Altered sulfite oxidase expression contributes to AMP-activated protein kinase-dependent mitochondrial dysfunction and metabolic dysregulation in polycystic ovary syndrome.

BACKGROUND

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by reproductive dysfunction and endocrine-metabolic abnormalities. However, its precise pathogenesis remains unclear. Increasing evidence indicates that ovarian granulosa cells (GCs) dysfunction and metabolic imbalance play critical roles in the initiation and progression of PCOS. This study investigated the regulatory role of the sulfite oxidase (SUOX)-AMP-activated protein kinase (AMPK) signaling axis in the development and function of ovarian GCs in PCOS.

METHODS

PCOS-associated gene variants were identified using high-throughput sequencing and subsequently validated using dual-luciferase reporter assays. SUOX expression was modulated in ovarian KGN cells using gene knockdown and overexpression approaches combined with pharmacological interventions to assess alterations in SUOX-AMPK signaling and its downstream effects. A mouse model of PCOS was established to further evaluate the biological role of SUOX in vivo.

RESULTS

SUOX expression was significantly reduced in follicular fluid samples from patients with PCOS. SUOX knockdown was associated with suppression of AMPK signaling, mitochondrial dysfunction, impaired autophagy, and increased lipid synthesis in KGN cells. Conversely, SUOX overexpression or AMPK pharmacological activation effectively reversed these pathological changes. Restoration of SUOX expression partially reduced ovarian metabolic dysfunction in PCOS mouse models.

CONCLUSION

These findings demonstrate that the SUOX-AMPK signaling axis plays an important role in the pathogenesis of PCOS. Reduced SUOX expression may contribute to disease progression by promoting oxidative stress, worsening mitochondrial damage, and impairing ovarian function, suggesting that SUOX may represent a potential molecular target for the diagnosis and treatment of PCOS.