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Journal Article

Abstract 17659: Mitochondrial Pyruvate Transport is Required for the Cardiac Adaptation to Pressure Overload

11 Nov 2016-Circulation (Lippincott Williams & WilkinsHagerstown, MD)-Vol. 134
TL;DR: Mitochondrial pyruvate uptake is dispensable for normal cardiac development and function in non-stressed juvenile hearts although pathological cardiac hypertrophy and heart failure eventually ensues.
Abstract: Glucose and lactate are important fuel substrates for the heart, particularly during acute hemodynamic stresses such as pressure overload or following exercise training. Cytosolic pyruvate that is generated by glycolytic metabolism of glucose or by conversion of lactate is transported into mitochondria via the mitochondrial pyruvate carrier complex, which has two subunits, MPC1 and MPC2. MPC1 and MPC2 transcripts were repressed in mouse hearts 4 weeks after transverse aortic constriction (TAC). We therefore, generated cardiomyocyte-restricted MPC1 knockout mice (CMPC1 -/- ) to investigate the role MPC1 in maintaining cardiac function under resting conditions and following pressure overload. Loss of MPC1 resulted in degradation of MPC2 leading to functional inactivation of the MPC complex in CMPC1 -/- mouse hearts. Cardiac function examined by echocardiography revealed that CMPC1 -/- mice exhibited normal cardiac function by the age of 8 weeks but overt systolic dysfunction by the age of 18 weeks. Survival analysis showed that only 61% of CMPC1 -/- mice remained alive at the age of 1-year relative to 98% of control mice. At the age of 8 weeks, heart weight (HW) and the heart weight to tibia ratio (HW/TL) were significantly increased, along with the transcriptional markers of pathological cardiac hypertrophy, NPPA, NPPB and Acta1. Substrate metabolism in isolated working hearts, revealed a 58% reduction in glucose oxidation in CMPC1 -/- mice relative to control mice while palmitate oxidation was increased by 35%. CMPC1 -/- mice were subjected to pressure overload at the age of 8 weeks. All CMPC1 -/- mice died within a week after TAC surgery while all control mice survived. Thus mitochondrial pyruvate uptake is dispensable for normal cardiac development and function in non-stressed juvenile hearts although pathological cardiac hypertrophy and heart failure eventually ensues. Importantly, mitochondrial pyruvate uptake is essential for maintaining cardiac function in response to pressure overload.
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TL;DR: It is highlighted that energy deficiency in end-stage failing human left ventricle predominantly involves concomitantly impaired activities of key electron transport chain and Krebs cycle enzymes rather than altered expression of respective genes or proteins.
Abstract: Energy insufficiency has been recognized as a key feature of systolic heart failure Although mitochondria have long been known to sustain myocardial work energy supply, the capacity to therapeutically target mitochondrial bioenergetics dysfunction is hampered by a complex interplay of multiple perturbations that progressively compound causing myocardial failure and collapse Compared to non-failing human donor hearts, activity rates of complexes I and IV, nicotinamide nucleotide transhydrogenase (NADPH-transhydrogenase, Nnt) and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase and aconitase are markedly decreased in end-stage heart failure Diminished REDOX capacity with lower total glutathione and coenzyme Q10 levels are also a feature of chronic left ventricular failure Decreased enzyme activities in part relate to abundant and highly specific oxidative, nitrosylative, and hyperacetylation modifications In this brief review we highlight that energy deficiency in end-stage failing human left ventricle predominantly involves concomitantly impaired activities of key electron transport chain and Krebs cycle enzymes rather than altered expression of respective genes or proteins Augmented oxidative modification of these enzyme subunit structures, and the formation of highly reactive secondary metabolites, implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, which contribute further to progressive decreases in bioenergetic capacity and contractile function in human heart failure

46 citations

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