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In support of this, within our study, m.1555A>G heteroplasmy level negatively correlated with systolic
blood pressure and positively correlated with HDL cholesterol, thus trending to be associated with lower
cardiometabolic risk.

Mutation m.3256C>T occurring in coding sequence of the MT-TL1 gene (encodes tRNA leucine) leads to
impaired protein synthesis due to reduced number of cellular organelles [28,29] . This effect can be enhanced
by mutation m.12315G>A, which is located in the coding sequence of another gene encoding tRNA leucine,
namely, the MT-TL2 gene. So, the impairments in tRNA leucine production may act as a previously
unknown mechanism for the development of metabolic abnormalities, with the m.12315G>A mutation
[30]
known to be associated with mitochondrial encephalomyopathy .
Three mutations (m.14459G>A, m.14846G>A, and m.15059G>A) occur in coding regions of two genes
responsible for the synthesis of subunit 6 of NADH dehydrogenase and cytochrome B (MT-ND6 and
MT-CYB genes, respectively). The impairments of these respiratory chain enzymes can attenuate NADH
oxidation and ubiquinone (CoQ) reduction and promote oxidative stress. Mutation m.14459G>A leads
to alanine to valine substitution in a conserved region of ND6 protein, and is associated with several
mitochondrial disorders (Leber’s hereditary visual neuropathy, hereditary ocular neuropathy, dysfunction
of basal ganglia, atrophy of visual nerve, musculospastic syndrome and encephalopathy) [31,32] . Mutations
m.14846G>A and m.15059G>A induce the damage of cytochrome B. The former (glycine to serine
substitution at position 34) affects intermediate transfer of electrons in mitochondrial respiratory chains.
The latter (glycine to stop codon substitution at position 190) stops translation and leads to the loss of 244
amino acids at C-terminal of protein. Both mutations reduce enzymatic function of cytochrome B, and are
associated with mitochondrial disorders in various myopathies [33,34] .

The list of mtDNA mutations associated with metabolic and atherosclerotic diseases obviously needs to be
supplemented with new variants deserving further investigation. As an example, the T/C substitution at
position 16189 in the hypervariable D-loop of the control region is suspected to be associated with various
multifactorial diseases; the frequency of this mtDNA variant in patients with coronary artery disease and
type 2 diabetes mellitus was higher as compared to healthy individuals of Middle European descent in
[35]
Austria .

Defective cell metabolism is considered as the main mechanism of MetS development, due to the disbalance
[36]
of nutrient intake and utilization for energy . It is supposed that decreased fatty acid oxidation, in turn,
increases the accumulation of fatty acyl-CoAs and other fat-derived molecules in various organs and
cells, this causing the inhibition of insulin signaling, resulting in hyperinsulinemia, which targets various
organs and tissues in metabolic diseases. It is known that mtDNA mutations correlate with increased ROS
production in cells [37,38] . Thus, oxidative stress induced by genetic factors, aging and mitochondrial biogenesis
can affect mitochondrial function, leading to insulin resistance and related pathological conditions, such as
MetS, Type 2 diabetes mellitus, cardiovascular and atherosclerotic disease [39-42] . However, it is still not clear
whether mitochondrial dysfunction is one of the primary causes of cardiometabolic disturbances, or merely
[43]
a secondary effect .

Beyond doubt, this study has certain limitations. First, the atherosclerotic state of study participants
was evaluated only by carotid ultrasonography and cIMT measurement, the latter being widely used as
[44]
a surrogate marker for detecting subclinical atherosclerosis for risk prediction and disease progress .
Ultrasound-derived atherosclerosis metrics are independent predictors of cardiovascular events and improve
[45]
risk prediction when added atop of conventional cardiovascular risk factors . However, it can be argued
that cIMT and carotid plaque measurement are insufficient for the diagnostics of systemic atherosclerosis,
and therefore may be supplemented by other diagnostic techniques, like computer tomography or magnetic
resonance imaging. However, it could be true if only these methods possessed much better resolution to