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Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

Nature volume 478, pages 114–118 (2011)Cite this article

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Abstract

Left ventricular mass (LVM) is a highly heritable trait1 and an independent risk factor for all-cause mortality2. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation3, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood4,5. Unbiased systems genetics approaches in the rat6,7 now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis8 but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function)9,10,11, interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.

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Figure 1: Positional cloning of Endog as the gene underlying the rat chromosome 3p cardiac mass QTL.
Figure 2: Endog regulates cardiac hypertrophy.
Figure 3: ENDOG is co-expressed with a mitochondria-specific gene network and is regulated by PGC1α and ERR-α.
Figure 4: Endog regulates mitochondrial function and cardiac lipid metabolism.

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Acknowledgements

We acknowledge funding from the Medical Research Council (UK), the National Institute for Health Research (UK), the Royal Brompton and Harefield Cardiovascular Biomedical Research Unit, the Imperial College Healthcare Biomedical Research Centre, the British Heart Foundation, Fondation Leducq, the Wellcome Trust, the Grant Agency of the Czech Republic (301/08/0166), the Ministry of Education of the Czech Republic (1M0520), the Ministerio de Ciencia e Innovacion (Spain; PTQ-08-03-07880, SAF2008-02271, SAF2008-03067 and SAF2010-19125), the Agència de Gestió d’Ajuts Universitaris i Recerca (Spain; 2009-SGR-346), the Fondo de Investigaciones Sanitarias (Spain; PS09/02034, PS09/01602 and PS09/01591), the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH-F4-2010-241504 (EURATRANS), and the German National Genome Research Network (NGFN-Plus) Heart Failure. We thank M. R. Lieber for providing the Endog deleted mice and E. Wahle for providing the CG4930 expression plasmid. We thank the National BioResource Project for the Rat (http://www.anim.med.kyoto-u.ac.jp/NBR/) for providing rat strains.

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Authors and Affiliations

  1. Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK

    Chris McDermott-Roe, Rizwan Ahmed, Xi-Ming Sun, James Ware, Leonardo Bottolo, Phil Muckett, Rachel Buchan, Han Lu, Adam Braithwaite, Enrico Petretto & Stuart A. Cook

  2. Cell Signaling & Apoptosis Group, University Lleida, Biomedical Research Institute of Lleida (IRBLLEIDA), Avenida Rovira Roure 80, 25198 Lleida, Spain

    Junmei Ye, Jisheng Zhang, Maria Cardona & Daniel Sanchis

  3. Platform of Applied Research on Laboratory Animal, Barcelona Science Park, Baldiri Reixac 4, 08028 Barcelona, Spain

    Anna Serafín & Xavier Cañas

  4. Cardiovascular Institute, Beth Israel Deaconess Medical Institute, CLS906, 3 Blackfan Circle, Boston, 02215, Massachusetts, USA

    Glenn C. Rowe & Zoltan Arany

  5. Department of Radiological, Oncological and Anatomo-Pathological Sciences, University of Rome, 00161 Sapienza, Italy

    Massimiliano Mancini

  6. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

    David Hauton

  7. Unitat de Patologia Mitocondrial i Neuromuscular CIBERER, Institut de Recerca Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain

    Ramon Martí & Elena García-Arumí

  8. Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany

    Norbert Hubner

  9. CC4, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany

    Norbert Hubner

  10. Department of Physiology, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USA

    Howard Jacob

  11. Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

    Tadao Serikawa

  12. Institute of Physiology, Academy of Sciences of the Czech Republic, Vídenska 1083, 142 20 Prague 4, Czech Republic

    Vaclav Zidek, Frantisek Papousek, Frantisek Kolar & Michal Pravenec

  13. Grup de Patologia Cardiovascular, Institut de Recerca Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Pg. Vall d’Hebron, 119, 08035 Barcelona, Spain

    Marisol Ruiz-Meana & David García-Dorado

  14. Cell Signaling & Apoptosis Group at CIBERNED and Vall d’Hebron Institute of Research (VHIR), Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain

    Joan X. Comella

  15. Department of Biochemistry and Molecular Biology and the Institut de Neurociencies at Universitat Autonoma de Barcelona, 08035 Barcelona, Spain

    Joan X. Comella

  16. Heart Science Centre, National Heart and Lung Institute, Imperial College London, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK

    Leanne E. Felkin & Paul J. R. Barton

  17. Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, UK

    Paul J. R. Barton & Stuart A. Cook

  18. Department of Epidemiology and Biostatistics, Faculty of Medicine, Imperial College London, Praed Street, London W2 1PG, UK

    Enrico Petretto

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  1. Chris McDermott-Roe
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Contributions

C.M.-R., J.Y., X.-M.S., A.S., J.Z., A.B., R.B., D.H., H.L., G.C.R., R.M. and E.G.-A. performed the laboratory-based experiments. R.A., P.M., M.M., V.Z., F.P., M.C., M.R.-M. and F.K. performed the physiology experiments. N.H., H.J., L.E.F., P.J.R.B. and T.S. provided gene expression and physiology data. J.W., L.B. and E.P. performed genetic mapping and network studies. X.C., J.X.C., Z.A., M.P. and D.C.-D. supervised the data analysis and contributed to the experimental design. S.A.C. and D.S. planned the experiments. S.A.C. wrote the manuscript with input and discussion from all of the co-authors.

Corresponding authors

Correspondence to Daniel Sanchis or Stuart A. Cook.

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The authors declare no competing financial interests.

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McDermott-Roe, C., Ye, J., Ahmed, R. et al. Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function. Nature 478, 114–118 (2011). https://doi.org/10.1038/nature10490

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