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Aminizadeh et al. | Journal of Clinical and Translational Research 2024; 10(6): 348-356 349
inflammation, which leads to a vicious cycle between chronic cycle progression, mitochondrial bioenergetics maintenance,
inflammation and mitochondrial reactive oxygen species (ROS) apoptosis, and autophagy, affect MFN2 expression [15].
production [2]. Moreover, mitochondrial fission is influenced by proteins such
Exercise training provides a powerful boost to initiate the as mitochondrial fission 1 protein (FIS1) and DRP1, while the
signaling pathways described above, which eventually create fusion process is mediated by the optic atrophy 1 (OPA1) and
strong phenotypic changes in the mitochondria and improve the mitofusins protein family [16].
quantity and quality of the organelle network, leading to greater MitoQ, a mitochondria-targeted antioxidant supplement,
muscle health [3]. Exercise triggers an adaptive response scavenges free radicals, reduces oxidant production and
through redox signaling that increases mitochondrial function lipid peroxidation, and removes peroxide nitrite [17], being
(a combination of quality and quantity), boosting metabolism ~800-fold more effective than untargeted antioxidants. It
and antioxidant stores, not only allowing the organism to condenses on the matrix surface of the inner mitochondrial
better control inflammation but also making it more resistant membrane and exerts antioxidative effects by oxidizing
to most stressors [4]. In addition, mitochondria can be involved ubiquinol to ubiquinone [18]. It has been shown that chronic
in the progression of sarcopenia as they are critical controllers administration of MitoQ ameliorates mitochondrial ROS
of an assortment of variables that contribute to the etiology production in the skeletal muscles of middle-aged men [19].
of the condition, such as ATP provision, oxidative stress, and The MitoQ supplement is an advanced orally used antioxidant
apoptosis, as well as inflammation and calcium ions (Ca ) that protects the mitochondria as the energy production site.
2+
handling [5]. Regular aerobic exercise can relieve inveterate MitoQ is designed to accumulate in the mitochondrial matrix
irritation in skeletal muscle by activating mitochondrial quality and ultimately exert beneficial effects by electron reduction and
control processes to improve organelle phenotypes, with the free radical attenuation [20]. MitoQ reduces the production of
possibility of reducing the release of mitochondrial damage- ROS and imbalance in mitochondrial membrane potential [21],
associated molecular patterns (mtDAMPs). This could attenuate prevents endothelial cell death, and normalizes vascular function
inflammasome activation and counteract the detrimental in various diseases [22]. However, the effectiveness of MitoQ
effects of chronic inflammation on muscle development and supplementation is not fully understood. In another study, the
function [6]. effect of MitoQ in combination with endurance training (ET) on
Mitochondrial stress, a consequence of stimuli such as male athletes showed that MitoQ supplementation increases the
exercise training, leads to the release of significant stress signals antioxidant capacity of skeletal muscle [23].
including ROS and Ca , which are crucial in regulating cellular Scientists have utilized a variety of exercise training protocols
2+
signaling cascades [7]. However, excessive mitochondrial stress to challenge skeletal muscle to determine the effect on acute
or failure of the adaptive response may result in irreversible mitochondrial signaling and chronic mitochondrial adaptation.
mitochondrial damage and the release of apoptotic signals, Moore et al. [24] showed that regulators of mitochondrial fission,
ultimately triggering cellular apoptosis [7]. During the apoptosis Fis1, and Dnm1L (encodes the protein DRP1) were upregulated
process, mitochondria are influenced by dynamic changes in in the skeletal muscle of mice after ET for 90 min, although
various proteins, such as dynamin-related protein 1 (Drp1) only Fis1 expression remained elevated during the 3-h recovery
and the apoptotic regulators BAX and BCL-2 [8]. In addition, period, and Dnm1L expression returned to baseline (90-min
peroxisome proliferator-activated receptor gamma coactivator exercise training + 3-h rest). In contrast to Fis1, mitochondrial
1-alpha (PGC-1α) is essential for regulating key factors that fission factor (Mff) expression was reduced during acute exercise
orchestrate mitochondrial dynamics and mitophagy, such as and this reduction in expression reached statistical significance
mitofusin 2 (MFN2), DRP1, PTEN-induced putative kinase during the 3-h recovery period (90-min exercise training + 3-h
protein 1 (PINK1), and parkin [9]. Furthermore, an interplay rest) [24]. Endurance exercise (one session) can be sufficient
between PGC-1α and nuclear factor erythroid 2-related factor to induce changes in the mitochondrial life cycle including
2 (NRF2) is crucial for modulating mitochondrial stress mitochondrial fission signaling through Drp1. Furthermore,
adaptations, highlighting their roles in promoting cell survival lacking Drp1 reduced exercise performance and altered
and reducing oxidative stress [10]. Inhibiting mitochondrial training-induced adaptations [24]. In mouse models of fission-
fission can delay downstream caspase activation and subsequent fusion incompetence, researchers have shown that impaired
apoptosis, while overexpression of mitofusin 1 (MFN1) or dynamic flux of mitochondrial remodeling is associated with
MFN2 may postpone apoptotic cell death. The fusion process derangements in metabolism and insulin sensitivity. Because
permits the integration of fragmented, viable mitochondria back the processes of mitochondrial fission, fusion, biogenesis, and
into the mitochondrial network [11]. Mitochondrial fusion is quality control are interdependent, strategies aimed at enhancing
regulated by two members of the large GTPase family, MFN1 mitochondrial lifecycle flux capacity may be effective in
and MFN2 [12]. The genetic deletion of mitofusins leads to the combating diseases associated with metabolic dysfunction.
accumulation of dysfunctional mitochondria and subsequent Mitochondrial health and function are critical for overall
cell damage [13]. MFN2 expression can be downregulated by cellular performance, and exercise training is a well-known
growth factors, cytokines, and lipid availability, but upregulated stimulus that can enhance mitochondrial quality. The effects
by exercise and energy consumption [14]. In addition, several of different training modalities, specifically ET and HIIT, on
intracellular pathways, including those associated with cell mitochondrial dynamics remain largely unexplored. In this

DOI: http://doi.org/10.36922/jctr.24.00044