Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration

Cells. 2020 Jul 13;9(7):1685. doi: 10.3390/cells9071685.


KMT2D encodes a methyltransferase responsible for histone 3 lysine 4 (H3K4) mono-/di-methylation, an epigenetic mark correlated with active transcription. Here, we tested the hypothesis that KMT2D pathogenic loss-of-function variants, which causes the Kabuki syndrome type 1, could affect the mitochondrial metabolic profile. By using Seahorse technology, we showed a significant reduction of the mitochondrial oxygen consumption rate as well as a reduction of the glycolytic flux in both Kmt2d knockout MEFs and skin fibroblasts of Kabuki patients harboring heterozygous KMT2D pathogenic variants. Mass-spectrometry analysis of intermediate metabolites confirmed alterations in the glycolytic and TCA cycle pathways. The observed metabolic phenotype was accompanied by a significant increase in the production of reactive oxygen species. Measurements of the specific activities of the mitochondrial respiratory chain complexes revealed significant inhibition of CI (NADH dehydrogenase) and CIV (cytochrome c oxidase); this result was further supported by a decrease in the protein content of both complexes. Finally, we unveiled an impaired oxidation of glucose and larger reliance on long-chain fatty acids oxidation. Altogether, our findings clearly indicate a rewiring of the mitochondrial metabolic phenotype in the KMT2D-null or loss-of-function context that might contribute to the development of Kabuki disease, and represents metabolic reprogramming as a potential new therapeutic approach.

Keywords: KMT2D; Kabuki syndrome; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Respiration / genetics
  • DNA-Binding Proteins / genetics*
  • Down-Regulation / genetics
  • Electron Transport Chain Complex Proteins / metabolism
  • Fatty Acids / metabolism
  • Fibroblasts / metabolism
  • Glucose / metabolism
  • Glycolysis / genetics
  • Histone-Lysine N-Methyltransferase / genetics*
  • Homeostasis
  • Humans
  • Loss of Function Mutation / genetics*
  • Membrane Potential, Mitochondrial
  • Metabolic Flux Analysis
  • Mice
  • Mitochondria / metabolism*
  • Models, Biological
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Neoplasm Proteins / genetics*
  • Oxidation-Reduction
  • Reactive Oxygen Species / metabolism
  • Substrate Specificity


  • DNA-Binding Proteins
  • Electron Transport Chain Complex Proteins
  • Fatty Acids
  • KMT2D protein, human
  • Neoplasm Proteins
  • Reactive Oxygen Species
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse
  • Glucose