The of oxidative stress, and has been associated with

The mitochondria, cellular organelles present in all animal
cells, are essential to sustaining cellular energy production and cell
metabolism. They play an essential role in ATP production, regulation of
intracellular calcium, production and scavenging of intracellular reactive
oxygen species (ROS) and regulation of apoptosis. ROS are continuously formed
in small quantities during metabolic processes, are fundamental to any biochemical
process and have an important role as signaling molecules , . However, the
excessive production of ROS is toxic and can oxidatively damage macromolecules
. ROS have different diffusion distance depending on their lifetime and
reactivity. For example, the highly reactive OH• has a short diffusion range,
while H2O2 has a relatively long diffusion range. Depending on their distance
from a target ROS may oxidize mitochondrial and cellular macromolecules, such
as DNA, proteins, lipids and carbohydrates triggering mitochondrial dysfunction
and mediating numerous redox mediated pathologies ,3. Direct oxidation of
amino acid residues of proteins may cause many post-translational
modifications. Oxidation of other cellular components may lead to the formation
of reactive intermediates that may further induce post-translational
modification of proteins . Polyunsaturated fatty acids (PUFAs) are
susceptible to ROS induced damage yielding reactive aldehydes. Peroxidation of
PUFAs leads to biomembrane destruction, alters membrane fluidity and
permeability yielding membrane dysfunction and also loss of viability .
Moreover, the cleavage of the PUFA backbone which leads to formation of species
such as reactive carbonyls leaves behind a shorter, fragment still attached to
a phosphatidyl unit. Such fragments are less hydrophobic and so tend to flip
over, exposing themselves on the outside of the membrane. These “lipid
whiskers” can serve to initiate the apoptotic cascades . Peroxidation of
lipids (LPO) is considered to be one of the most important mechanisms on cell
injury under condition of oxidative stress, and has been associated with the
pathology of numerous diseases including metabolic syndrome. ROS induced LPO
starts with the abstraction of hydrogen at the PUFA bisallylic site, i.e.
–CH=CH-CH2-CH=CH–, yielding bisallylic radical . The final products of lipid
peroxidation are reactive aldehydes, such as 4-hydroxyalkenals and other
similar ?,?-unsaturated aldehydes, among which the most important are
4-hydroxynonenal (HNE), 4-hydroxyhexenal (HHE), malondialdehyde (MDA) and
acrolein . LPO-derived reactive aldehydes are more stable than ROS and can
diffuse from their site of origin and affect targets distant from the initial
free radical attack 5, because of which they are also known as second
messengers of free radicals in health and disease such is diabetes mellitus ,
. The ?,?-unsaturated aldehydes were shown to regulate signaling kinases
through functional modification and thus regulate inflammation, apoptosis, and
other signaling pathways , . A great number of these aldehydes have been
isolated from biological samples, where they may promote and reinforce cell
damage induced by oxidative stress . More hydrophobic species such as HNE are
confined to the lipid membranes thus mostly affecting the membrane proteins,
while less hydrophobic carbonyls can do damage in the aqueous phase outside of
the membranes. Such reactive aldehydes are subject to Michael addition
reactions with the side chains of lysine, histidine, and cysteine residues as
we have recently reviewed in the Journal of Proteomics . The common effect
of protein carbonylation is enzyme inactivation i.e. loss of function, however
protein carbonylation may also result in a gain of function 5,15, .  In response to oxidative stress, the
transcription factor nuclear respiratory factor 2 (NRF2) is considered as the
central protein that interacts with the antioxidant response element sequence to
activate gene transcription .

Cardiovascular diseases, diabetes and obesity are some of
the components of the metabolic syndrome that are closely associated with
excessive ROS production promoting mitochondrial dysfunction and are marked by
decreased mitochondrial biogenesis, altered membrane potential and impairment
in mitochondrial oxidative metabolism , . In the last decades, an effort has
been made to establish and improve mitochondria-targeted strategies to reduce
oxidative stress and to maintain mitochondrial function and dynamics in
metabolic syndrome. Current strategies include both pharmacological and
lifestyle interventions in order to reduce / delay the progression of metabolic
disorders. Still, till today the underlying mechanisms of ROS induced
mitochondrial dysfunction for metabolic syndrome pathogenesis are largely
unknown. Mitochondrial biogenesis, commonly present in metabolic disorders, is
regulated by several transcription factors such as peroxisome
proliferator-activated receptor ? coactivator-1? (PGC-1?). Lifestyle interventions
like physical activity mediates mitochondrial PGC-1? downstream signaling among
which are NRF1, NRF2 and mitochondrial transcription factors A (Tfam) that
promote mitochondrial biogenesis . AMP-activated protein kinase (AMPK) and
sirtuin (SIRT1) regulate PGC-1? and consequently mitochondrial biogenesis.
During the normal growth process of cells fission and fusion of mitochondria
are in a fine balance. However, disruption in mitochondrial dynamics directly
causes mitochondrial dysfunction affecting calcium homeostasis, ATP release,
activity of mitochondrial enzymes and promotes excessive production of ROS .
Cardiovascular or other metabolic disorders lead to fragmentation of
mitochondria that are cleared from the cells by the mitophagy process. However,
when mitophagy is inhibited the malfunctional mitochondria promote excessive
production of ROS and further reduce mitochondrial biogenesis , . The
imbalance in the body energy metabolism consequently leads to the imbalance in
cellular metabolism and promoting metabolic syndrome, as in the case of obesity
and other metabolic disorders. Altered cellular metabolism homeostasis due to
elevated glucose levels leads to accumulation of lipids and free fatty acids
(FFA), impairment of insulin signaling pathway and excessive ROS that further
induce morphological mitochondrial changes , . Overproduction of ROS by
malfunctional mitochondrial and altered oxidation of citrate shuttle acetyl
coenzyme A consequently inhibits insulin signaling. However it is still not
clear whether mitochondrial dysfunction is induced by insulin resistance or
insulin resistance is induced by mitochondrial dysfunction. It has been
documented that enhanced ROS production and mitochondrial dysfunction in
skeletal muscle is associated with insulin resistance and metabolic syndrome
suggesting that normal mitochondrial oxidative function is crucial to maintain
the cellular energy and insulin signaling homeostasis. Accumulation of lipids
and FFA and decreased fatty acid oxidation decreases ATP synthesis and
mitochondrial oxidative function contributing to insulin resistance and
development of metabolic disorders , .

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Earlier studies demonstrated the ability of steroids to
stimulate mitochondrial biogenesis , . Androgen deficiency, on the other
hand, has been associated with mitochondrial dysfunction and metabolic syndrome
. Ecdysteroids are a legal compounds whose structure are somewhat similar to
androgens, however the mechanism of action are different as they do not bind to
cytosolic steroid receptor. Despite the differences in the signaling cascade
they seem to exert in humans many effects similar to androgens . Most of the
pharmacological effects of ecdysteroids are reported to be beneficial to
humans, e.g. in diabetes and asthenia , . The mechanism of action of
ecdysteroids includes both genomic and non-genomic actions. Recent study
proposed that one of the mechanisms of action might be through modulation of
mitochondrial function as it was observed a co-localization of ecdysteroid
receptor with mitochondria . However, to the best of our knowledge no
studies have shown a direct effect of ecdysteroids on mitochondrial biogenesis.
Thus understanding mitochondrial function and the underlying mechanisms of
modulation of mitochondrial function by different mitochondria-targeted
approaches is one of the crucial steps in understanding the development and
progression of metabolic syndrome.