Mitochondrial Dysfunction in Leukocytes from PCOS

Mitochondrial dysfunction in leukocytes from PCOS women with insulin resistance was evident by a decrease in mitochondria oxygen (O2) consumption. This was indicated by an increase in ROS production, the oxidized glutathione/glutathione ratio, and TNF? levels, as well as a decrease in mitochondrial membrane potential. Additionally, a defect was observed in the activity of complex I of the mitochondria, which may contribute to the oxidative stress evident in these PCOS women [72].

Furthermore, PCOS women with IR exhibited impaired endothelium and mitochondrial dysfunction in leukocytes accompanied by an increase in the inflammatory markers linked to IR.

This suggests that impaired oxidative stress and leukocyte-endothelium interaction may account for the heightened risk of vascular disease in these women [73]. Gene expression profiles and global pathway analysis in the skeletal muscle of PCOS women with insulin-resistant and well-matched healthy control women revealed the most downregulated pathway as the electron transport chain. Additionally, there was a reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism (Table 1)[74].

In 2011, Lee et al found that mitochondrial DNA copy numbers in peripheral blood were significantly lower in women with PCOS (P < .01) than in the control group. It was also observed that these numbers were negatively correlated with indices of insulin resistance, waist circumference, and triglyceride levels, but positively correlated with sex hormone-binding globulin levels [75]. A recent study demonstrated that adolescent non-obese women with PCOS have peripheral insulin resistance that relates to muscle mitochondrial dysfunction during exercise. The ADP time constant and PCr time constant, which represent the rates of recovery of PCr and ADP depletion after exercise, were slower in girls with PCOS than in normal controls.

However, the study also had limitations such as a small sample size, and the age range of the women was between 12 to 19 years, which meant that the differential effects of the growth hormone axis could not be excluded [76]. When comparing the mitochondrial contribution to obesity-induced insulin resistance, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H2O2 (mtH2O2) emissions compared with lean women; it was found to be identical in IR women and well-matched controls. Yet, maximal whole-body and mitochondrial oxygen consumption were found to be equal between obese and lean women.

According to a study by Konopka et al in 2015, exercise training in obese PCOS women restores mitochondrial physiology to that of lean, insulin-sensitive individuals. It reversed obesity-related mitochondrial derangements by enhancing mitochondrial bioenergetic efficiency and decreasing mtH2O2 production. Consequently, there was a concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage, implying an improved cellular redox status and potential mechanism contributing to enhanced insulin sensitivity.

The analysis of BCL2-associated X protein (BAX) and B-cell leukaemia/lymphoma gene-2 (BCL2), pro- and anti-apoptotic proteins of the BCL2 family that participate in the mitochondria-dependent apoptosis pathway, revealed significantly higher BCL2 mRNA expression and no variation in BAX mRNA concentrations in cumulus cells associated with mature oocytes than those associated with immature oocytes in women with PCOS. Moreover, even the BCL2 mRNA content found in cumulus cells enclosing fertilized oocytes was higher. Hence, BCL2 expression is strongly associated with the ability of oocytes to complete nuclear maturation and to be fertilized (Filali et al., 2009).

In 2015, a study by Zhao et al. highlighted that a cross-talk between metabolic signals in the follicular niche and mitochondria in the cumulus cells of classical PCOS women may be involved in the pathogenesis of PCOS (Zhao et al., 2015). Zhao and his team performed a targeted metabolomics study of the follicular fluid of classic PCOS women and showed altered metabolic pathways such as an upregulated glycolysis pathway, an upregulated TCA cycle, an upregulated BCAA catabolism pathway with increased fatty acid ?-oxidation and decreased NAD catabolism. The results pointed to mitochondrial dysfunction in the cumulus cells of women with PCOS, revealing abnormal mitochondrial structures (small, spherical mitochondria with fewer and disarrayed cristae, membrane rupture, and the presence of vacuoles and apoptotic bodies), decreased mitochondrial membrane potential, decreased perinuclear mitochondrial distribution, decreased mitochondrial biogenesis, and dysregulated mitophagy.

Thus, altered levels of intermediate metabolites in the follicular microenvironment play important roles in epigenetic modification that could induce mitochondrial dysfunction and vice versa. Recently, impaired glycolysis and increased mitochondrial activity and mitochondria-dependent apoptosis have been shown in women with PCOS who have endometrial hyperplasia, an early hallmark of endometrial cancer. This suggests mitochondrial pathways for inducing endometrial cancer in women with PCOS.

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