Mitochondrial Dysfunction in Leukocytes from PCOS

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

Further PCOS women with IR showed impaired endothelium and mitochondrial dysfunction in leukocytes along with increase in inflammatory markers linked to IR suggesting that impaired oxidative stress and leukocyte-endothelium interaction may be responsible for the increased risk of vascular disease in these women [73]. Gene expression profiles and global pathway analysis in skeletal muscle of PCOS women with insulin-resistant and well-matched healthy control women revealed most downregulated pathway as the electron transport chain and reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism (Table 1)[74].

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

However, the study had some limitations such as small sample size and age range of women being 12 to 19 years hence differential effects of the growth hormone axis cannot be excluded [76]. Comparison of mitochondrial contribution to obesity-induced insulin resistance compared with lean, insulin-sensitive women with PCOS revealed aberrant skeletal muscle mitochondrial physiology as compared with lean, insulin-sensitive women. Obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H2O2 (mtH2O2) emissions compared with lean women. However, Maximal whole-body and mitochondrial oxygen consumption were not found to be different between obese and lean women.

Exercise training in obese PCOS women restores mitochondrial physiology toward that of lean, insulin-sensitive individuals as it reversed obesity-related mitochondrial derangements by enhancing mitochondrial bioenergetics efficiency and decreased mtH2O2 production. Also, a concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity (Konopka et al 2015).

Analysis of BCL2-associated X protein (BAX) and B-cell leukaemia/lymphoma gene-2 (BCL2), pro- and anti-apoptotic proteins of 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 of PCOS women. Even 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).

A study by Zhao et al in 2015 highlight 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 group performed targeted metabolomics study of follicular fluid of classic PCOS women and showed altered metabolic pathways such as upregulated glycolysis pathway, upregulated TCA cycle, upregulated BCAA catabolism pathway with increased Fatty acid ?-oxidation and decreased NAD catabolism. Mitochondrial dysfunction in cumulus cells of PCOS revealed 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 micro environment have important epigenetic modifying roles that could induce mitochondrial dysfunction and vice versa. Recently, impaired glycolysis and increased mitochondrial activity and mitochondria-dependent apoptosis was shown in PCOS women with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer suggesting mitochondrial pathways for inducing endometrial cancer in PCOS women.

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Mitochondrial Dysfunction in Leukocytes from PCOS. (2021, May 10). Retrieved from

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