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MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date :  , DOI: 10.1038/nsmb.3481
Melanija Posavec Marjanović 1, 2 , Sarah Hurtado-Bagès 2, 3 , Maximilian Lassi 4, 5 , Vanesa Valero 3 , Roberto Malinverni 3 , Hélène Delage 6 , Miriam Navarro 7, 8 , David Corujo 3 , Iva Guberovic 3 , Julien Douet 3 , Pau Gama-Perez 9 , Pablo M Garcia-Roves 9 , Ivan Ahel 10 , Andreas G Ladurner 11 , Oscar Yanes 7, 8 , Philippe Bouvet 6, 12 , Mònica Suelves 1 , Raffaele Teperino 4, 5, 13 , J Andrew Pospisilik 13 , Marcus Buschbeck 1, 3
Affiliation  

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.

中文翻译:


MacroH2A1.1 通过限制核 NAD+ 消耗来调节线粒体呼吸



组蛋白变体是真核染色质的结构成分,可以取代核小体中的复制偶联组蛋白。组蛋白变体 MacroH2A1.1 包含能够结合 NAD +衍生代谢物的大结构域。在这里,我们报告,macroH2A1.1 在成肌分化过程中通过选择性剪接的转换被快速诱导,并且缺乏 MacroH2A1.1 的肌管线粒体呼吸能力存在缺陷。我们发现代谢物结合大结构域对于维持最佳线粒体功能至关重要,但对于基因调控来说却是可有可无的。通过直接结合,macroH2A1.1 抑制基础聚 ADP 核糖聚合酶 1 (PARP-1) 活性,从而减少核 NAD +消耗。 NAD +前体 NMN 的积累可以维持对呼吸至关重要的线粒体 NAD +库。我们的数据表明,含有 MacroH2A1.1 的染色质通过限制核 NAD +消耗并在分化细胞中建立 NAD +前体缓冲液来调节线粒体呼吸。
更新日期:2017-10-11
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