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dc.contributor.author
Vanderperre, Benoît
dc.contributor.author
Herzig, Sébastien
dc.contributor.author
Krznar, Petra
dc.contributor.author
Hörl, Manuel
dc.contributor.author
Ammar, Zeinab
dc.contributor.author
Montessuit, Sylvie
dc.contributor.author
Pierredon, Sandra
dc.contributor.author
Zamboni, Nicola
dc.contributor.author
Martinou, Jean-Claude
dc.date.accessioned
2018-10-31T17:21:38Z
dc.date.available
2017-06-12T07:57:16Z
dc.date.available
2018-10-31T17:21:38Z
dc.date.issued
2016-05-13
dc.identifier.issn
1553-7390
dc.identifier.issn
1553-7404
dc.identifier.other
10.1371/journal.pgen.1006056
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/117646
dc.identifier.doi
10.3929/ethz-b-000117646
dc.description.abstract
Mitochondrial import of pyruvate by the mitochondrial pyruvate carrier (MPC) is a central step which links cytosolic and mitochondrial intermediary metabolism. To investigate the role of the MPC in mammalian physiology and development, we generated a mouse strain with complete loss of MPC1 expression. This resulted in embryonic lethality at around E13.5. Mouse embryonic fibroblasts (MEFs) derived from mutant mice displayed defective pyruvate-driven respiration as well as perturbed metabolic profiles, and both defects could be restored by reexpression of MPC1. Labeling experiments using 13C-labeled glucose and glutamine demonstrated that MPC deficiency causes increased glutaminolysis and reduced contribution of glucose-derived pyruvate to the TCA cycle. Morphological defects were observed in mutant embryonic brains, together with major alterations of their metabolome including lactic acidosis, diminished TCA cycle intermediates, energy deficit and a perturbed balance of neurotransmitters. Strikingly, these changes were reversed when the pregnant dams were fed a ketogenic diet, which provides acetyl-CoA directly to the TCA cycle and bypasses the need for a functional MPC. This allowed the normal gestation and development of MPC deficient pups, even though they all died within a few minutes post-delivery. This study establishes the MPC as a key player in regulating the metabolic state necessary for embryonic development, neurotransmitter balance and post-natal survival.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Public Library of Science (PLoS)
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Embryonic Lethality of Mitochondrial Pyruvate Carrier 1 Deficient Mouse Can Be Rescued by a Ketogenic Diet
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
PLoS Genetics
ethz.journal.volume
12
en_US
ethz.journal.issue
5
en_US
ethz.journal.abbreviated
PLoS Genet
ethz.pages.start
e1006056
en_US
ethz.size
20 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
Novel avenues in mitochondrial function and diabetes
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.identifier.nebis
005410305
ethz.publication.place
San Francisco, CA
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::03713 - Sauer, Uwe / Sauer, Uwe
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::03713 - Sauer, Uwe / Sauer, Uwe
ethz.grant.agreementno
147637
ethz.grant.fundername
SNF
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.program
SNF: Sonstige
ethz.date.deposited
2017-06-12T08:02:40Z
ethz.source
ECIT
ethz.identifier.importid
imp5936547d1c18276452
ethz.ecitpid
pub:179563
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-17T08:35:19Z
ethz.rosetta.lastUpdated
2018-10-31T17:21:43Z
ethz.rosetta.versionExported
true
ethz.COinS
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