动脉粥样硬化相关的 m.15059G>A 突变因其在改变线粒体功能和细胞健康方面的潜在作用而受到特别关注:本研究旨在探讨动脉粥样硬化相关m.15059G>A突变在类单核细胞线粒体功能障碍发展过程中的作用:方法:使用含有mtDNA m.15059G>A突变的单核细胞样胞质杂交细胞系TC-HSMAM1。利用MitoCas9载体消除TC-HSMAM1细胞杂交体中携带m.15059G>A突变的mtDNA拷贝。使用流式细胞术评估线粒体膜电位、活性氧的生成和脂质过氧化水平。使用共聚焦显微镜评估细胞还原型谷胱甘肽水平。采用极谱氧呼吸测定法测量耗氧率:结果:消除 m.15059G>A 突变后,线粒体膜电位显著增加,线粒体效率提高,同时活性氧的生成、脂质过氧化以及质子泄漏和非线粒体耗氧量等细胞生物能参数也有所下降。同时,线粒体基因组编辑后细胞内抗氧化系统没有发生变化:结论:m.15059G>A 基因突变通过降低线粒体膜电位、增加活性氧和脂质过氧化的产生以及改变线粒体生物能,导致线粒体功能障碍。消除含有致动脉粥样硬化突变的 mtDNA 可改善线粒体功能。
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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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