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MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption
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Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A.1.1 contains a macrodomain able to bind NAD+ derived metabolites. Here, we report that macroH2A.1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing. Importantly, myotubes lacking macroH2A.1.1 display a defect in mitochondrial respiratory capacity. We find that the metabolite-interacting macrodomain is essential for sustaining optimal mitochondrial function, but dispensable for gene regulation. Through direct binding, macroH2A.1.1 inhibits basal poly-ADP ribose polymerase 1 activity and thus reduces nuclear NAD+ consumption. Consequentially, accumulation of the NAD+ precursor NMN allows the maintenance of mitochondrial NAD+ pools critical for respiration. Our data indicate that macroH2A.1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells.
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MARJANOVIĆ, Melanija posavec, HURTADO-BAGÈS, Sarah, LASSI, Maximilian, VARELA VÁZQUEZ, Vanesa, MALINVERNI, Roberto, DELAGE, Hélène, NAVARRO, Miriam, CORUJO GARCÍA, David, GUBEROVIC, Iva, DOUET, Julien, GAMA-PEREZ, Pau, GARCÍA-ROVES, Pablo m. (pablo miguel), AHEL, Ivan, LADURNER, Andreas g., YANES, Oscar, BOUVET, Philippe, SUELVES ESTEBAN, Mònica, TEPERINO, Raffaele, POSPISILIK, J. andrew, BUSCHBECK, Marcus. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption. _Nature Structural & Molecular Biology_. 2017. Vol. 24, núm. 11, pàgs. 902-910. [consulta: 21 de gener de 2026]. ISSN: 1545-9993. [Disponible a: https://hdl.handle.net/2445/127975]