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

Left ventricular mass (LVM) is a highly heritable trait(1) and an independent risk factor for all-cause mortality(2). To date, genome-wide association studies (GWASs) have not identified the genetic factors underlying LVM variation(3) and the regulatory mechanisms for blood pressure (BP)-independent cardiac hypertrophy remain poorly understood(4,5). Unbiased systems-genetics approaches in the rat(6,7) now provide a powerful complementary tool to GWAS and we applied integrative genomics to dissect a highly replicated, BP-independent LVM locus on rat chromosome 3p. We identified endonuclease G (Endog), previously implicated in apoptosis(8) but not hypertrophy, as the gene at the locus and demonstrated loss-of-function mutation in Endog 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 inferred ENDOG in fundamental mitochondrial processes unrelated to apoptosis. We showed direct regulation of ENDOG by ERRα and PGC1α, 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, Endog deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated reactive oxygen species (ROS), which was associated with enlarged and steatotic cardiomyocytes. Our studies establish further the link between mitochondrial dysfunction, ROS and heart disease and demonstrate a new role for Endog in maladaptive cardiac hypertrophy.