Endonuclease G: The Link Between Mitochondria and Cardiac Hypertrophy?

Abstract

### Endonuclease G Is a Novel Determinant of Cardiac Hypertrophy and Mitochondrial Function McDermott-Roe et al Nature . 2011;478:114–118. A recent study proposes novel functions of the long known mitochondrial endonuclease, endonuclease G (ENDOG).1 ENDOG was identified via quantitative trait loci analysis as a mediator of blood-pressure–independent cardiac hypertrophy and identified as a novel component in the mitochondrial biogenesis signaling network. Blood pressure-independent cardiac hypertrophy is commonly observed in subjects with obesity and Type 2 diabetes mellitus.2 It is likely that multiple predisposing factors and genetic modifiers interact in a complex fashion, to induce left ventricular (LV) hypertrophy. In the study by McDermott-Roe et al, the authors analyzed quantitative trait loci for blood pressure-independent cardiac mass in rats using an intercross of spontaneously hypertensive rats (SHR) and Brown Norway rats and identified ENDOG as a novel determinant of LV mass and cardiac function.1 Expression of ENDOG was reduced in SHR rats due to a frame-shift insertion in exon 1 of ENDOG that correlated with LV hypertrophy and impaired cardiac function. In subsequent studies, the authors demonstrated that shRNA-mediated knockdown of ENDOG in isolated neonatal rat cardiomyocytes resulted in increased cardiomyocyte size and that cardiomyocyte area was increased in mice lacking ENDOG. Thus, ENDOG may be a novel determinant of blood pressure-independent LV hypertrophy in rodents. To determine the potential relevance to cardiac hypertrophy in humans, a genome-wide coexpression network analysis in a large human cardiac expression data set was performed. ENDOG was identified as participating in a network that was highly enriched for mitochondrial genes and oxidative metabolism processes. Subsequently, the authors demonstrated that ENDOG is a direct target of ERRα and PGC-1α, master regulators of mitochondrial biogenesis. Overexpression of ENDOG increased mitochondrial mass in HEK293 and H9C2 cardiomyocytes. ENDOG directly binds to mitochondrial DNA suggesting a role in the regulation of mitochondrial gene transcription. Functionally, ENDOG−/− mice showed impaired mitochondrial respiration rates and increased …