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

Cells
Consiglia PacelliG. Merla

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 cl...Continue Reading

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Citations

Sep 28, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Rona Merdler-RabinowiczAnnick Raas-Rothschild

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Methods Mentioned

BETA
biopsies
FACS
PCR
Protein Assay
confocal microscopy
acetylation
Chip-seq
RNA-Seq

Software Mentioned

LasX
Graph Pad
Cas
ImageJ Lab
Leica
ImageJ1
Graph Pad Prism

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