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

Autori
Posavec Marjanović, Melanija ; Hurtado-Bagès, Sarah ; Lassi, Maximilian ; Valero, Vanesa ; Malinverni, Roberto ; Delage, Hélène ; Navarro, Miriam ; Corujo, David ; Guberovic, Iva ; Douet, Julien ; Gama-Perez, Pau ; Garcia-Roves, Pablo M ; Ahel, Ivan ; Ladurner, Andreas G ; Yanes, Oscar ; Bouvet, Philippe ; Suelves, Mònica ; Teperino, Raffaele ; Pospisilik, J Andrew ; Buschbeck, Marcus

Izvornik
Nature Structural & Molecular Biology (1545-9993) 24 (2017), 11; 902-910

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
histone variant macroH2A ; subcellular compartmentation ; epigenetic regulator ; stem-cells ; metabolism ; activation ; isoforms ; poly(adp-ribose) ; transcription ; chromatin

Sažetak
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

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Interdisciplinarne prirodne znanosti

POVEZANOST RADA