title: Genetic modifications of Mecr reveal a role for mitochondrial 2-enoyl-CoA/ACP reductase in placental development in mice.
abstract: Mitochondrial fatty acid synthesis (mtFAS) is an underappreciated but highly conserved metabolic process, indispensable for mitochondrial respiration. It was recently reported that dysfunction of mtFAS causes childhood onset of dystonia and optic atrophy in humans (MEPAN). To study the role of mtFAS in mammals, we generated three different mouse lines with modifications of the Mecr gene, encoding mitochondrial enoyl-CoA/ACP reductase (Mecr). A knock-out-first type mutation, relying on insertion of a strong transcriptional terminator between the first two exons of Mecr, displayed embryonic lethality over a broad window of time and due to a variety of causes. Complete removal of exon 2 or replacing endogenous Mecr by its functional prokaryotic analogue fabI (Mecrtm(fabI)) led to more consistent lethality phenotypes and revealed a hypoplastic placenta. Analyses of several mitochondrial parameters indicate that mitochondrial capacity for aerobic metabolism is reduced upon disrupting mtFAS function. Further analysis of the synthetic Mecrtm(fabI) models disclosed defects in development of placental trophoblasts consistent with disturbed peroxisome proliferator-activated receptor signalling. We conclude that disrupted mtFAS leads to deficiency in mitochondrial respiration, which lies at the root of the observed pantropic effects on embryonic and placental development in these mouse models.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Remya R
authors.initials: RR
authors.lastname: Nair
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Juha M
authors.initials: JM
authors.lastname: Kerätär
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Kaija J
authors.initials: KJ
authors.lastname: Autio
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Ali J
authors.initials: AJ
authors.lastname: Masud
authors.affiliation: Department of Applied Physics, University of Eastern Finland, FI-70211 Kuopio, Finland.|Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Mikko A J
authors.initials: MAJ
authors.lastname: Finnilä
authors.affiliation: Department of Pathology and Medical Research Center Oulu, Oulu University Hospital, FI-90220 Oulu, Finland.
authors.forename: Helena I
authors.initials: HI
authors.lastname: Autio-Harmainen
authors.affiliation: Electron Microscopy Core Facility, Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Ilkka J
authors.initials: IJ
authors.lastname: Miinalainen
authors.affiliation: Medical Informatics and Statistics Research group, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Pentti A
authors.initials: PA
authors.lastname: Nieminen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Kastaniotis
mesh_terms: D000818:Animals; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000235:genetics* / Q000378:metabolism*; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics* / Q000378:metabolism*; D010920:Placenta; D010929:Placentation / Q000235:genetics / Q000502:physiology; D011247:Pregnancy
chemical_list: D005227:Fatty Acids; D010088:Oxidoreductases; D044943:Fatty Acid Desaturases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C434934:trans-2-enoyl-CoA reductase (NADPH); D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)