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ABSTRACTPropionic acidemia (PA) is a metabolic disorder caused by a deficiency of the mitochondrial enzyme propionyl?CoA carboxylase (PCC) due to mutations in the PCCA or PCCB genes, which encode the two PCC subunits. PA may lead to several types of cardiomyopathy and has been linked to cardiac electrical abnormalities such as QT interval prolongation, life?threatening arrhythmias, and sudden cardiac death. To gain insights into the mechanisms underlying PA?induced proarrhythmia, we recorded action potentials (APs) and ion currents using whole?cell patch?clamp in ventricular?like induced pluripotent stem cells?derived cardiomyocytes (hiPSC?CMs) from a PA patient carrying two pathogenic mutations in the PCCA gene (p.Cys616_Val633del and p.Gly477Glufs*9) (PCCA cells) and from a healthy subject (healthy cells). In cells driven at 1?Hz, PCC deficiency increased the latency and prolonged the AP duration (APD) measured at 20% of repolarization, without modifying resting membrane potential or AP amplitude. Moreover, delayed afterdepolarizations appeared at the end of the repolarization phase in unstimulated and paced PCCA cells. PCC deficiency significantly reduced peak sodium current (I Na) but increased the late I Na (I NaL) component. In addition, L?type Ca2+ current (I CaL) density was reduced, while the inward and outward density of the Na+/Ca2+ exchanger current (I NCX) was increased in PCCA cells compared to healthy ones. In conclusion, our results demonstrate that at the cellular level, PCC deficiency can modify the ion currents controlling cardiac excitability, APD, and intracellular Ca2+ handling, increasing the risk of arrhythmias independently of the progressive late?onset cardiomyopathy induced by PA disease.