Abstract 18502: Defects of Myocardial Mitochondrial Function in Patients With End-stage Heart Failure Are Associated With Reduced EndonucleaseG
Introduction: The role of mitochondrial function impairment in heart failure (HF) is poorly understood. Endonuclease G (EndoG) is nuclear-encoded, mitochondria-localised nuclease, experimentally implicated in apoptosis, mtDNA function, ROS production and cardiac mass regulation, but its relevance to human HF has never been addressed.
Hypothesis: Mitochondrial function is reduced in advanced human HF and is paralleled by reduction in EndoG.
Methods: LV free-wall samples was obtained from 62 consecutive patients undergoing heart transplantation (HF group; LVEF 23±9%, age 51±12y, 80% males, 31% diabetes-DM, 41%CAD) and from 20 HF-free organ donors (CON group; LVEF 55±12%, age 41±15y, 55% males, 12% DM).
Results: Compared to CON, HF patients had reduced mtDNA content (-24%, p<0.001). HF patients displayed reduced activity of citrate synthase (CS: -26%, p<0.001) and of OXPHOS enzymes NCCR (-24%,p<0.01), SCCR (-40%, p<0.001) and cytocrome-c oxidase (COX: -38%, p<0.001). Oxygraphy confirmed the reduction in COX respiration (-21%, p=0.01) and succinate-supported respiration (-25%, p=0.01) in HF. SDS-PAGE WB showed similar porin (mitochondrial protein abundance), but decreased components of respiratory chain complex I (NDUFA9: -15%), II (SDH70: -17%), III (core2: -20%) and V (F1α: -14%) paralleled by reduction in antioxidant enzymes glutathion-reductase and peroxidase (GR: -24%, GPX: -20%, all p<0.01). EndoG was downregulated in HF (-17.6%, p=0.01) and correlated with mtDNA (Fig), complex I-III and V (r=0.33-0.42, p<0.01), CS (r=0.34, p=0.008) and strongly with GR and GPX (both r=0.6,p≤0.005, Fig). HF aetiology (ischemic/non-ischemic), DM or age had no consistent effect on these alterations.
Conclusions: Advanced HF is associated with reduction of myocardial mtDNA content, lower respiratory chain components and OXPHOS activity and reduced mitochondrial respiration. Reduced myocardial EndoG may contribute to mitochondrial dysfunction in human HF.
- Heart failure
- Energy metabolism
- Mitochondrial energetics, heart failure, arrhythmias
- Reactive oxygen intermediates
Author Disclosures: V. Melenovsky: None. T. Mracek: None. J. Benes: None. H. Nuskova: None. D. Zdenek: None. J. Kovalcikova: None. J. Pirk: None. R. Poledne: None. J. Houstek: None.
- © 2014 by American Heart Association, Inc.