Innate Short-Circuiting of Mitochondrial Metabolism in Cardiac Hypertrophy

Abstract

See related articles, pages 805–812 Cardiac hypertrophy is a precursor to the development of heart failure and an independent clinical risk factor for sudden death and myocardial infarction.1 Although energetic deficits are associated with clinical heart failure, their relative contribution to the transition from cardiac hypertrophy to heart failure has been challenging to elucidate, in large part because of the unpredictability of the timing of this transition and limitations of studying human cardiac energetics in vivo. Nevertheless, our understating of this pathophysiology is being illuminated using experimental models. In the normal heart, the oxidation of exogenous fats is the major fuel source, with additional significant contributions from glucose and lactate. The relative contribution of fats diminishes with enhanced reliance on glucose utilization during the development of cardiac hypertrophy. The regulatory programs attenuating fat utilization have been extensively investigated and include regulation at the transcriptional and posttranscriptional levels.2–5 Moreover, this reduction involves coordinate downregulation of proteins controlling fatty acid uptake by the heart and mitochondria as well as of the enzymes controlling mitochondrial fatty acid β-oxidation (FAO).2,6–9 The increased utilization of glucose is similarly regulated at multiple levels and interestingly, at least with robust hypertrophy, the coupling of glycolysis and pyruvate oxidation becomes disrupted with an insufficient increase in glucose oxidation to completely compensate for the reduced FAO.10,11 The mechanisms orchestrating this uncoupling have not been fully delineated, …