Inhibiting TRIM21 Neddylation Rejuvenates Oocyte Quality in PCOS by Regulating Ubiquitination of CPT1A.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting women of childbearing age. Infertility caused by ovulatory disorders and low follicle quality is an urgent problem. Abnormal fatty acid oxidation (FAO) contributes critically to the etiology and progression in PCOS. However, the potential mechanism by which FAO affects follicular development in PCOS patients is unclear. Here, we demonstrate that increased expression of tripartite motif-containing protein 21 (TRIM21) (an E3 ubiquitin ligase) in the prenatal anti-Müllerian hormone PCOS mouse model leads to abnormal FAO in ovarian granulosa cells. Functionally, knocking down TRIM21 increased mitochondrial membrane potential homeostasis and improved fatty acid-dependent aerobic respiration and oxidative phosphorylation functions. TRIM21 regulated the ubiquitination and degradation of carnitine palmitoyltransferase 1A (CPT1A), a key enzyme for FAO, at the K161 site. TRIM21 is regulated by the E2 ubiquitin ligase ubiquitin conjugating enzyme E2 M (UBE2M), which enhances its protein expression and ubiquitination by TRIM21 neddylation. MLN4924 (a neddylation inhibitor) reversed the ubiquitination degradation of CPT1A by inhibiting TRIM21 neddylation. The phenotype of PCOS mice treated with MLN4924 was alleviated, and the maturation of oocytes and embryonic development improved. Together, these findings indicate that TRIM21-CPT1A plays an indispensable role in FAO of granulosa cells, and inhibiting TRIM21 neddylation may be a therapeutic strategy to improve abnormal follicular development in PCOS.