Mitochondrial Quality Control in PMOS/PCOS: A Review of Mechanisms, Biomarkers and Therapeutic Opportunities
TL;DR
The results reveal that MQC is dysfunctional across ovarian, metabolic, and endocrine tissues, with defects in its biogenesis, dynamics, mitophagy, proteostasis, and mtDNA integrity, and MQC biomarkers positions PMOS as a bioenergetic disorder.
Abstract
Polyendocrine Metabolic Ovarian Syndrome (PMOS), affecting 8-13% of reproductive-age women, is the leading cause of anovulatory infertility and carries a substantial risk of metabolic and cardiovascular morbidity. Despite therapeutic advances, fundamental pathophysiological mechanisms remain incompletely characterised. Mitochondrial dysfunction has emerged as a central driver. Yet, mitochondrial quality control (MQC), the integrated network that maintains mitochondrial structure, function, and quantity, has not been systematically adopted as the organising framework for PMOS pathobiology. This review synthesises contemporary evidence to propose an integrated systems biology framework positioning MQC dysfunction as the central regulatory hub linking endocrine dysregulation, metabolic reprogramming, inflammatory activation, and reproductive pathology in PMOS. The results reveal that MQC is dysfunctional across ovarian, metabolic, and endocrine tissues, with defects in its biogenesis, dynamics, mitophagy, proteostasis, and mtDNA integrity. Alterations in MQC are cell type-specific and associated with tissue-level dysfunction, such as loss of developmental competence due to mitochondrial fragmentation in the oocyte. OXPHOS insufficiency in granulosa cells leads to impaired steroidogenesis, and a decreased mitochondrial burden in skeletal muscle leads to insulin resistance beyond the effects of obesity. The crosstalk of AMPK/SIRT1 suppression, ROS accumulation, mtDNA mutations, ER-mitochondrial calcium dysregulation, and NLRP3-mediated pyroptosis/necroptosis creates a vicious cycle orchestrated by MQC dysregulation. Circulating markers of MQC dysfunction, such as cell-free mtDNA, exosomal miRNAs, and mtDNA copy number, stratify PMOS phenotypes and predict therapeutic responses. There is a synergistic benefit when multi-targeted MQC restoration strategies are combined with precision biomarker-guided stratification. This review highlights the significant role of MQC as the integrative mechanistic hub that helps explain the heterogeneity of PMOS and brings together seemingly divergent results within a single bioenergetic-redox-inflammatory framework. Adopting MQC biomarkers positions PMOS as a bioenergetic disorder, enabling early diagnosis, individualised therapeutic decisions, and objective monitoring of intervention efficacy to ensure that the appropriate healthcare approach is undertaken. To provide precision mitochondrial medicine, large-scale longitudinal multi-omics studies, AI-driven phenotyping, clinical trials of therapies targeting the MQC, and biomarker standardisation are needed.