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

Marjanović MP; Hurtado-Bagès S; Lassi M; Valero V; Malinverni R; Delage H; Navarro M; Corujo D; Guberovic I; Douet J; Gama-Perez P; Garcia-Roves PM; Ahel I; Ladurner AG; Yanes O; Bouvet P; Suelves M; Teperino R; Pospisilik JA; Buschbeck M.


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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