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

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 mitocho...

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Autores principales: Pacelli, Consiglia, Adipietro, Iolanda, Malerba, Natascia, Squeo, Gabriella Maria, Piccoli, Claudia, Amoresano, Angela, Pinto, Gabriella, Pucci, Pietro, Lee, Ji-Eun, Ge, Kai, Capitanio, Nazzareno, Merla, Giuseppe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407568/
https://www.ncbi.nlm.nih.gov/pubmed/32668765
http://dx.doi.org/10.3390/cells9071685
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author Pacelli, Consiglia
Adipietro, Iolanda
Malerba, Natascia
Squeo, Gabriella Maria
Piccoli, Claudia
Amoresano, Angela
Pinto, Gabriella
Pucci, Pietro
Lee, Ji-Eun
Ge, Kai
Capitanio, Nazzareno
Merla, Giuseppe
author_facet Pacelli, Consiglia
Adipietro, Iolanda
Malerba, Natascia
Squeo, Gabriella Maria
Piccoli, Claudia
Amoresano, Angela
Pinto, Gabriella
Pucci, Pietro
Lee, Ji-Eun
Ge, Kai
Capitanio, Nazzareno
Merla, Giuseppe
author_sort Pacelli, Consiglia
collection PubMed
description 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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spelling pubmed-74075682020-08-25 Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration Pacelli, Consiglia Adipietro, Iolanda Malerba, Natascia Squeo, Gabriella Maria Piccoli, Claudia Amoresano, Angela Pinto, Gabriella Pucci, Pietro Lee, Ji-Eun Ge, Kai Capitanio, Nazzareno Merla, Giuseppe Cells Article 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. MDPI 2020-07-13 /pmc/articles/PMC7407568/ /pubmed/32668765 http://dx.doi.org/10.3390/cells9071685 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pacelli, Consiglia
Adipietro, Iolanda
Malerba, Natascia
Squeo, Gabriella Maria
Piccoli, Claudia
Amoresano, Angela
Pinto, Gabriella
Pucci, Pietro
Lee, Ji-Eun
Ge, Kai
Capitanio, Nazzareno
Merla, Giuseppe
Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration
title Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration
title_full Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration
title_fullStr Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration
title_full_unstemmed Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration
title_short Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration
title_sort loss of function of the gene encoding the histone methyltransferase kmt2d leads to deregulation of mitochondrial respiration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407568/
https://www.ncbi.nlm.nih.gov/pubmed/32668765
http://dx.doi.org/10.3390/cells9071685
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