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 ...