Polycystic ovary syndrome (PCOS) is a lifelong illness, and its metabolic and reproductive syndromes manifest in all periods of life [
1]. Its prevalence ranges from 8 to 13% in accordance with the investigated population and definitions used [
2]. After several revisions, a consensus was reached that the diagnosis of PCOS should be based on the Rotterdam criteria, which include two of the three following characteristics: oligomenorrhea, hyperandrogenism (clinical or biochemical), and polycystic ovary on ultrasound after the exclusion of other endocrinopathies [
3]. PCOS is frequently accompanied by abnormal follicular development, obesity, insulin resistance (IR), compensatory hyperinsulinemia, hyperandrogenism, and low-grade inflammation [
4]. Ovarian hyperandrogenism, IR, hyperinsulinemia, and changes in follicular endocrine signals can interfere with follicular activation, survival, growth, and selection in women with PCOS. These effects result in the accumulation of small follicles around the ovary, polycystic morphology, and damage to follicular maturation and anovulation. The majority of women with PCOS are overweight, obese, or abdominally obese. Obesity can exacerbate the progression of various PCOS-related dysfunctions, such as anovulation, hyperandrogenism, IR, and inflammation. The progression of these dysfunctions subsequently increases adipogenesis and decreases lipolysis. Changes in fat–ovarian interactions, especially in the case of excess fat, exacerbate these events, which have adverse effects on follicular development and may damage oocytes [
5,
6]. Obesity can aggravate IR and inflammation through the secretion of several inflammatory adipokines, sensitize thecal cells to luteinizing hormone (LH) stimulation, and upregulate ovarian androgen production. Thus, obese women with PCOS have more severe phenotypes, irregular menstruation, infertility, abortion, glucose intolerance, and metabolic syndrome than non-obese women with PCOS [
7‐
9]. IR is a major factor of excessive adipogenesis in PCOS and is a key feature of the pathophysiology of PCOS. Generally, 75% of lean women and 95% of obese women with PCOS exhibit IR accompanied by severe metabolic disorders and late-stage complications [
10]. IR and compensatory hyperinsulinemia can induce hyperandrogenemia by acting on the pituitary gland, ovaries, and liver [
11]. An in vitro study has suggested that insulin can stimulate androgen secretion by theca cells, and androgen secretion is remarkably enhanced in theca cells from women with PCOS [
12]. Similarly, insulin enhances adrenal androgen secretion in response to adrenocorticotropic hormone stimulation [
13,
14], decreases the serum levels of sex hormone binding protein (SHBG), and then increases free androgen concentration. Thus, IR can promote the occurrence of hyperandrogenism from different aspects in patients with PCOS. Androgen excess is the main physiological and pathological mechanism of PCOS. It leads to reproductive, metabolic, and cosmetic changes that negatively affect the quality of life of patients with PCOS [
15]. PCOS is caused by the vicious cycle of androgen excess. In this cycle, androgen excess impairs follicular development and promotes abdominal adipose tissue deposition by inducing IR and compensatory hyperinsulinism, which promotes androgen secretion by the ovaries and adrenal gland [
16]. Recent studies have suggested that chronic inflammation may play a role in the pathogenesis of PCOS given that numerous inflammatory markers are elevated in women with PCOS. A relationship has also been found between proinflammatory status and PCOS, linked to polymorphism of gene coding for tumor necrosis factor-ɑ (TNF-ɑ), interleukin-6 (IL-6), and its receptor [
17]. The inflammation associated with PCOS is explained in part by the coexistence of IR and obesity but is further fueled by androgen excess. PCOS is closely related to the dysfunction of adipose tissue. Similar to patients with PCOS, when exposed to androgen excess, adipocytes seem to be prone to hypertrophy. Hypertrophy of adipose tissue and androgen excess are related to IR. Inflammation is also closely associated with adipocyte hypertrophy, which leads to vascular compression, hypoxia, and elevated inflammatory markers [
18]. Local inflammation in the ovary stimulates ovarian steroidogenic activity and theca cell proliferation and phosphorylation of the receptor, further increasing androgen excess and IR [
19,
20]. The relationship between PCOS and inflammation may be confirmed by the association between the increased levels of inflammatory markers with the pathological development of other diseases, including type 2 diabetes(T2DM), atherosclerosis, and hypertension, in patients with PCOS [
21‐
23]. In addition to IR, low-grade inflammation, obesity, and oxidative stress (OS) have been repeatedly shown to be prevalent in women with PCOS. Many studies have shown that the oxidative circulating markers in patients with PCOS are significantly higher than those in normal people; this condition is considered a potential cause of the pathogenesis of PCOS [
24]. Mitochondria are important structures for regulating OS. Mitochondrial dysfunction has been proven to be a vital factor of T2DM, cardiovascular diseases, and cancer [
25]. The role of mitochondrial gene and function disorders in the pathogenesis of PCOS has been investigated. It may account for several characteristics of PCOS, such as androgen excess, IR, obesity, abnormal follicular development, and inflammation [
26]. Although the participation of mitochondrial dysfunction in the pathogenesis of PCOS is unclear, some results of current studies are important for the mechanism and treatment of PCOS. This review summarizes the recent findings for PCOS-associated mitochondrial genome (mtDNA) mutations and discusses the association among mitochondrial dysfunction and the clinical manifestations and progression of PCOS and related complications.
Mitochondria play a fundamental role in cell energy metabolism and apoptosis and are involved in signal transduction for cell proliferation [
27]. Mitochondria translate nutrients into available energy and release reactive oxygen species (ROS) as by-products [
28]. ROS are chemically reactive molecules containing oxygen. They include hydroxyl radicals (·OH), superoxide anions (O
2·−), singlet oxygen (1O2), and hydrogen peroxide (H
2O
2) [
29]. At appropriate levels, ROS have a pivotal impact on the biological functions of mammalian cells, such as multiplication, metabolism, gene expression, and immune response [
30]. However, increased ROS production induces organism impairment. For example, the enhancement of OS in tissues and organisms causes related damage; harms mitochondrial components, such as mtDNA, proteins, and lipids; and induces mitochondrial-mediated apoptosis [
31]. Typically, the deleterious effects of ROS are counteracted by a delicate antioxidant system that includes enzymatic antioxidants, such as superoxide dismutase (SOD), catalase (CAT), peroxidase (GPx), and paraoxonase, and nonenzymatic antioxidants, including glutathione (GSH), thioredoxin, thiols, vitamin C, vitamin A, vitamin E, selenium, and zinc [
32]. Usually, SOD dismutate O
2· − into H
2O
2. H
2O
2 is degraded to harmless water by CAT and GPx [
33]. Thus, reductions in the amounts of these enzymes will result in excessive ROS production. GSH is a cofactor of several antioxidant enzymes. It can detoxify H
2O
2 and lipid peroxide by catalyzing GPx and regenerating vitamins C and E into their active forms [
24]. Thiols are antioxidant compounds that neutralize oxidants into slightly toxic products [
34]. Given that the direct measurement of OS in biological systems is not always feasible, the concentrations of various products of reactive oxygen metabolites are used to ascertain the redox state of tissues and mitochondrial function [
35]. Malondialdehyde (MDA), total antioxidant capability (TAC), total antioxidant status (TAOS), mitochondrial membrane potential (MMP), advanced oxidation protein products (AOPPs), SOD, carbonyl, and GSH are common markers used to evaluate OS levels. MDA, a common marker of oxidant-mediated damage, is an end product of lipid peroxidation [
36]. TAC refers to the capacity of scavenging harmful free radicals in blood and cells [
37]. TAOS is described as the ability of serum to remove free radicals and protect cell structures from damage. AOPPs are novel biochemical markers of oxidant-mediated protein damage and represent a class of proinflammatory mediators [
38]. Carbonyl can perform the oxidative modification of proteins and is an indicator of OS in plasma proteins [
24]. MMP presents the ability to pump hydrogen ions through the inner membrane during oxidative phosphorylation (OXPHOS). The reduction in MMP is indicative of increased ROS production [
39].
Mitochondria are controlled by the mitochondrial and nuclear genomes. MtDNA is a molecule with 16,569 base pairs (bps) and encode 22 tRNAs, two rRNAs, and 13 polypeptides that are indispensable for adenosine triphosphate (ATP) production [
40]. All other proteins, including respiratory complex subunits, required for the normal function of mitochondria are encoded by nuclear genes [
41]. The important enzyme involved in mtDNA replication and repair is DNA polymerase gamma, which is encoded by the POLG gene [
42]. POLG is associated with numerous diseases. More than 150 different point mutations in POLG have been found to cause a wide range of diseases [
43,
44]. Mitochondrial transcription factor A (TFAM), a major structural packaging protein of mtDNA, participates in mtDNA transcription and replication [
45]. Defects in mitochondrial DNA replication result in mtDNA mutation, multiple deletions, and mtDNA molecule depletion [
46]. Moreover, mtDNA has a higher mutation rate than nuclear DNA because it lacks histone protection and a DNA damage repair system and approaches the electron transport chain (ETC) system, which produces oxygen-free radicals [
47]. Existing studies have shown that mtDNA mutations contribute to many diseases, such as PCOS.