Mitochondrial unfolded protein response: a stress response with implications for fertility and reproductive aging.

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 (UPRmt) 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 UPRmt-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.