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Together, these data a support the claim that estrogen influences the preservation of mitochondrial respiration, once again, suggesting a neuroprotective mechanism mediated by estrogen. This is particularly interesting as NRF-1 is a nuclear transcription factor that regulates the expression of the mitochondrial transcription factor A (TFAM), a nuclear encoded mitochondrial gene that controls transcription of mitochondrial DNA (mtDNA) (Mattingly et al., 2008). Receptors for these hormones have been found at varying levels in the mitochondria of both males and females (Picard and McEwen, 2014; Velarde, 2014). Taken together, this review aims to assess the influence of E2 on mitochondrial function within the brain via exploration of E2-ER interactions within neural mitochondria and how they may act to influence the development and presentation of neurodegenerative and neurocognitive diseases with known sex differences. Testosterone deficiency induced the mitochondrial dysfunction and reduced the activity of complex I of the four mitochondrial respiratory chain complexes in the substantia nigra.
Uptake of EVs has been reported to occur via endocytosis or direct fusion with the acceptor cell membrane39. Consistent with this, EV-contained mitochondria exhibited markedly lower MitoSOX signals (Fig. 5q,r). Functionally, EV-encapsulated mitochondria maintained a responsive MMP, depolarizing with FCCP and hyperpolarizing with oligomycin (Fig. 5l). Staining with MitoTracker Red (MTR) revealed that the majority (77.37 ± 1.92%) of tMac-EVs contained mitochondria (Fig. 5i). Among the 1,057 identified proteins, almost 60% were ascribed as components of mitochondrion (26.35%), plasma membrane (25.99%) and cytoplasmic vesicle (6.56%; Fig. 5f). M,o,q, Scale bars, 3 μm (left) and 2 μm (right; magnified views of the boxed regions).
An increase in Ca2+ concentration induces mPTP opening, which further exacerbates the imbalance of intracellular Ca2+ homeostasis, possibly caused by leaky ryanodine receptors in aged skeletal muscle (49). Considering the age-related decline in cellular antioxidant activity, the accumulation of cellular macromolecular damage induced by free radicals may be a critical driving force for muscle degeneration. Thus, dysfunctional mitochondria trigger a cascade of signals that initiate the signaling pathways that lead to sarcopenia. Furthermore, motor neuron death coincides with skeletal muscle cell death, i.e., the apoptotic removal of alpha motor neuron nuclei. Sufficient nuclear death in a muscle cell will result in the death and removal of the entire muscle cell. The mPTP is a weakly-selective, large-conductance channel that is closed under non-stressed conditions, which can be triggered to open by mitochondrial ROS (mROS) and Ca2+ overloading.
In males, the primary source of estrogen is maintained through the conversion of testosterone to estrogen via the enzyme aromatase (Chen et al., 2005; Gervais et al., 2019; Saldanha et al., 2009). When released from the ovaries, estrogen circulates throughout the body, and crosses the blood-brain barrier to act upon the cells within the brain (Rettberg et al., 2014). Due to the dynamic nature of mitochondria, the changing cellular environment caused by external stimuli alter both the localization (Fang et al., 2012) and structure (Flameng et al., 1980; Rossi and Pekkurnaz, 2019) of the mitochondria within the cell. Finally, review of mitochondria as a biomarker of disease and data supporting efforts in targeting mitochondria as a therapeutic target for the amelioration of these disorders will be discussed.
Studies indicate that aging provokes certain alternations of several key mitophagy regulators, leading to mitophagy deficiency and subsequent accumulation of dysfunctional mitochondria in skeletal muscle (91, 92). Mitophagy is a particular type of macroautophagy (autophagy) and, as mentioned above, can selectively remove dysfunctional and damaged mitochondria to maintain mitochondrial homeostasis. Therefore, further investigation will be needed to clarify the precise molecular mechanisms of mitochondrial dynamics alteration in aging muscle and develop an efficient strategy to prevent or delay the onset of sarcopenia. Mitochondrial fission is necessary for subsequent mitophagy to dissipate dysfunctional parts from the mitochondrial network (90). These studies mentioned above indicated the essential role of mitochondrial dynamics in muscle aging and sarcopenia.
A consequence of the action of these sex hormones is mitochondrial protection, although the specific mechanism of action has not yet been elucidated. In the nucleus, the dimer of the receptors binds to estrogen response elements (ERE) or androgen response elements (ARE) and affects the transcription of nuclear-encoded mitochondrial genes. Both steroids trigger complex molecular mechanisms involving crosstalk between mitochondria, the nucleus, and the plasma membrane, and the result of this action is mitochondrial protection (Figure 2). Age-related muscle degeneration is caused when mitochondria are defective or abnormal and cannot be cleared or degraded effectively. However, little is known about the role of AR in mitochondrial Localization, and further studies are needed to elucidate the underlying mechanisms. These studies suggest that androgens may maintain mitochondrial mass by inducing mitochondrial biogenesis and inhibiting autophagy. In the cell cytoplasm, testosterone is converted into its active form, dihydrotestosterone (DHT), by 5α-reductase.
Testosterone-mediated modulation of mitochondrial gene expression may lead to an increase in mitochondrial biogenesis and function. Building upon our previous investigations, these findings reinforce the significant contribution of testosterone to the inhibition of various cellular pathways within muscle cells that acting in concert conduce to apoptosis. This study demonstrates that oxidative stress induced by H2O2 significantly downregulates the mRNA expression of the MRC proteins ND1, ND4, CytB, Cox1, and Cox2, in C2C12 cells compared to the control in C2C12. We propose testosterone's involvement in mitochondrial biogenesis through this primary mechanism of action, modulating mitochondrial gene transcription and contributing to the proper functioning of mitochondrial machinery.
From a macrophage-centric perspective, the divergence between MHCIIhi and CD206hi tMacs in mitochondrial transfer reflects antagonistic cellular programmes that are unlikely to coexist in a single state31,44. In addition, continuously rebuilding mitochondrial reticulum or maintaining excess mitochondrial reserves would impose significant energy costs and compromise cellular efficiency43. This process of delegated mitochondrial clearance by tMacs seems to be an adaptive strategy that allows long-lived LCs to sustain continuous function throughout the lifespan of an organism7.