title: Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet.
abstract: Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.
authors: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Philippe
authors: P
authors: Krebs
authors: Weiwei
authors: W
authors: Fan
authors: Yen-Hui
authors: YH
authors: Chen
authors: Kimimasa
authors: K
authors: Tobita
authors: Michael R
authors: MR
authors: Downes
authors: Malcolm R
authors: MR
authors: Wood
authors: Lei
authors: L
authors: Sun
authors: Xiaohong
authors: X
authors: Li
authors: Yu
authors: Y
authors: Xia
authors: Ning
authors: N
authors: Ding
authors: Jason M
authors: JM
authors: Spaeth
authors: Eva Marie Y
authors: EM
authors: Moresco
authors: Thomas G
authors: TG
authors: Boyer
authors: Cecilia Wen Ya
authors: CW
authors: Lo
authors: Jeffrey
authors: J
authors: Yen
authors: Ronald M
authors: RM
authors: Evans
authors: Bruce
authors: B
authors: Beutler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism; D055423:Diet, Ketogenic; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D015870:Gene Expression; D005804:Genes, Lethal; D053208:Kaplan-Meier Estimate; D008297:Male; D056892:Mediator Complex / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014886:Weaning
chemical_list: C570716:Med30 protein, mouse; D056892:Mediator Complex; D021122:Protein Subunits