Atherosclerosis is a multifactorial disease of the cardiovascular system associated with aging, inflammation, and oxidative stress. An important role in the development of atherosclerosis play elevated plasma lipoproteins. A number of external factors (smoking, diabetes, infections) can also contribute to the development of the disease. For a long time, atherosclerosis remains asymptomatic, therefore, the search for early markers of the disease is critical for the timely management and better outcomes for patients. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage appear to connect different aspects of atherosclerosis pathogenesis. To date, multiple lines of research have demonstrated the strong association of mitochondrial dysfunction with the development of various human diseases. Therapies aimed at restoring the mitochondrial function are being actively developed, and are expected to broaden the therapeutic possibilities for several chronic human diseases. The development of such therapies depends on our understanding of the functional roles of different mtDNA variants associated with one or another disorder, and the molecular mechanisms linking mitochondrial dysfunction with a given pathological feature. These questions are, however, challenging and require future intensive research. This review summarizes the recent studies and describes the central processes of the development of atherosclerosis, and shows their relationship with mitochondrial dysfunction. One of the promising therapeutic approaches for future atherosclerosis treatments is the use of mitochondria-targeted antioxidants. Future studies should focus on characterizing the mechanisms of mitochondrial involvement in cardiovascular pathologies to better direct the search for novel therapies.

Trace amines are a group of biogenic amines that are structurally and functionally close to classical monoamine neurotransmitters. Trace amine-associated receptors (TAARs) are emerging as promising targets for treating neuropsychiatric disorders. It has been documented that all TAARs, apart from TAAR1, function as olfactory receptors involved in sensing innate odors encoded by volatile amines. However, recently, brain expression and function of TAAR5 were also demonstrated. In this study, we assessed the behavior, brain neurochemistry, and electrophysiology changes in knock-out mice lacking Trace amine-associated receptor 2 (TAAR2) but expressing beta-Galactosidase mapping expression of TAAR2 receptors. As expected, we detected beta-Galactosidase staining in the glomerular layer of the olfactory bulb. However, we also found staining in the deeper layers of the olfactory bulb and several brain regions, including the hippocampus, cerebellum, cortex, raphe nuclei, hypothalamus, and habenula, indicating that TAAR2 receptors are not only expressed in the olfactory system but are also present in the limbic brain areas that receive olfactory input. In behavioral experiments, TAAR2 knock-out (TAAR2-KO) mice showed increased locomotor activity and less immobility in the forced swim test, with no changes in anxiety level. Furthermore, TAAR2-KO mice showed alterations in brain electrophysiological activity—particularly, decreased spectral power of the cortex and striatum in the 0, 9–20 Hz range. TAAR2-KO mice also had elevated tissue dopamine levels in the striatum and an increased dopaminergic neuron number in the Substantia Nigra. In addition, an increased brain-derived neurotrophic factor (BDNF) mRNA level in the striatum and Monoamine Oxidase B (MAO-B) mRNA level in the striatum and midbrain was found in TAAR2-KO mice. Importantly, TAAR2-KO mice demonstrated an increased neuroblast-like and proliferating cell number in the subventricular and subgranular zone, indicating increased adult neurogenesis. These data indicate that in addition to its role in the innate olfaction of volatile amines, TAAR2 is expressed in limbic brain areas and regulates the brain dopamine system, neuronal electrophysiological activity, and adult neurogenesis. These findings further corroborated observations in TAAR1-KO and TAAR5-KO mice, indicating common for TAAR family pattern of expression in limbic brain areas and role in regulating monoamine levels and adult neurogenesis, but with variable involvement of each subtype of TAAR receptors in these functions.

Classical monoamines are well-known modulators of sensorimotor neural networks. However, the role of trace amines and their receptors in sensorimotor function remains unexplored. Using trace amine-associated receptor 5 knockout (TAAR5-KO) mice, that express beta-galactosidase mapping its localization, we observed TAAR5 expression in the Purkinje cells of the cerebellum and the medial vestibular nucleus, suggesting that TAAR5 might be involved in the vestibular and motor control. Accordingly, in various behavioral tests, TAAR5-KO mice demonstrated lower endurance, but better coordination and balance compared to wild-type controls. Furthermore, we found specific changes in striatal local field potentials and motor cortex electrocorticogram, such as a decrease in delta and an increase in theta oscillations of power spectra, respectively. The obtained data indicate that TAAR5 plays a considerable role in regulation postural stability, muscle force, balance, and motor coordination during active movements, likely via modulation of monoaminergic systems at different levels of sensorimotor control involving critical brain areas such as the brainstem, cerebellum, and forebrain.

Atherosclerosis is a complex pathology that involves both metabolic dysfunction and chronic inflammatory process. During the last decade, a considerable progress was achieved in describing the pathophysiological features of atherosclerosis and developing approaches that target the abnormal lipid metabolism and chronic inflammation. However, early events in the arterial wall that initiate the disease development still remain obscure. Finding effective therapeutic targets in these early processes would allow developing methods for disease prevention and, possibly, atherosclerotic plaque regression. Currently, these early events are being actively studied by several research groups. One of the processes that are being investigated is the development of mitochondrial dysfunction, which was demonstrated to be present in the affected areas of the arterial wall. Detection and characterization of mitochondrial dysfunction associated with several chronic human disorders was made possible by the improved methods of studying mitochondrial biology and detecting mitochondrial DNA (mtDNA) mutations. It was found to be involved in several key atherogenic processes, such as oxidative stress, chronic inflammation, and intracellular lipid accumulation. Mitochondrial dysfunction can occur in all types of cells involved in the pathogenesis of atherosclerosis: monocytes and macrophages, smooth muscle cells, lymphocytes, and the endothelial cells. However, therapies that would specifically target the mitochondria to correct mitochondrial dysfunction and neutralize the defective organelles are still remain to be developed and characterized. The aim of this review is to outline the prospects for mitochondrial therapy for atherosclerosis. We discuss mechanisms of mitochondria-mediated atherogenic processes, known mitochondria-targeting therapy strategies, and novel mitochondria-targeting drugs in the context of atherosclerosis.