Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function
McDermott Roe, Chris
Rowe, Glenn C.
García Arumí, Elena
Cardona Colom, Maria
Ruiz Meana, Marisol
García Dorado, David
Comella i Carnicé, Joan Xavier
Felkin, Leanne E.
Barton, Paul J. R.
Cook, Stuart A.
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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.
Is part ofNature , 2011, vol. 478, p. 114-118
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EndoG links Bnip3-induced mitochondrial damage and caspase-independent DNA fragmentation in ischemic cardiomyocytes Zhang, Jisheng; Ye, Junmei; Altafaj, Albert; Cardona Colom, Maria; Bahi i Pla, Núria; Llovera i Tomàs, Marta; Cañas, Xavier; Cook, Stuart A.; Comella i Carnicé, Joan Xavier; Sanchis, Daniel (Public Library of Science (PLoS), 2011)Mitochondrial dysfunction, caspase activation and caspase-dependent DNA fragmentation are involved in cell damage in many tissues. However, differentiated cardiomyocytes repress the expression of the canonical apoptotic ...
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Cardiomyocyte hypertrophy induced by Endonuclease G deficiency requires reactive oxygen radicals accumulation and is inhibitable by the micropeptide humanin. Blasco Angulo, Natividad; Cámara, Yolanda; Núñez, Estefanía; Beà Tàrrega, Aida; Barés Junqué, Gisel; Forné Izquierdo, Carles; Ruiz Meana, Marisol; Girón, Cristina; Barba, Ignasi; García Arumí, Elena; García Dorado, David; Vázquez, Jesús; Martí, Ramón; Llovera i Tomàs, Marta; Sanchis, Daniel (Elsevier, 2018-03-01)The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we aimed at finding the ...