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

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 (DCM). Detailed molecular disease mechanisms remain unclear. Two OCTN2-defective human induced pluripotent stem cell lines were generated, carrying a full OCTN2-knockout and a homozygous OCTN2 (N32S) loss of function mutation. OCTN2-defective genotypes exhibited lower cardiac differentiation efficiency, lower force development and resting length in engineered heart tissue format. 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, proteomic- and single nuclear RNA sequencing analysis identified ferroptosis, an iron and lipid-dependent cell death pathway linked to fibroblast activation as a novel PCD disease mechanism. This finding paves the way for specific cardiomyopathy treatment developments.