NLRP5 Mediates Mitochondrial Function in Mouse Oocytes and Embryos1

Abstract

Unraveling molecular pathways responsible for regulation of early embryonic development is crucial for our understanding of female infertility. Maternal determinants that control the transition from oocyte to embryo are crucial molecules that govern developmental competence of the newly conceived zygote. We describe a series of defects that are triggered by a disruption of maternal lethal effect gene, Nlrp5. Previous studies have shown that Nlrp5 hypomorph embryos fail to develop beyond the two-cell stage. Despite its importance in preimplantation development, the mechanism by which the embryo arrest occurs remains unclear. We confirmed that Nlrp5 mutant and wild-type females possess comparable ovarian germ pool and follicular recruitment rates. However, ovulated oocytes lacking Nlrp5 have abnormal mitochondrial localization and increased activity in order to sustain physiological ATP content. This results in an accumulation of reactive oxygen species and increased cellular stress causing mitochondrial depletion. Compromised cellular state is also accompanied by increased expression of cell death inducer Bax and depletion of cytochrome c. However, neither genetic deletion (Bax/Nlrp5 double knockout) nor mimetic interference (BH4 domain or Bax inhibitory peptide) were sufficient to alleviate embryo demise caused by depletion of Nlrp5. We therefore conclude that lack of Nlrp5 in oocytes triggers premature activation of the mitochondrial pool, causing mitochondrial damage that cannot be rescued by inactivation of Bax.

Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: ancestral origins of polycystic ovarian syndrome and primary ovarian insufficiency

“…A gene that was present in the DDT and vinclozolin DMR associated genes and ovarian disease associated genes was Pkp4, plakophilins 4 [34,55]. The mRNA genes that were present in the DDT and vinclozolin mRNA genes and ovarian disease associated genes were Nlrp5 and Egr1 [34,56,57]. The Nlrp5 is associated with mitochondrial function in oocytes and embryo [56].…”

“…The mRNA genes that were present in the DDT and vinclozolin mRNA genes and ovarian disease associated genes were Nlrp5 and Egr1 [34,56,57]. The Nlrp5 is associated with mitochondrial function in oocytes and embryo [56]. The Egr1 is associated with granulosa cell apoptosis during atresia through the NF-KB pathway [57].…”

The Therapeutic Potential of Modifying Inflammasomes and NOD-Like Receptors

“…NLRP5 has a role in preimplantation development, probably by controlling mitochondrial metabolism and cellular localization in ovulated oocytes (Fernandes et al, 2012). NLRP7 was initially identified as a factor involved in the pathogenesis of molar pregnancies, a rare genetic condition associated with appearance of hydatidiform moles (Murdoch et al, 2006;Wang et al, 2009).…”

The subcortical maternal complex: multiple functions for one biological structure?

“…A relationship between the SCMC and mitochondria was demonstrated by an interesting work carried out by Fernandes and collaborators [44] that showed that NLRP5 mediates mitochondrial function in mouse oocytes and embryos. They observed that ovulated oocytes lacking Nlrp5 have altered localization of mitochondria: they are scattered throughout the cytoplasm, rather than concentrated in the subcortical layer, and show increased activity in order to sustain the oocyte physiological ATP requirement.…”