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

Autor:	Khotina VA; Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315Moscow, Russia., Vinokurov AY; Cell Physiology and Pathology Laboratory of R&D Center of Biomedical Photonics, Orel State University, 95 Komsomolskaya Street, 302026 Orel, Russia., Sinyov VV; Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia.; Institute of Experimental Cardiology named after V.N. Smirnov, Federal State Budgetary Institution ' National Medical Research Center of Cardiology named after E.I. Chazov', 15A Academician Chazov Street, 121359 Moscow, Russia.; A.P. Avtsyn Research Institute of Human Morphology, Federal State Budgetary Scientific Institution 'Petrovsky National Research Centre of Surgery', 3 Tsyurupa Street, 117418 Moscow, Russia., Zhuravlev AD; Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia.; A.P. Avtsyn Research Institute of Human Morphology, Federal State Budgetary Scientific Institution 'Petrovsky National Research Centre of Surgery', 3 Tsyurupa Street, 117418 Moscow, Russia., Popov DY; Cell Physiology and Pathology Laboratory of R&D Center of Biomedical Photonics, Orel State University, 95 Komsomolskaya Street, 302026 Orel, Russia., Sukhorukov VN; Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia.; Institute of Experimental Cardiology named after V.N. Smirnov, Federal State Budgetary Institution ' National Medical Research Center of Cardiology named after E.I. Chazov', 15A Academician Chazov Street, 121359 Moscow, Russia.; A.P. Avtsyn Research Institute of Human Morphology, Federal State Budgetary Scientific Institution 'Petrovsky National Research Centre of Surgery', 3 Tsyurupa Street, 117418 Moscow, Russia.; Institute for Atherosclerosis Research, 4-1-207 Osennyaya Street, 121096 Moscow, Russia., Sobenin IA; Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia.; Institute of Experimental Cardiology named after V.N. Smirnov, Federal State Budgetary Institution ' National Medical Research Center of Cardiology named after E.I. Chazov', 15A Academician Chazov Street, 121359 Moscow, Russia., Orekhov AN; Institute of General Pathology and Pathophysiology, 8 Baltiyskaya Street, 125315 Moscow, Russia.; A.P. Avtsyn Research Institute of Human Morphology, Federal State Budgetary Scientific Institution 'Petrovsky National Research Centre of Surgery', 3 Tsyurupa Street, 117418 Moscow, Russia.; Institute for Atherosclerosis Research, 4-1-207 Osennyaya Street, 121096 Moscow, Russia.
Jazyk:	angličtina
Zdroj:	Current medicinal chemistry [Curr Med Chem] 2024 Oct 11. Date of Electronic Publication: 2024 Oct 11.
DOI:	10.2174/0109298673323639240926095549
Abstrakt:	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. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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