Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy

Abstract

Cardiomyocytes rely on metabolic substrates, not only to fuel cardiac output, but also for growth and remodelling during stress. Here we show that mitochondrial pyruvate carrier (MPC) abundance mediates pathological cardiac hypertrophy. MPC abundance was reduced in failing hypertrophic human hearts, as well as in the myocardium of mice induced to fail by angiotensin II or through transverse aortic constriction. Constitutive knockout of cardiomyocyte MPC1/2 in mice resulted in cardiac hypertrophy and reduced survival, while tamoxifen-induced cardiomyocyte-specific reduction of MPC1/2 to the attenuated levels observed during pressure overload was sufficient to induce hypertrophy with impaired cardiac function. Failing hearts from cardiomyocyte-restricted knockout mice displayed increased abundance of anabolic metabolites, including amino acids and pentose phosphate pathway intermediates and reducing cofactors. These hearts showed a concomitant decrease in carbon flux into mitochondrial tricarboxylic acid cycle intermediates, as corroborated by complementary 1,2-[ 13 C 2 ]glucose tracer studies. In contrast, inducible cardiomyocyte overexpression of MPC1/2 resulted in increased tricarboxylic acid cycle intermediates, and sustained carrier expression during transverse aortic constriction protected against cardiac hypertrophy and failure. Collectively, our findings demonstrate that loss of the MPC1/2 causally mediates adverse cardiac remodelling.Healthy myocardial mitochondria primarily utilize oxidative phosphorylation to generate adenosine triphosphate (ATP), which is required to meet the heart's energy-demanding function as a blood pump. In healthy myocardium with sufficient oxygen supply, oxidation of fatty acids provides approximately 60-90% of the myocardial acetyl-coenzyme A that contributes to ATP generation, with 10-40% arising from pyruvate oxidation 1,2 . However, the stressed human heart changes its fuel preference 3,4 , switching from fatty acids to glucose as a favoured carbon source 5,6 . Consistent with this observation, several studies with animal models of pressure overload-induced hypertrophy have shown reduced fatty acid oxidation rates with enhanced glucose uptake and glycolysis, accompanied by a compensatory anaplerosis to maintain the tricarboxylic acid cycle flux in the pathological heart [7][8][9] . Interestingly, this enhanced glycolysis and carbon influx via anaplerosis did not augment ATP production, consistent with an 'uncoupling' between glycolysis and glucose oxidation during pathological hypertrophy 7,10,11 . Furthermore, instead of pyruvate predominantly being oxidized in the mitochondria, it is metabolized by alternative pathways, including reductive fermentation to lactate, despite sufficient oxygen availability 12,13 . This is reminiscent of the Warburg effect, whereby many cancer cells increase glucose uptake and convert it to lactate via the reduction of pyruvate despite oxygen availability.Since the identification of the mitochondrial pyruvate carrier (MPC) in 2012 (refs. 14,15 ...

FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity

“…Reductions in glucose oxidation may lead to systolic dysfunction because mice with a cardiac-specific mitochondrial pyruvate carrier subunit 1 deficiency exhibit impaired myocardial glucose oxidation rates, which leads to a marked decline in LVEF by $8 months of age (Zhang et al, 2020). Similarly, another study using the same mice also reported a significant decline in LVEF, but nearly all mice died of cardiac failure by $20 weeks of age (Fernandez-Caggiano et al, 2020). With regard to FoxO1, findings in 8-month-old db/db mice with a cardiac-specific FoxO1 deficiency have demonstrated alleviation of the decline in systolic functional parameters (LVEF and LVFS), although glucose oxidation was not assessed in this particular study (Qi et al, 2015).…”

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“…Within CMs, mitochondria are one of the most important organelles. Mitochondria are involved in almost all the major biological process of CMs, including supporting cellular morphology, ATP production through the electron transport chain (ETC), regulation of intracellular calcium ion signaling, and balance of reactive oxygen species (ROS) levels (Huss and Kelly, 2005;Koo and Guan, 2018;Fernandez-Caggiano et al, 2020). The mitochondria occupy a large fraction of CM cell volume (35-40%) and supply more than 90% energy of the cells' energy requirements.…”

Run for your life: can exercise be used to effectively target GLUT4 in diabetic cardiac disease?

“…Indeed, many would argue that metabolic perturbations precede functional changes in many examples of cardiac malfunction. A striking example is provided by recent work showing that levels of the mitochondrial pyruvate carrier mediates pathological cardiac hypertrophy in human heart, and mouse knockout of cardiomyocyte mitochondrial pyruvate carriers resulted in cardiac hypertrophy and reduced survival ( Fernandez-Caggiano et al, 2020 ). Hence, we focus the remainder of this review on cardiac metabolism and substrate use as our thesis is that alterations in metabolism and substrate use may be key aetiological factors in the development of DCM.…”

“…Similarly, glucose is rapidly converted to glucose-6-phosphate and metabolised to pyruvate in the cytosol and then enters the TCA cycle. Reduced expression of the mitochondrial pyruvate carrier protein is associated with cardiac hypertrophy in human heart ( Fernandez-Caggiano et al, 2020 ). Hence, cardiomyocyte metabolism is considered to be highly adaptive and tightly regulated by hormonal and contraction signals, coupling fuel use with available substrate and metabolic need.…”