Title:Relationship between Cellular Oxygen Consumption and Atherosclerosis-associated Mitochondrial Mutations (Variants of the Mitochondrial Genome)
Volume: 33
Issue: 8
Author(s): Alexander Nikolaevich Orekhov*, Vasily Vladimirovich Sinyov, Mikhail Yurievich Vyssokikh, Ludmila Manukhova, Maria Vladimirovna Marey, Plamena Rumyanova Angelova, Andrey Vladimirovich Omelchenko, Andrey Yurievich Vinokurov, Zukhra B. Khasanova and Igor Aleksandrovich Sobenin
Affiliation:
- Institute for Atherosclerosis Research, Moscow, Russsia
Keywords:
Atherosclerosis, mitochondria, mtDNA mutation, respiration, mitochondrial dysfunction, cybrid cells.
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.
Methods: 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.
