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

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Issue date
2011
Author
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, Ramón
García Arumí, Elena
Hubner, Norbert
Jacob, Howard
Serikawa, Tadao
Zidek, Vaclav
Papousek, Frantisek
Kolar, Frantisek
Cardona Colom, Maria
Ruiz Meana, Marisol
García Dorado, David
Comella i Carnicé, Joan Xavier
Felkin, Leanne E.
Barton, Paul J. R.
Zoltan Arany
Pravenec, Michal
Petretto, Enrico
Sanchis, Daniel
Cook, Stuart A.
Suggested citation
McDermott Roe, Chris; Ye, Junmei; Ahmed, Rizwan; Sun, Xi-Ming; Serafín, Anna; Ware, James; ... Cook, Stuart A.. (2011) . Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function. Nature , 2011, vol. 478, p. 114-118. https://doi.org/10.1038/nature10490.
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Abstract
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.
URI
http://hdl.handle.net/10459.1/58625
DOI
https://doi.org/10.1038/nature10490
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Nature , 2011, vol. 478, p. 114-118
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