Abstract 11245: Endonuclease G Regulates Mitochondrial Biogenesis and Cardiac Hypertrophy
The rat genome is unique in containing regions of replicated association with left ventricular mass (LVM) and notably has four overlapping LVM quantitative trait loci (QTLs) on chromosome 3p. We confirmed the chromosome 3 QTL (LOD=4.3), which was independent of blood pressure, in a BN x SHR F2 intercross and in two SHR.BN congenic strains. Haplotype analyses refined the region to 700 Kb across five loci in the QTL region. At these loci, endonuclease G (EndoG) was the most significant expression QTL (P<1x10-6) and was the only gene with consistent differential expression in all five mapping strains. Sequencing of EndoG revealed a 38 bp SHR-specific insertion that caused a frameshift, a premature stop codon and resulted in the absence of detectable EndoG protein or activity, which we mapped to the EndoG locus only (LOD=14). EndoG protein was most highly expressed in the heart and localised to cardiac myocytes. Knockdown and overexpression of EndoG in cultured cardiac myocytes induced and inhibited hypertrophy, respectively. As compared to wildtype mice, EndoG deleted mice (EndoG-/-) had larger cardiac myocytes at baseline (P<6x10-6) and following angiotensin II stimulation (P<1x10-20), which lead to increased LVM. EndoG was most highly expressed in metabolically active tissues, correlated strongly with respiratory chain genes and was shown to be PGC1-regulated in PGC1-transgenic and -deleted mice. EndoG gain of function in vitro led to increased mitochondrial abundance whilst hearts from Endog-/- mice had depleted mitochondrial content and marked lipid accumulation. Consistent with a role in mitochondrial biogenesis, ChIP experiments demonstrated an association between EndoG and mitochondrial DNA. Taken together our studies identify EndoG as a PGC1-regulated determinant of mitochondrial biogenesis and cardiac hypertrophy.
- © 2011 by American Heart Association, Inc.