CLPP
ATP-dependent Clp protease proteolytic subunit, mitochondrial precursor (EC 3.4.21.92) (Endopeptidase Clp)
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Mitochondria play a central role in the regulation of energy metabolism in oocytes and preimplantation embryos, where the number and morphology of mitochondria and mitochondrial DNA (mtDNA) content are tightly regulated. A number of mouse models with mitochondrial dysfunction result in infertility, further confirming the key role of mitochondria in female reproductive function. When cells and organisms detect mitochondrial dysfunction they use response mechanisms directed at recovering salvageable mitochondria and eliminating mitochondria that can no longer be rescued. Among these mechanisms, mitochondrial unfolded protein response (UPR ) has recently been linked with prevention of aging, as compromised mitochondrial stress response contributes to age-related accumulation of damaged proteins, reduced oxidative phosphorylation, and increased reactive oxygen species (ROS) production. These mechanisms seem to be especially relevant for reproduction, as targeted deletion of the UPR -regulatory gene Clpp results in female infertility, with impaired oocyte maturation and two-cell embryo development, and failure to form blastocysts. In addition, absence of CLPP results in accelerated depletion of follicles, and a phenotype similar to premature reproductive aging. Further studies will provide novel mechanistic insights for physiologic and pathologic control of oocyte and early embryonic mitochondrial function, which can be exploited for the development of novel therapeutic approaches for the promotion of fertility during the aging process.
MeSH Terms
- Age Factors
- Aging
- Animals
- Blastocyst
- Cellular Senescence
- Endopeptidase Clp
- Female
- Fertility
- Humans
- Infertility
- Male
- Mitochondria
- Mitochondrial Dynamics
- Oocytes
- Reproductive Health
- Reproductive Techniques, Assisted
- Unfolded Protein Response
Keywords
- Aging
- CLPP
- mitochondria
- mitochondrial unfolded protein response
- oocyte
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.
MeSH Terms
- Aging
- Animals
- Embryonic Development
- Endopeptidase Clp
- Female
- Mice
- Mice, Knockout
- Mitochondria
- Oocytes
- Ovarian Follicle
- Ovary
- Unfolded Protein Response
Keywords
CLPP
- aging
- mTOR
- mitochondria
- mitochondrial unfolded protein response
- oocyte
- rapamycin