MacroH2A1.1 Regulates Mitochondrial Respiration by Limiting Nuclear NAD Consumption

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2017 Oct 10

PMID 28991266

Citations 36

Authors

Melanija Posavec Marjanovic

Sarah Hurtado-Bages

Maximilian Lassi

Vanesa Valero

Roberto Malinverni

Helene Delage

Miriam Navarro

David Corujo

Iva Guberovic

Julien Douet

Pau Gama-Perez

Pablo M Garcia-Roves

Ivan Ahel

Andreas G Ladurner

Oscar Yanes

Philippe Bouvet

Monica Suelves

Raffaele Teperino

J Andrew Pospisilik

Marcus Buschbeck

Affiliations

Soon will be listed here.

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.

Citing Articles

Identification of a novel DNA oxidative damage repair pathway, requiring the ubiquitination of the histone variant macroH2A1.1.

Ouararhni K, Mietton F, Sabir J, Ibrahim A, Molla A, Albheyri R BMC Biol. 2024; 22(1):188.

PMID: 39218869 PMC: 11368025. DOI: 10.1186/s12915-024-01987-x.

Deficiency of histone variant macroH2A1.1 is associated with sexually dimorphic obesity in mice.

Chiodi V, Rappa F, Lo Re O, Chaldakov G, Lelouvier B, Micale V Sci Rep. 2023; 13(1):19123.

PMID: 37926763 PMC: 10625986. DOI: 10.1038/s41598-023-46304-8.

MacroH2A1.1 as a crossroad between epigenetics, inflammation and metabolism of mesenchymal stromal cells in myelodysplastic syndromes.

Giallongo C, Dulcamare I, Giallongo S, Duminuco A, Pieragostino D, Cufaro M Cell Death Dis. 2023; 14(10):686.

PMID: 37852977 PMC: 10584900. DOI: 10.1038/s41419-023-06197-x.

Metabolo-epigenetic interplay provides targeted nutritional interventions in chronic diseases and ageing.

Gomez de Cedron M, Moreno Palomares R, Ramirez de Molina A Front Oncol. 2023; 13:1169168.

PMID: 37404756 PMC: 10315663. DOI: 10.3389/fonc.2023.1169168.

High-Dosage NMN Promotes Ferroptosis to Suppress Lung Adenocarcinoma Growth through the NAM-Mediated SIRT1-AMPK-ACC Pathway.

Zhang M, Cui J, Chen H, Wang Y, Kuai X, Sun S Cancers (Basel). 2023; 15(9).

PMID: 37173894 PMC: 10177531. DOI: 10.3390/cancers15092427.

References

Ouararhni K, Hadj-Slimane R, Ait-Si-Ali S, Robin P, Mietton F, Harel-Bellan A . The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev. 2006; 20(23):3324-36. PMC: 1686608. DOI: 10.1101/gad.396106. View

Pasque V, Gillich A, Garrett N, Gurdon J . Histone variant macroH2A confers resistance to nuclear reprogramming. EMBO J. 2011; 30(12):2373-87. PMC: 3116279. DOI: 10.1038/emboj.2011.144. View

Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner A . Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol. 2005; 12(7):624-5. DOI: 10.1038/nsmb956. View

Stein L, Imai S . The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol Metab. 2012; 23(9):420-8. PMC: 3683958. DOI: 10.1016/j.tem.2012.06.005. View

Jankevicius G, Hassler M, Golia B, Rybin V, Zacharias M, Timinszky G . A family of macrodomain proteins reverses cellular mono-ADP-ribosylation. Nat Struct Mol Biol. 2013; 20(4):508-14. PMC: 7097781. DOI: 10.1038/nsmb.2523. View

Podrini C, Koffas A, Chokshi S, Vinciguerra M, Lelliott C, White J . MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis. FASEB J. 2014; 29(5):1676-87. DOI: 10.1096/fj.14-262717. View

Creppe C, Janich P, Cantarino N, Noguera M, Valero V, Musulen E . MacroH2A1 regulates the balance between self-renewal and differentiation commitment in embryonic and adult stem cells. Mol Cell Biol. 2012; 32(8):1442-52. PMC: 3318583. DOI: 10.1128/MCB.06323-11. View

DellOrso S, Wang A, Shih H, Saso K, Berghella L, Gutierrez-Cruz G . The Histone Variant MacroH2A1.2 Is Necessary for the Activation of Muscle Enhancers and Recruitment of the Transcription Factor Pbx1. Cell Rep. 2016; 14(5):1156-1168. PMC: 4749450. DOI: 10.1016/j.celrep.2015.12.103. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

10.

Buschbeck M, Uribesalgo I, Ledl A, Gutierrez A, Minucci S, Muller S . PML4 induces differentiation by Myc destabilization. Oncogene. 2006; 26(23):3415-22. DOI: 10.1038/sj.onc.1210128. View

11.

Yang H, Yang T, Baur J, Perez E, Matsui T, Carmona J . Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell. 2007; 130(6):1095-107. PMC: 3366687. DOI: 10.1016/j.cell.2007.07.035. View

12.

Buschbeck M, Uribesalgo I, Wibowo I, Rue P, Martin D, Gutierrez A . The histone variant macroH2A is an epigenetic regulator of key developmental genes. Nat Struct Mol Biol. 2009; 16(10):1074-9. DOI: 10.1038/nsmb.1665. View

13.

Wettenhall J, Smyth G . limmaGUI: a graphical user interface for linear modeling of microarray data. Bioinformatics. 2004; 20(18):3705-6. DOI: 10.1093/bioinformatics/bth449. View

14.

Timinszky G, Till S, Hassa P, Hothorn M, Kustatscher G, Nijmeijer B . A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nat Struct Mol Biol. 2009; 16(9):923-9. DOI: 10.1038/nsmb.1664. View

15.

Sporn J, Kustatscher G, Hothorn T, Collado M, Serrano M, Muley T . Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene. 2009; 28(38):3423-8. DOI: 10.1038/onc.2009.26. View

16.

Pittelli M, Formentini L, Faraco G, Lapucci A, Rapizzi E, Cialdai F . Inhibition of nicotinamide phosphoribosyltransferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J Biol Chem. 2010; 285(44):34106-14. PMC: 2962509. DOI: 10.1074/jbc.M110.136739. View

17.

Rosenthal F, Feijs K, Frugier E, Bonalli M, Forst A, Imhof R . Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases. Nat Struct Mol Biol. 2013; 20(4):502-7. DOI: 10.1038/nsmb.2521. View

18.

Rivera-Casas C, Gonzalez-Romero R, Cheema M, Ausio J, Eirin-Lopez J . The characterization of macroH2A beyond vertebrates supports an ancestral origin and conserved role for histone variants in chromatin. Epigenetics. 2016; 11(6):415-25. PMC: 4939916. DOI: 10.1080/15592294.2016.1172161. View

19.

Gibson B, Kraus W . New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol. 2012; 13(7):411-24. DOI: 10.1038/nrm3376. View

20.

Houtkooper R, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G . Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013; 497(7450):451-7. PMC: 3663447. DOI: 10.1038/nature12188. View