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Propionic acidemia (PA) is a rare metabolic disease associated with mutations in genes encoding the α and β subunits of the enzyme propionyl-CoA carboxylase. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species production and oxidative damage, which have been associated with the disease pathophysiology. Clinical symptoms are heterogeneous and include cardiac complications, mainly cardiac dysfunction and arrhythmias, which are recognized as one of the major life-threatening manifestations in patients. We aimed to investigate the molecular mechanisms underlying the cardiac phenotype using a hypomorphic mouse model (Pcca -/- (A138T)) that recapitulates some biochemical and clinical characteristics of PA. We demonstrate that Pcca -/- (A138T) mice present with depressed cardiac function along with impaired cell contractility when compared to the wild-type mice. Cardiac dysfunction in Pcca -/- (A138T) mice was associated with lower systolic Ca 2+ release ([Ca 2+ ] i transients), impairment in the sarcoplasmic reticulum (SR) Ca 2+ load and decreased Ca 2+ re-uptake by SR-Ca 2+ ATPase (SERCA2a). These functional changes correlated well with the depressed activity of SERCA2a, the elevated ROS levels and SERCA2a oxidation rate in cardiomyocytes isolated from Pcca -/- (A138T) mice. In addition, decreased SR-Ca 2+ load in Pcca -/- (A138T) cardiomyocytes was associated with increased diastolic Ca 2+ release. The increase in Ca 2+ sparks, Ca 2+ waves and spontaneous [Ca 2+ ] i transients in Pcca -/- (A138T) cardiomyocytes could be responsible for the induction of ventricular arrhythmias detected in these mice. Overall, our results uncover the role of impaired Ca 2+ handling in arrhythmias and cardiac dysfunction in PA, and identify new targets for the development of therapeutic approaches for this devastating metabolic disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)