MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption

Abstract : 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.
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Contributor : Philippe Bouvet <>
Submitted on : Friday, August 2, 2019 - 11:13:29 AM
Last modification on : Saturday, August 3, 2019 - 1:29:36 AM

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Melanija Posavec Marjanović, Sarah Hurtado-Bagès, Maximilian Lassi, Vanesa Valero, Roberto Malinverni, et al.. MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption. Nature Structural and Molecular Biology, Nature Publishing Group, 2017, 24 (11), pp.902-910. ⟨10.1038/nsmb.3481⟩. ⟨hal-02262278⟩

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