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

Abstract

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 (p62flox/flox αGSUcre) 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 LβT2 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 LβT2 cells. Furthermore, the gonadotropin-releasing hormone (GnRH)-stimulating test in p62flox/flox αGSUcre mice and LβT2 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.

m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

“…C57BL/6 mice were purchased from SLAC Laboratory Animal Co., Ltd. Atg7 flox/flox mice were gifts from Dr. Jianrong Wang, Medical College of Soochow University ( 20 ). SQSTM1 flox/flox mice were gifts from Dr. Hongting Zheng, Xinqiao Hospital, Army Medical University ( 21 ). All mice were housed with a standard 12-h light/dark cycle, climate-controlled, and pathogen-free facility.…”

Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging

“…Other studies have demonstrated the importance of p62 by investigating the effects of p62 knockout. For example, loss of p62 in the pituitary has a detrimental effect on female mouse fertility due to impaired luteinizing hormone production through mitochondrial OXPHOS signaling ( Li X. et al, 2021 ). Another study showed that p62 protects against glycation-derived toxicity by driving the autophagic degradation of harmful age-associated advanced glycation end products ( Aragones et al, 2020 ).…”

P62 promotes FSH-induced antral follicle formation by directing degradation of ubiquitinated WT1

“…Interestingly, p62 is deeply involved in cyclic follicle development through the hypothalamus–pituitary–ovary axis. The specificity of p62 in female reproduction is that it not only participates in regulating LH secretion in the pituitary [ 52 , 61 , 62 ], but also acts in response to FSH induction in ovarian GCs, as shown in this study. For instance, systematic knockout of p62 in mice resulted in obesity accompanied by female infertility, including pituitary dysfunction, as indicated by decreased LH levels during estrus, and ovarian dysfunction, as indicated by abnormal menstrual cycles, follicular formation, anovulation, and steroidogenesis [ 62 , 63 ].…”