Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology

Abstract

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease, all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under the transcriptional regulation of both the nuclear and mitochondrial genome to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, as well as the dynamics that regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted, the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function, causing disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs, including the ovary (oocytes and granulosa cells), uterus, placenta, and circulation, causing reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in the transgenerational transmission of PCOS and metabolic disorders.

Mitigation of letrozole induced polycystic ovarian syndrome associated inflammatory response and endocrinal dysfunction by Vitex negundo seeds

“…Oxidative stress hinders the production and release of SHBG by reducing the activity of HNF-4α, which could potentially play a significant role in the development of hyperandrogenism in PCOS [ 34 ]. Several studies highlight substantial mitochondrial dysfunction and heightened oxidative stress in PCOS, influencing both reproductive and transgenerational outcomes [ 35 ]. In the present study, we examined the expression of MnSOD, localized in mitochondria, emphasizing its direct relevance in addressing PCOS-associated mitochondrial issues.…”

Role of the mitophagy‐apoptosis axis in the pathogenesis of polycystic ovarian syndrome

“…Although there were fewer reports on mitochondrial ultrastructure in PCOS patients, these authors demonstrated ultrastructural features of mitochondria including decreased number of mitochondria, decreased mitochondrial mass, increased mitochondrial fragmentation, and mitochondrial swelling and membrane defects. 27,[34][35][36] Therefore, the PCOS model is thought to mimic the phenotypes of the human PCOS through mitochondrial dysfunction. 19,20 The ovarian antral follicle consists of theca cells and granulosa cells.…”

“…Recently, Siemers et al suggested that PCOS alters the quality and quantity of mitochondria via mitochondrial quality control, which are likely to contribute to reproductive dysfunction and transgenerational transmission. 27 Indeed, genetic, epigenetic, and genomic changes in molecules that control glycolysis, OXPHOS, mitochondrial biogenesis, mitochondrial fusion and fission dynamics, mitophagy, and apoptosis have been observed in PCOS patients and in animal models and their offspring.…”

A Mendelian randomization study identifies the causal association between plasma mitochondrial CHCHD proteins and polycystic ovary syndrome

“…Studies suggested a possible relationship between mitochondrial dysfunction and PCOS [7,8]. Mitochondrial dysfunction in women with PCOS may contribute to metabolic abnormalities, such as insulin resistance and obesity [9,10]. Impaired mitochondrial function in PCOS may decrease energy production and increase oxidative stress, contributing to insulin resistance and hormonal imbalances [11].…”