Impaired Mitochondrial Stress Response due to CLPP Deletion Is Associated with Altered Mitochondrial Dynamics and Increased Apoptosis in Cumulus Cells

Abstract

Caseinolytic peptidase P (CLPP) plays a central role in mitochondrial unfolded protein response (mtUPR) and is required for maintaining protein homeostasis in the mitochondria. Global germline Clpp deletion causes female infertility and accelerated follicular depletion. In the current study, we aimed to characterize the role of CLPP in cumulus cell function, gene expression, and mitochondrial ultrastructure. We found that mitochondria in Clpp-deficient cumulus cells have a smaller aspect ratio (length/width) and have a larger coverage area (mitochondrial area/cytoplasmic area) under electron microscopy. These ultrastructural changes were accompanied with diminished expression of mitochondrial dynamics genes. RNA sequencing analysis revealed a significant change in genes related to cellular metabolism in Clpp-deficient cumulus cells compared to wild type. In addition, apoptosis and phagosome pathways were significantly affected. Immunofluorescence assessment confirmed increased apoptotic activity and decreased cell proliferation in cumulus oophorus complexes (COCs) of Clpp-deficient mice. Our findings demonstrate that deletion of CLPP results in significant structural and functional changes in cumulus cells and suggests that mtUPR is required for cumulus cell function.