Format

Send to

Choose Destination
Nat Struct Mol Biol. 2017 Nov;24(11):902-910. doi: 10.1038/nsmb.3481. Epub 2017 Oct 9.

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

Author information

1
Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain.
2
Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain.
3
Josep Carreras Leukemia Research Institute (IJC), Campus ICO-Germans Trias I Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
4
Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
5
German Center for Diabetes Research (DZD), Neuherberg, Germany.
6
Université de Lyon, Centre de Recherche en Cancérologie de Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
7
Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili, Tarragona, Spain.
8
Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
9
Department of Physiological Sciences II, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
10
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
11
Biomedical Center Munich (BMC)-Physiological Chemistry, Center for Integrated Protein Science Munich, Munich Cluster for Systems Neurology, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany.
12
Université de Lyon, Ecole Normale Supérieure de Lyon, Lyon, France.
13
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.

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.

PMID:
28991266
PMCID:
PMC5791885
DOI:
10.1038/nsmb.3481
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center