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MacroH2A1.1 regualtes mitochondrial respiration by limiting nuelcear NAD+ consumption

MPG-Autoren

Teperino,  Raffaele
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Pospisilik,  J Andrew
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Zitation

Marjanović, M. P., Hurtado-Bagès, S., Lassi, M., Valero, V., Malinverni, R., Delage, H., et al. (2017). MacroH2A1.1 regualtes mitochondrial respiration by limiting nuelcear NAD+ consumption. Nature Structural and Molecular Biology, 902-910. doi:10.1038/nsmb.3481.


Zitierlink: http://hdl.handle.net/21.11116/0000-0000-AF46-D
Zusammenfassung
Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD+ consumption. The resultant accumulation of the NAD+ precursor NMN allows for maintenance of mitochondrial NAD+ pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells.