Summary: 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.

Maternal effect genes play essential roles in early embryonic development. However, the mechanisms by which maternal effect genes regulate mammalian early embryonic development remain largely unknown. Recently, we identified a subcortical maternal complex (SCMC) that is composed of at least four proteins encoded by Mater, Floped, Tle6 and Filia and is critical for mouse preimplantation development. The present study demonstrates that human SCMC homologous genes (NLRP5, OOEP, TLE6 and KHDC3L) are specifically expressed in the oocytes of human fetal ovaries. The proteins of this complex co-localize in the subcortex of human oocytes and early embryos. Furthermore, the SCMC proteins physically interact with each other when they are co-expressed in cell lines. These results indicate that human NLRP5, OOEP, TLE6 and KHDC3L function as a complex in the oocytes and early embryos of Homo sapiens. Considering the important roles of the SCMC in mouse early embryogenesis, the characterization of the human SCMC will provide a basis for investigating human early embryonic development and will have clinical implications in human female infertility or recurrent spontaneous abortion.

The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on EGFR, ERBB2, FOXO1, MAPK1, NFKB1, IGF1, TP53 and MAPK9 may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.