Nature Structural & Molecular Biology | Article Print Share/bookmark MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption Melanija Posavec Marjanović, Sarah Hurtado-Bagès, Maximilian Lassi, Vanesa Valero, Roberto Malinverni, Hélène Delage, Miriam Navarro, David Corujo, Iva Guberovic, Julien Douet, Pau Gama-Perez, Pablo M Garcia-Roves, Ivan Ahel, Andreas G Ladurner, Oscar Yanes, Philippe Bouvet, Mònica Suelves, Raffaele Teperino, J Andrew Pospisilik & Marcus Buschbeck Affiliations Contributions Corresponding authors Nature Structural & Molecular Biology (2017) doi:10.1038/nsmb.3481 Received 07 March 2017 Accepted 13 September 2017 Published online 09 October 2017 Article tools PDF Citation Rights & permissions Article metrics Abstract Abstract• Introduction• Results• Discussion• Methods• Additional information• Accession codes• References• Acknowledgments• Author information• Supplementary information 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.