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

• Published in: Nature (London) Vol. 478; no. 7367; pp. 114 - 118
• Main Authors: McDermott-Roe, Chris, Ye, Junmei, Ahmed, Rizwan, Sun, Xi-Ming, Serafín, Anna, Ware, James, Bottolo, Leonardo, Muckett, Phil, Cañas, Xavier, Zhang, Jisheng, Rowe, Glenn C., Buchan, Rachel, Lu, Han, Braithwaite, Adam, Mancini, Massimiliano, Hauton, David, Martí, Ramon, García-Arumí, Elena, Hubner, Norbert, Jacob, Howard, Serikawa, Tadao, Zidek, Vaclav, Papousek, Frantisek, Kolar, Frantisek, Cardona, Maria, Ruiz-Meana, Marisol, García-Dorado, David, Comella, Joan X., Felkin, Leanne E., Barton, Paul J. R., Arany, Zoltan, Pravenec, Michal, Petretto, Enrico, Sanchis, Daniel, Cook, Stuart A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.10.2011; Nature Publishing Group
• Subjects: 631/443/319/333; 631/443/592/1540; 631/80/304; 692/699/317; Animals; Apoptosis; Biological and medical sciences; Biomarkers; Blood; Blood pressure; Body Weight - genetics; Cardiology. Vascular system; Cardiomegaly - enzymology; Cardiomegaly - genetics; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiomyocytes; Cardiovascular diseases; Cell Respiration; Chromosomes, Mammalian - genetics; Crosses, Genetic; Diagnosis; Endodeoxyribonucleases - deficiency; Endodeoxyribonucleases - genetics; Endodeoxyribonucleases - metabolism; ERRalpha Estrogen-Related Receptor; Female; Gene Expression Regulation; Genes, Mitochondrial - genetics; Genetic aspects; Genetic factors; Genetics; Genomes; Heart; Heart enlargement; Humanities and Social Sciences; Hypertrophy, Left Ventricular - enzymology; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - physiopathology; Kinases; letter; Lipid Metabolism; Male; Medical sciences; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; multidisciplinary; Myocarditis. Cardiomyopathies; Nucleases; Organ Size - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physiological aspects; Quantitative Trait Loci - genetics; Rats; Rats, Inbred Strains; Reactive Oxygen Species - metabolism; Receptors, Estrogen - metabolism; Risk factors; RNA-Binding Proteins - metabolism; Rodents; Science; Science (multidisciplinary); Studies; Transcription Factors - metabolism; United States; United Kingdom; Hypertrophic cardiomyopathy; Cardiovascular disease; Mitochondria; Pathogenesis; Myocardial disease; Heart disease
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10490

Endonuclease G and heart disease Elevated left ventricular mass, a highly heritable trait, is an important risk factor for heart failure and death. Stuart Cook and colleagues genetically dissect a locus in the rat associated with blood-pressure-independent cardiac hypertrophy and identify endonuclease G (ENDOG) as a key regulator of hypertrophy at this locus. They further show that the Endog gene is involved in proper mitochondrial function and is modulated by ERR-α and PGC1α, master regulators of mitochondrial and cardiac function. Loss of function of ENDOG causes impaired mitochondrial respiration and increased production of reactive oxygen species, which may contribute to the observed cardiac hypertrophy. Left ventricular mass (LVM) is a highly heritable trait 1 and an independent risk factor for all-cause mortality 2 . So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation 3 , and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood 4 , 5 . Unbiased systems genetics approaches in the rat 6 , 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 apoptosis 8 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.