Metabolic signaling mechanisms are increasingly recognized to mediate the cellular response to alterations in workload demand as a consequence of physiological and pathophysiological challenges. support of contractile function in the heart and is implicated in the pathogenesis of heart failure. Deficiencies in metabolic reserve and impaired metabolic transduction in the cardiomyocyte can result from inherent deficiencies in metabolic phenotype or maladaptive changes in metabolic enzyme expression and regulation in the response to pathogenic stress. This review examines both current and emerging concepts of the functional linkage between the cytosol and the mitochondrial matrix with a specific focus on metabolic reserve and energetic efficiency. These principles of exchange and transport mechanisms across the mitochondrial membrane are reviewed for the failing heart from the perspectives of chronic pressure overload and diabetes mellitus. Keywords: cytosol diabetes mellitus heart failure metabolic pathways metabolism mobilization mitochondria The mammalian heart can increase its pump work 3-fold despite limited capacity to store chemical energy. Changes in energy demand therefore require a rapid response from the mitochondria. The size of the total cardiac ATP pool changes little over a wide range of workloads whereas ATP turnover varies substantially. At high workload the total ATP pool can turn over in as little as 2 s.1 2 As a result even modest changes in cardiac metabolism can have a significant impact on contractile function. Just as the heart has a large contractile reserve the heart also has a large metabolic reserve to meet changes in Rabbit Polyclonal to ERN2. energy demand. This review explores the function and dysfunction of the intracellular mechanisms that transduce the pathophysiological state of the heart to the mitochondria to provide this metabolic reserve. Heart failure is a syndrome that is characterized by the heart’s inability to provide sufficient blood flow to the body. Changes in cardiac metabolism contribute to the organ’s impaired contractile function.3 Here we discuss 2 models in particular the hypertrophic heart and the diabetic heart focusing on the changes in mitochondrial function and how these may contribute to heart failure. Although these 2 pathologies are vastly different in their clinical presentation the hypertrophic and diabetic hearts share signs of a PF-3635659 return to the fetal gene program and impaired metabolic reserve.4 We discuss potential defects in several parallel pathways that could limit the ability of the failing heart to meet energetic demand. Specifically we examine the role of intracellular and mitochondrial calcium in regulating mitochondrial metabolism changes in mitochondrial transporter expression signaling between the mitochondria and the cytosol via intermediate exchange PF-3635659 and redox regulation the mitochondria as signaling organelles PF-3635659 and finally the role of the triacylglyceride pool in regulating mitochondrial function through fuel provision and lipid signaling. Metabolic Reserve Metabolic reserve is defined as the available potential energy that is demand PF-3635659 accessible in response to an increase in cardiac work. In the hypertrophic heart increased workload or β-adrenergic stimulation leads to a decrease in the ATP concentration and a reduction in intracellular buffer of ATP and the primary energy buffer in the heart-phosphocreatine (PCr).5 This along with findings of restricted fuel utilization 6 suggests that the metabolic reserve of the hypertrophic heart is reduced leading Ingwall7 and Neubauer8 to speculate initially that the hypertrophic heart is an engine out of fuel. Metabolic reserve of the heart in diabetes mellitus is less understood and conceptually different from that of hypertrophic heart. In diabetes mellitus the heart resembles an engine oversupplied with fuel yet no less restricted in metabolic signaling and the ability to recruit alternative mechanisms of ATP synthesis. Despite an oversupply of energy-rich long-chain fatty acids the heart in diabetes mellitus is energetically compromised in a similar manner to the hypertrophic heart that is a decrease in the cellular energy charge reflected by the relative contents of PCr and PF-3635659 ATP.9 Despite this apparent oversupply substrates are sequestered into storage pools and are uncoupled from mitochondrial metabolism during the later stages of disease progression into overt heart failure.10-13 Consideration of pathological.