title: Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function.
abstract: Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat 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 apoptosis 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), 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.
authors: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
authors: Chris
authors: C
authors: McDermott-Roe
authors: Junmei
authors: J
authors: Ye
authors: Rizwan
authors: R
authors: Ahmed
authors: Xi-Ming
authors: XM
authors: Sun
authors: Anna
authors: A
authors: Serafín
authors: James
authors: J
authors: Ware
authors: Leonardo
authors: L
authors: Bottolo
authors: Phil
authors: P
authors: Muckett
authors: Xavier
authors: X
authors: Cañas
authors: Jisheng
authors: J
authors: Zhang
authors: Glenn C
authors: GC
authors: Rowe
authors: Rachel
authors: R
authors: Buchan
authors: Han
authors: H
authors: Lu
authors: Adam
authors: A
authors: Braithwaite
authors: Massimiliano
authors: M
authors: Mancini
authors: David
authors: D
authors: Hauton
authors: Ramon
authors: R
authors: Martí
authors: Elena
authors: E
authors: García-Arumí
authors: Norbert
authors: N
authors: Hubner
authors: Howard
authors: H
authors: Jacob
authors: Tadao
authors: T
authors: Serikawa
authors: Vaclav
authors: V
authors: Zidek
authors: Frantisek
authors: F
authors: Papousek
authors: Frantisek
authors: F
authors: Kolar
authors: Maria
authors: M
authors: Cardona
authors: Marisol
authors: M
authors: Ruiz-Meana
authors: David
authors: D
authors: García-Dorado
authors: Joan X
authors: JX
authors: Comella
authors: Leanne E
authors: LE
authors: Felkin
authors: Paul J R
authors: PJ
authors: Barton
authors: Zoltan
authors: Z
authors: Arany
authors: Michal
authors: M
authors: Pravenec
authors: Enrico
authors: E
authors: Petretto
authors: Daniel
authors: D
authors: Sanchis
authors: Stuart A
authors: SA
authors: Cook
mesh_terms: D000818:Animals; D017209:Apoptosis; D001835:Body Weight / Q000235:genetics; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D019069:Cell Respiration; D033481:Chromosomes, Mammalian / Q000235:genetics; D003433:Crosses, Genetic; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D050259:Genes, Mitochondrial / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D050356:Lipid Metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D040641:Quantitative Trait Loci / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D004706:Endodeoxyribonucleases; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C501429:Ppargc1a protein, rat; C052391:endonuclease G