title: NLRP5 mediates mitochondrial function in mouse oocytes and embryos.
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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Fernandes
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tsuda
authors.forename: Alagammal L
authors.initials: AL
authors.lastname: Perumalsamy
authors.forename: Taline
authors.initials: T
authors.lastname: Naranian
authors.forename: Jasmine
authors.initials: J
authors.lastname: Chong
authors.forename: Beth M
authors.initials: BM
authors.lastname: Acton
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Tong
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nelson
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004527:Egg Proteins / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D010053:Ovary / Q000196:embryology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000941:Antigens; C494827:Bax protein, mouse; D004527:Egg Proteins; C416503:Nalp5 protein, mouse; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D000255:Adenosine Triphosphate; D045304:Cytochromes c