Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19678-82. doi: 10.1073/pnas.1117835108. Epub 2011 Nov 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cardiomyopathies / diet therapy*
  • Cardiomyopathies / genetics
  • Cardiomyopathies / metabolism
  • Diet, Ketogenic*
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Gene Expression
  • Genes, Lethal
  • Kaplan-Meier Estimate
  • Male
  • Mediator Complex / genetics*
  • Mediator Complex / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Microscopy, Electron
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / ultrastructure
  • Mitochondrial Myopathies / diet therapy*
  • Mitochondrial Myopathies / genetics
  • Mitochondrial Myopathies / metabolism
  • Mutation, Missense*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Weaning


  • Med30 protein, mouse
  • Mediator Complex
  • Protein Subunits