Loss of function of the gene encoding the histone methyltransferase KMT2D leads to deregulation of mitochondrial respiration

C Pacelli, I Adipietro, N Malerba, GM Squeo, C Piccoli… - Cells, 2020 - mdpi.com
C Pacelli, I Adipietro, N Malerba, GM Squeo, C Piccoli, A Amoresano, G Pinto, P Pucci
Cells, 2020mdpi.com
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 …
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.
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