Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility

Abstract

Mitochondrial unfolded protein stress response (mtUPR) plays a critical role in regulating cellular and metabolic stress response and helps maintain protein homeostasis. Caseinolytic peptidase P (CLPP) is one of the key regulators of mtUPR and promotes unfolded protein degradation. Previous studies demonstrated that global deletion of Clpp resulted in female infertility, whereas no impairment was found in the mouse model with targeted deletion of Clpp in cumulus/granulosa cells. These results suggest the need to delineate the function of Clpp in oocytes. In this study, we aimed to further explore the role of mtUPR in female reproductive competence and senescence using a mouse model. Oocyte-specific targeted deletion of Clpp in mice resulted in female subfertility associated with metabolic and functional abnormalities in oocytes, thus highlighting the importance of CLPP-mediated protein homeostasis in oocyte competence and reproductive function.

Targeting mitochondria for ovarian aging: new insights into mechanisms and therapeutic potential

“…Activated in response to mitochondrial stress, UPRmt orchestrates processes such as protein refolding, degradation of damaged proteins, and the promotion of mitochondrial biogenesis to ensure a stable mitochondrial environment ( 61 ). ClpP (caseinolytic peptidase P), a protease enzyme located in the mitochondrial matrix, plays a key role in UPRmt ( 62 ).…”