In the catabolism process, substrates such as glucose, fatty acids, and amino acids are broken down to generate ATP or heat through OXPHOS, which is used as energy for cellular activities. Treatment often leads to visceral fat reduction and improved insulin sensitivity. Although the hormone treatment is effective in most studies, there are reports of inefficacy in some studies (8, 9). Injection of male hormones is a treatment strategy for obesity and type 2 diabetes in male patients with hypogonadism. Myocardial contractility was analyzed using isolated papillary muscles at baseline (Figure 10A) and with different extracellular calcium concentrations (Figure 10B). Western blot analyses for NOX-1 (A), gp91phox(B), superoxide dismutase Cu -Zn (C), angiotensin converting enzyme 1 (D) in cardiac tissue from SHAM, OQT and OQT + T groups. Again, the reduction in TFAM could be prevented by testosterone replacement (Figure 7A). Ca2+-induced MPTP was also assessed by measuring the ability of isolated mitochondria to take up added Ca2+. There was a decrease in absorbance with addition of either 100 or 500 nmol Ca2+/mg protein in all groups, but no difference was found between the groups (data not shown). In some cases, however, hypogonadism can be the result of obesity due to hypothalamus–pituitary axis inhibition by aromatase conversion of androgen into estradiol in peripheral tissues such as white adipose tissue (WAT) (7). Testosterone deficiency (hypogonadism) increases the risk of metabolic disorders in male subjects and animals (4–6). DHT directly activates the androgen receptor (AR) for induction of target gene transcription. Testosterone is converted into the more active form, dihydrotestosterone (DHT), in the cell cytoplasm by 5α-reductase. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. The exact mechanism underlying the complex activities of androgens remains unknown. Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. This increase in SHBG levels leads to increased estrogen production and decreased T activity.54 The low level of testosterone in heart failure could also be caused by drugs. Estrogens have a similar activity in females in the control of energy metabolism through their effects on mitochondria. Androgens are required for the maintenance of energy balance in male subjects through the promotion of mitochondrial function. In a study of the acute effect of androgen on β-cells, androgen was found to induce hypersecretion of insulin through activation of the cAMP/PKA pathway, which was followed by β-cell dysfunction in the female mice (13). In PCOS, excessive androgen levels may synergize with estrogen to cause mitochondrial overactivation, which in turn leads to mitochondrial dysfunction through the mechanisms discussed above. The insulin-sensitizing medicine, metformin, inhibits mitochondrial ATP production in the liver, thereby pharmacologically inducing insulin sensitization. In a recent review, excessive substrate availability in obesity has been proposed as a major factor contributing to mitochondrial overproduction of ATP in the mechanism of insulin resistance (134). We propose that through hormone synergy, androgen may overactivate mitochondria in the presence of estrogen in the female body, leading to insulin resistance. Therefore, one may predict that the two hormones may synergize in the regulation of mitochondrial function to control obesity and insulin resistance. Taken together, estrogen plays vital roles in the regulation of energy metabolism through its positive impacts on mitochondrial biogenesis and function. In ovariectomized mice, estrogen therapy improved mitochondrial function in the skeletal muscle by correcting membrane viscosity, bioenergetic function, respiration (complex I, III activities), and antioxidant activities (128). ERβ-selective ligands prevented high fat diet-induced lipid accumulation and promoted the expression of mitochondrial biogenesis-related indicators in brown adipose tissue (BAT) and WAT in male and female mice (109, 110). These practices induce activation of AMPK and SIRT1, while reducing mTOR activity at the molecular level (50). In these conditions, mitochondria suffer from an oversupply of fuel substrates such as lipids, glucose, amino acids, and their derivatives. Obesity and type 2 diabetes represent the body’s compensatory responses to energy surplus conditions. Irreversibly damaged mitochondria are removed by the process of mitophagy (42), a specific form of autophagy in the quality control system of mitochondria. Mitochondrial components are frequently damaged by high levels of reactive oxygen species (ROS). NRF-2, an isoform of NRF-1, is required for expression of the cytochrome c oxidase (COX) in complex IV of the respiratory chain, in which NRF-2 interacts with PGC-1α (30). Estradiol and thyroid hormone are among the most powerful regulators of mitochondrial function in the human brain. Do Val Lima PR, Ronconi KS, Morra EA, Rodrigues PL, Ávila RA, Merlo E, Graceli JB, Simões MR, Stefanon I and Ribeiro Júnior RF (2023) Testosterone deficiency impairs cardiac interfibrillar mitochondrial function and myocardial contractility while inducing oxidative stress. As previously reported, overexpression of mitochondrial catalase attenuates pressure overload-induced heart failure (53). The transcription of genes for mitochondrial ATP production and the genes for proteins that consume large amounts of ATP (Serca2a) are regulated by the same transcription factor.
