title: Mitochondrial benzodiazepine receptors regulate oxygen homeostasis in the early mouse embryo.
abstract: The peripheral benzodiazepine receptor (Bzrp) has been implicated in the control of several processes, including mitochondrial biogenesis and embryo development. The present study examined the impact that specific Bzrp ligands have on oxygen homeostasis in the early mouse embryo. Day 9 embryos at the 16-18 somite pair stage were exposed to standard (21% oxygen) and suboptimal (5% oxygen) oxygen tensions in whole embryo culture. Analysis of gene expression used relative PCR to monitor changes in nuclear respiratory factor-1 (Nrf1), mitochondrial 16S ribosomal RNA (16S rRNA), and genes for several glycolytic enzymes. Ocular development was highly sensitive to periods of hypoxia through a mechanism blocked with the potent Bzrp ligand PK11195. Hypoxia led to a decline of Nrf1 and 16S rRNA levels also through a mechanism blocked with PK11195. Similar activity was observed for FGIN-1-27 whereas Ro5-4864 had contradictory effects. Morpholino-based gene knockdown of Nrf1 (anti-NRF1) produced a sequence-specific decrease in 16S rRNA insensitive to PK11195. These functional relationships suggest that Bzrp-dependent signals regulate the Nrf1 --> Tfam1 --> mtDNA --> 16S rRNA pathway in response to oxygen levels. The activity of PK11195 most likely has a pharmacodynamic basis with regards to specific embryonic precursor target cell populations, transducing a mitochondrial signal to an Nrf1 response analogous to retrograde regulation in yeast for mitochondria-to-nucleus signaling.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: O'Hara
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Nibbio
authors.forename: Robert C
authors.initials: RC
authors.lastname: Craig
authors.forename: Kimberly Rozett
authors.initials: KR
authors.lastname: Nemeth
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Charlap
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D005124:Eye Abnormalities / Q000139:chemically induced; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D006706:Homeostasis / Q000235:genetics*; D007210:Indoleacetic Acids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D010100:Oxygen / Q000633:toxicity*; D012336:RNA, Ribosomal, 16S / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D004268:DNA-Binding Proteins; D007210:Indoleacetic Acids; D007546:Isoquinolines; D008024:Ligands; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D012336:RNA, Ribosomal, 16S; D011963:Receptors, GABA-A; D015534:Trans-Activators; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C028513:4'-chlorodiazepam; D010100:Oxygen; C037850:PK 11195