Matrix Revisited

Abstract

Metabolic signaling mechanisms are increasingly recognized to mediate the cellular response to alterations in workload demand, as a consequence of physiological and pathophysiological challenges. Thus, an understanding of the metabolic mechanisms coordinating activity in the cytosol with the energy-providing pathways in the mitochondrial matrix becomes critical for deepening our insights into the pathogenic changes that occur in the stressed cardiomyocyte. Processes that exchange both metabolic intermediates and cations between the cytosol and mitochondria enable transduction of dynamic changes in contractile state to the mitochondrial compartment of the cell. Disruption of such metabolic transduction pathways has severe consequences for the energetic 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.

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…As a reflection of impaired or dysregulated FAO, the elevated plasma LCAC observed may suggest a shared metabolic impairment of the HF clinical syndrome independent of LVEF 13, 53, 54. Given that FAO impairments or dysregulation may result from a variety of mitochondrial insults, further investigation will be needed to identify the causal processes underlying the LCAC elevations reported in this study 12, 83. Given mounting evidence that LCACs are proinflammatory, arrhythmogenic, and induce cell stress, our findings may suggest a benefit for mitochondrial therapies that decrease LCAC production by increasing glucose oxidation, decreasing FAO flux, or improving mitochondrial function by antioxidant activity 63, 64, 65, 66, 67, 68.…”

“…In recent years, greater attention has been focused on systemic mediators, such as oxidative stress, inflammation, and mitochondrial dysfunction 8, 9, 11. Emerging evidence is also reviving interest in metabolic impairment as a contributor to HFpEF development and progression 8, 9, 12, 13. However, these investigations have largely been conducted in animal models; there is a paucity of data characterizing metabolism in human HFpEF.…”

Probing the cardiac malate–aspartate shuttle non‐invasively using hyperpolarized [1,2‐13C2]pyruvate

“…Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. 38 Via the [2-13 C]pyruvate label, 13 C-glutamate production remained constant on adrenergic activation, such that the 13 C-glutamate produced relative to the amount of 13 C-labeled acetyl-CoA entering the TCA cycle was decreased by 36%.…”

Metabolic syndrome is associated with different clinical outcome after cardiac resynchronization therapy in patients with ischemic and non-ischemic cardiomyopathy

“…It is well known that falling heart will switch fuel metabolism from long chain fatty acids to glucose, but in people with MS also glucose is less available for the heart due to the fact that people with MS have profound insulin resistance and reduced glucose uptake, especially in the presence of ischemia [23]. This may explain why the presence of non-ischemic etiology for HF is associated with better clinical response after CRT-D in general population [19,24] and in our study, in people with MS.…”