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

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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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.

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Correspondence to Daniel Sanchis or Stuart A. Cook.

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The authors declare no competing financial interests.

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Supplementary Information 1

This file contains Supplementary Tables 1-3 and Supplementary Figures 1-13 with legends. (PDF 4367 kb)

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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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