Pituitary P62 deficiency leads to female infertility by impairing luteinizing hormone production

P62 is a protein adaptor for various metabolic processes. Mice that lack p62 develop adult-onset obesity. However, investigations on p62 in reproductive dysfunction are rare. In the present study, we explored the effect of p62 on the reproductive system. P62 deficiency-induced reproductive dysfunction occurred at a young age (8 week old). Young systemic p62 knockout (p62(-/-)) and pituitary-specific p62 knockout (p62(flox/flox) alpha GSU(cre)) mice both presented a normal metabolic state, whereas they displayed infertility phenotypes (attenuated breeding success rates, impaired folliculogenesis and ovulation, etc.) with decreased luteinizing hormone (LH) expression and production. Consistently, in an infertility model of polycystic ovary syndrome (PCOS), pituitary p62 mRNA was positively correlated with LH levels. Mechanistically, p62(-/-) pituitary RNA sequencing showed a significant downregulation of the mitochondrial oxidative phosphorylation (OXPHOS) pathway. In vitro experiments using the pituitary gonadotroph cell line L beta T2 and siRNA/shRNA/plasmid confirmed that p62 modulated LH synthesis and secretion via mitochondrial OXPHOS function, especially Ndufa2, a component molecule of mitochondrial complex I, as verified by Seahorse and rescue tests. After screening OXPHOS markers, Ndufa2 was found to positively regulate LH production in L beta T2 cells. Furthermore, the gonadotropin-releasing hormone (GnRH)-stimulating test in p62(flox/flox) alpha GSU(cre) mice and L beta T2 cells illustrated that p62 is a modulator of the GnRH-LH axis, which is dependent on intracellular calcium and ATP. These findings demonstrated that p62 deficiency in the pituitary impaired LH production via mitochondrial OXPHOS signaling and led to female infertility, thus providing the GnRH-p62-OXPHOS(Ndufa2)-Ca2+/ATP-LH pathway in gonadotropic cells as a new theoretical basis for investigating female reproductive dysfunction. Reproductive biology: Linking metabolism and ovulation A protein that helps maintain normal metabolic function also regulates the production of hormones that govern female fertility. Problems with ovulation are the most common cause of infertility, and these are in turn commonly associated with endocrine abnormalities and obesity. Researchers led by Min Long and Hongting Zheng of the Army Medical University in Chongqing, China, have now determined that a protein called P62 links these conditions. P62 is associated with obesity and diabetes, and the researchers showed that mice lacking this protein become overweight late in life but also exhibited impaired ovulation at an early age. Closer analysis revealed that P62 activity in the pituitary gland helps coordinate production of luteinizing hormone, which regulates ova maturation and release. These findings thus offer new insights into the connection between metabolic and reproductive health.

Automated summary

P62 deficiency in the pituitary impairs luteinizing hormone production, affecting ovulation in young mice. P62 modulates LH synthesis and secretion via the mitochondrial OXPHOS pathway, particularly through Ndufa2, providing new insights into the link between metabolic and reproductive health.