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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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References

  1. Post, W. S., Larson, M. G., Myers, R. H., Galderisi, M. & Levy, D. Heritability of left ventricular mass: the Framingham Heart Study. Hypertension 30, 1025–1028 (1997)

    Article  CAS  PubMed  Google Scholar 

  2. Lorell, B. H. & Carabello, B. A. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102, 470–479 (2000)

    Article  CAS  PubMed  Google Scholar 

  3. Vasan, R. S. et al. Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. J. Am. Med. Assoc. 302, 168–178 (2009)

    Article  CAS  Google Scholar 

  4. McGavock, J. M., Victor, R. G., Unger, R. H. & Szczepaniak, L. S. Adiposity of the heart, revisited. Ann. Intern. Med. 144, 517–524 (2006)

    Article  CAS  PubMed  Google Scholar 

  5. Wong, C. & Marwick, T. H. Obesity cardiomyopathy: pathogenesis and pathophysiology. Nature Clin. Pract. Cardiovasc. Med. 4, 436–443 (2007)

    Article  CAS  Google Scholar 

  6. Heinig, M. et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Petretto, E. et al. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass. Nature Genet. 40, 546–552 (2008)

    Article  CAS  PubMed  Google Scholar 

  8. Li, L. Y., Luo, X. & Wang, X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412, 95–99 (2001)

    Article  CAS  ADS  PubMed  Google Scholar 

  9. Dufour, C. R. et al. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRα and γ. Cell Metab. 5, 345–356 (2007)

    Article  CAS  PubMed  Google Scholar 

  10. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999)

    Article  CAS  PubMed  Google Scholar 

  11. Finck, B. N. & Kelly, D. P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 116, 615–622 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hill, J. A. & Olson, E. N. Cardiac plasticity. N. Engl. J. Med. 358, 1370–1380 (2008)

    Article  CAS  PubMed  Google Scholar 

  13. Inomata, H. et al. Identification of quantitative trait loci for cardiac hypertrophy in two different strains of the spontaneously hypertensive rat. Hypertens. Res. 28, 273–281 (2005)

    Article  CAS  PubMed  Google Scholar 

  14. Siegel, A. K. et al. Genetic loci contribute to the progression of vascular and cardiac hypertrophy in salt-sensitive spontaneous hypertension. Arterioscler. Thromb. Vasc. Biol. 23, 1211–1217 (2003)

    Article  CAS  PubMed  Google Scholar 

  15. Büttner, S. et al. Endonuclease G regulates budding yeast life and death. Mol. Cell 25, 233–246 (2007)

    Article  CAS  PubMed  Google Scholar 

  16. David, K. K., Sasaki, M., Yu, S. W., Dawson, T. M. & Dawson, V. L. EndoG is dispensable in embryogenesis and apoptosis. Cell Death Differ. 13, 1147–1155 (2006)

    Article  CAS  PubMed  Google Scholar 

  17. Irvine, R. A. et al. Generation and characterization of endonuclease G null mice. Mol. Cell. Biol. 25, 294–302 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Temme, C. et al. The Drosophila melanogaster gene cg4930 encodes a high affinity inhibitor for endonuclease G. J. Biol. Chem. 284, 8337–8348 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bahi, N. et al. Switch from caspase-dependent to caspase-independent death during heart development: essential role of endonuclease G in ischemia-induced DNA processing of differentiated cardiomyocytes. J. Biol. Chem. 281, 22943–22952 (2006)

    Article  CAS  PubMed  Google Scholar 

  20. Arad, M. et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J. Clin. Invest. 109, 357–362 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dai, D. F. et al. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Gαq overexpression-induced heart failure. Circ. Res. 108, 837–846 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seddon, M., Looi, Y. H. & Shah, A. M. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 93, 903–907 (2007)

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, B. & Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, 17 (2005)

    Article  MathSciNet  MATH  Google Scholar 

  24. Spiegelman, B. M. Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found. Symp. 287, 60–69 (2007)

    CAS  PubMed  Google Scholar 

  25. Cote, J. & Ruiz-Carrillo, A. Primers for mitochondrial DNA replication generated by endonuclease G. Science 261, 765–769 (1993)

    Article  CAS  ADS  PubMed  Google Scholar 

  26. Tiranti, V. et al. Chromosomal localization of mitochondrial transcription factor A (TCF6), single-stranded DNA-binding protein (SSBP), and endonuclease G (ENDOG), three human housekeeping genes involved in mitochondrial biogenesis. Genomics 25, 559–564 (1995)

    Article  CAS  PubMed  Google Scholar 

  27. Rothfuss, O. et al. Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair. Hum. Mol. Genet. 18, 3832–3850 (2009)

    Article  CAS  PubMed  Google Scholar 

  28. Wang, J. et al. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Nature Genet. 21, 133–137 (1999)

    Article  CAS  PubMed  Google Scholar 

  29. Lewis, W. et al. Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ. Lab. Invest. 87, 326–335 (2007)

    Article  CAS  PubMed  Google Scholar 

  30. Vahsen, N. et al. AIF deficiency compromises oxidative phosphorylation. EMBO J. 23, 4679–4689 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Supplementary information

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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