Cardiovascular Research Advance Access first published online on August 8, 2009
This version [Corrected Proof] published online on August 31, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp276
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Critical role of complex III in the early metabolic changes following myocardial infarction
1 Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK
2 Institute of Neurology, University College London, London, UK
3 Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK
* Corresponding author. Tel: +44 1865 282253, Fax: +44 1865 282272, Email: lisa.heather{at}dpag.ox.ac.uk
Aims: The chronically infarcted rat heart has multiple defects in metabolism, yet the location of the primary metabolic abnormality arising after myocardial infarction is unknown. Therefore, we investigated cardiac mitochondrial metabolism shortly after infarction.
Methods and results: Myocardial infarctions (n = 11) and sham operations (n = 9) were performed on Wistar rats, at 2 weeks cardiac function was assessed using echocardiography, and rats were grouped into failing (ejection fraction 
45%), moderately impaired (46–60%), and sham-operated (>60%). Respiration rates were decreased by 28% in both subsarcolemmal and interfibrillar mitochondria isolated from failing hearts, compared with sham-operated controls. However, respiration rates were not impaired in mitochondria from hearts with moderately impaired function. The mitochondrial defect in the failing hearts was located within the electron transport chain (ETC), as respiration rates were suppressed to the same extent when fatty acids, ketone bodies, or glutamate were used as substrates. Complex III protein levels were decreased by 46% and complex III activity was decreased by 26%, in mitochondria from failing hearts, but all other ETC complexes were unchanged. Decreased complex III activity was accompanied by a three-fold increase in complex III-derived H2O2 production, decreased cardiolipin content, and a 60% decrease in mitochondrial cytochrome c levels from failing hearts. Respiration rates, complex III activity, cardiolipin content, and reactive oxygen species generation rates correlated with ejection fraction.
Conclusion: In conclusion, a specific defect in complex III occurred acutely after myocardial infarction, which increased oxidative damage and impaired mitochondrial respiration. The extent of mitochondrial dysfunction in the failing heart was proportional to the degree of cardiac dysfunction induced by myocardial infarction.
KEYWORDS Metabolism; Mitochondria; Fatty acids; Complex III; Infarction
Time for primary review: 17 days