Cardiovascular disease (CVD) is a leading cause of mortality worldwide. Proper mitochondrial function is necessary in tissues and organs that are of high energy demand, including the heart. Mitochondria are very sensitive to nutrient and oxygen supply and undergo metabolic adaptation to the changing environment. In CVD, such an adaptation is impaired, which, in turn, leads to a progressive decline of the mitochondrial function associated with abnormalities in the respiratory chain and ATP synthesis, increased oxidative stress, and loss of the structural integrity of mitochondria. Uncoupling of the electron transport chain in dysfunctional mitochondria results in enhanced production of reactive oxygen species, depletion of cell ATP pool, extensive cell damage, and apoptosis of cardiomyocytes. Mitophagy is a process, during which cells clear themselves from dysfunctional and damaged mitochondria using autophagic mechanism. Deregulation of this process in the failing heart, accumulation of dysfunctional mitochondria makes the situation even more adverse. In cardiac pathology, aberrations of the activity of the respiratory chain and ATP production may be considered as a core of mitochondrial dysfunction. Indeed, therapeutic restoration of these key functional properties can be considered as a primary goal for improvement of mitochondrial dysfunction in CVD. Key messages Mitochondrial dysfunction plays a crucial role in cardiovascular disease pathogenesis. Cardiovascular disease is associated with altered mithochondrial biogenesis and clearance. In cardiovascular disease, impaired mitochondrial function results in decreased ATP production and enhanced ROS formation.

Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H(2) from its oxidized form that appears as a result of the antioxidant activity of SkQ1H(2). SkQ1H(2) prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H(2)O(2)-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondria-mediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast "biochemical suicide" of an organism after a severe metabolic crisis.

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There are several types of mitochondrial cytopathies, which cause a set of disorders, arise as a result of mitochondria’s failure. Mitochondria’s functional disruption leads to development of physical, growing and cognitive disabilities and includes multiple organ pathologies, essentially disturbing the nervous and muscular systems. The origins of mitochondrial cytopathies are mutations in genes of nuclear DNA encoding mitochondrial proteins or in mitochondrial DNA. Nowadays, numerous mtDNA mutations significant to the appearance and progress of pathologies in humans are detected. In this mini-review, we accent on the mitochondrial cytopathies related to mutations of mtDNA. As well known, there are definite set of symptoms of mitochondrial cytopathies distinguishing or similar for different syndromes. The present article contains data about mutations linked with cytopathies that facilitate diagnosis of different syndromes by using genetic analysis methods. In addition, for every individual, more effective therapeutic approach could be developed after wide-range mutant background analysis of mitochondrial genome.

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Myocardial infarction is one of the clinical manifestations of coronary heart disease. In some cases, the cause of myocardial infarction may be atherosclerotic plaques which occurred in the human aorta. The association of mtDNA mutations with atherosclerotic lesions in human arteries was previously detected by our research group. In this study, we used samples of white blood cells collected from 225 patients with myocardial infarction and 239 control persons with no health complaints. DNA was isolated from the blood leukocyte samples. Then, PCR fragments of DNA were obtained. They contained the investigated regions of 11 mitochondrial genome mutations (m.5178C>A, m.3336T>C, m.652delG, m.12315G>A, m.14459G>A, m.652insG, m.14846G>A, m.13513G>A, m.1555A>G, m.15059G>A, m.3256C>T). According to the obtained results, three mutations of the human mitochondrial genome correlated with myocardial infarction. A positive correlation was observed for mutation m.5178C>A. At the same time, a highly significant negative correlation with myocardial infarction was observed for mutation m.14846G>A. One single-nucleotide substitution of m.12315G>A had a trend towards negative correlation. These mutations can potentially be useful for creating molecular/cellular models for studying the mechanisms of myocardial infarction and designing novel therapies. Moreover, these mutations can possibly be used for diagnostic purposes.

In the present work, a pilot creation of four cybrid cultures with high heteroplasmy level was performed using mitochondrial genome mutations m.12315G>A and m.1555G>A. According to data of our preliminary studies, the threshold heteroplasmy level of mutation m.12315G>A is associated with atherosclerosis. At the same time, for a mutation m.1555G>A, such a heteroplasmy level is associated with the absence of atherosclerosis. Cybrid cultures were created by fusion of rho0-cells and mitochondria from platelets with a high heteroplasmy level of the investigated mutations. To create rho0-cells, THP-1 culture of monocytic origin was taken. According to the results of the study, two cybrid cell lines containing mutation m.12315G>A with the heteroplasmy level above the threshold value (25% and 44%, respectively) were obtained. In addition, two cybrid cell lines containing mutation m.1555G>A with a high heteroplasmy level (24%) were obtained. Cybrid cultures with mtDNA mutation m.12315G>A can be used to model both the occurrence and development of atherosclerosis in cells and the titration of drug therapy for patients with atherosclerosis. With the help of cybrid cultures containing single nucleotide replacement of mitochondrial genome m.1555G>A, it is possible to develop approaches to the gene therapy of atherosclerosis.

Experimental evidence suggests an immense variety of processes associated with and aimed at producing reactive oxygen and/or nitrogen species. Clinical studies implicate an enormous range of pathologies associated with reactive oxygen/nitrogen species metabolism deregulation, particularly oxidative stress. Recent advances in biochemistry, proteomics and molecular biology/biophysics of cells suggest oxidative stress to be an endpoint of complex dysregulation events of conjugated pathways consolidated under the term, proposed here, "oxidative status". The oxidative status concept, in order to allow for novel diagnostic and therapeutic approaches, requires elaboration of a new logic system comprehending all the features, versatility and complexity of cellular pro- and antioxidative components of different nature. We have developed a curated and regularly updated interactive interactome map of human cellular-level oxidative status allowing for systematization of the related most up-to-date experimental data. A total of more than 600 papers were selected for the initial creation of the map. The map comprises more than 300 individual factors with respective interactions, all subdivided hierarchically for logical analysis purposes. The pilot application of the interactome map suggested several points for further development of oxidative status-based technologies.