Abstract
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.
Highlights
Growing evidence highlights the tight interaction between metabolism and epigenetics [1].Covalent modification of DNA and histones require, the availability of amino acid derivatives, cofactors, and central metabolites to feed the plethora of epigenetic-modifying enzymes
Since mitochondria have emerged as an important source of metabolites utilized as co-substrates by both epigenetic writers and erasers [14], we investigated this issue by focusing on the role of KMT2D in mitochondrial aerobic metabolism
By combining biochemical and metabolomic approaches in mouse and human cell models, we demonstrated a rewiring of the mitochondrial metabolic phenotype due to KMT2D alteration that might contribute to the onset of Kabuki syndrome
Summary
Growing evidence highlights the tight interaction between metabolism and epigenetics [1]. Covalent modification of DNA and histones require, the availability of amino acid derivatives, cofactors, and central metabolites to feed the plethora of epigenetic-modifying enzymes. Cells 2020, 9, 1685 to induce epigenetic modulations, such as chromatin remodeling, impact the metabolic phenotype. The mechanisms that confer selectivity of chromatin remodeling in regulating the metabolic phenotype remain to be fully understood. Histone-lysine N-methyltransferase 2D (KMT2D) belongs to the SET1 family of histone H3K4 methyltransferases and is part of the ASCOM multi-protein complex that catalyzes mono-, di-, and tri-methylation of H3K4 using S-adenosyl methionine as a co-substrate [2]. KMT2D is a positive key regulator of gene expression in the context of cellular differentiation in different tissues
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