title: Embryonic Lethality of Mitochondrial Pyruvate Carrier 1 Deficient Mouse Can Be Rescued by a Ketogenic Diet.
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.
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Benoît
authors.initials: B
authors.lastname: Vanderperre
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Herzig
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Krznar
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hörl
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Ammar
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Montessuit
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pierredon
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zamboni
authors.affiliation: Department of Cell Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Martinou
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics*; D002952:Citric Acid Cycle / Q000235:genetics*; D055423:Diet, Ketogenic; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005804:Genes, Lethal; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics*; D027501:Monocarboxylic Acid Transporters; D011247:Pregnancy; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; C000595573:MPC1 pyruvate carrier protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D005973:Glutamine; D019289:Pyruvic Acid; D005947:Glucose