University of Oulu

Nair, R., Kerätär, J., Autio, K., Masud, A., Finnilä, M., Autio-Harmainen, H., Miinalainen, I., Nieminen, P., Hiltunen, J., Kastaniotis, A. (2017) Genetic modifications of Mecr reveal a role for mitochondrial 2-enoyl-CoA/ACP reductase in placental development in mice. Human Molecular Genetics, 26 (11), 2104-2117. doi:10.1093/hmg/ddx105

Genetic modifications of Mecr reveal a role for mitochondrial 2-enoyl-CoA/ACP reductase in placental development in mice

Saved in:
Author: Nair, Remya R.1; Kerätär, Juha M.1; Autio, Kaija J.1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland
2Department of Applied Physics, University of Eastern Finland, FI-70211 Kuopio, Finland
3Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, FI-90014 Oulu, Finland
4Department of Pathology and Medical Research Center Oulu, Oulu University Hospital, FI-90220 Oulu, Finland
5Electron Microscopy Core Facility, Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland
6Medical Informatics and Statistics Research group, University of Oulu, FI-90014 Oulu, Finland
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2017121355804
Language: English
Published: Oxford University Press, 2017
Publish Date: 2018-03-24
Description:

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.

see all

Series: Human molecular genetics
ISSN: 0964-6906
ISSN-E: 1460-2083
ISSN-L: 0964-6906
Volume: 26
Issue: 11
Pages: 2104 - 2117
DOI: 10.1093/hmg/ddx105
OADOI: https://oadoi.org/10.1093/hmg/ddx105
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
Subjects:
Funding: The project was funded by the Academy of Finland, the Sigrid Juselius Foundation and Biocenter Finland. Part of this work has been supported by the INFRAFRONTIER-I3 project under the EU contract Grant Agreement Number (3123250 of the EU FP7 Capacities Specific Programme) and the European commission FP-INFRASTRUCTURES Grant 227490 (Transnational access to EMMA mice).
Copyright information: © The Author 2017. Published by Oxford University Press. All rights reserved. This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Nair, R., Kerätär, J., Autio, K., Masud, A., Finnilä, M., Autio-Harmainen, H., Miinalainen, I., Nieminen, P., Hiltunen, J., Kastaniotis, A. (2017) Genetic modifications of Mecr reveal a role for mitochondrial 2-enoyl-CoA/ACP reductase in placental development in mice. Human Molecular Genetics, 26 (11), 2104-2117. doi:10.1093/hmg/ddx105 is available online at: https://doi.org/10.1093/hmg/ddx105.