Human model of primary carnitine deficiency cardiomyopathy reveals ferroptosis as a novel disease mechanism

Abstract: Primary carnitine deficiency (PCD) is an autosomal recessive monogenic disorder caused by mutations in SLC22A5. This gene encodes for OCTN2 which transports the essential metabolite carnitine into the cell. PCD patients suffer from muscular weakness and dilated cardiomyopathy. Detailed molecular disease mechanisms remain unclear. Two OCTN2-defective human induced pluripotent stem cell lines were generated from a healthy control line, carrying a full OCTN2-knockout and a homozygous OCTN2 (N32S) loss of function mutation. OCTN2-defective genotypes showed lower cardiac differentiation efficiency, lower force development, and resting length in engineered heart tissue format compared to isogenic control. Force was sensitive to fatty acid-based media and associated with lipid accumulation, mitochondrial alteration, higher glucose uptake, and metabolic remodelling, replicating findings in animal models. Importantly, genome wide analysis and pharmacological inhibitor experiments identified ferroptosis, an iron- and lipid-dependent cell death pathway linked to fibroblast activation as a novel PCD cardiomyopathy disease mechanism.