Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre-implantation embryos

Aging Cell
Tianren WangEmre Seli

Abstract

Caseinolytic peptidase P mediates degradation of unfolded mitochondrial proteins and activates mitochondrial unfolded protein response (mtUPR) to maintain protein homeostasis. Clpp-/- female mice generate a lower number of mature oocytes and two-cell embryos, and no blastocysts. Clpp-/- oocytes have smaller mitochondria, with lower aspect ratio (length/width), and decreased expression of genes that promote fusion. A 4-fold increase in atretic follicles at 3 months, and reduced number of primordial follicles at 6-12 months are observed in Clpp-/- ovaries. This is associated with upregulation of p-S6, p-S6K, p-4EBP1 and p-AKT473, p-mTOR2481 consistent with mTORC1 and mTORC2 activation, respectively, and Clpp-/- oocyte competence is partially rescued by mTOR inhibitor rapamycin. Our findings demonstrate that CLPP is required for oocyte and embryo development and oocyte mitochondrial function and dynamics. Absence of CLPP results in mTOR pathway activation, and accelerated depletion of ovarian follicular reserve.

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Citations

Jul 14, 2019·Reproductive Biology and Endocrinology : RB&E·Mauro CozzolinoGiovanni Sisti
Jan 23, 2020·International Journal of Molecular Sciences·Willy RoqueFreddy Romero
Jan 14, 2020·Endocrinology·Işıl Kasapoğlu, Emre Seli
Dec 22, 2020·Free Radical Biology & Medicine·Li ZhuLinxi Chen
Sep 19, 2020·Endocrinology·Manasi DasNicholas J G Webster
Aug 10, 2021·World Journal of Stem Cells·Li-Fang GuYan-Zhou Yang
Mar 19, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Sylvia Torres-OdioA Phillip West

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Methods Mentioned

BETA
Fluorescence
RNA seq
RNAseq

Software Mentioned

Graph Pad Prism

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