Pantothenate kinase-associated neurodegeneration is an early onset autosomal recessive
movement disorder caused by mutation of the pantothenate kinase-2 gene, which encodes a mitochondrial
enzyme involved in
coenzyme A synthesis. The disorder is characterised by high
iron levels in the brain, although the pathological mechanism leading to this accumulation is unknown. To address this question, we tested primary skin fibroblasts from three patients and three healthy subjects, as well as neurons induced by direct fibroblast reprogramming, for oxidative status, mitochondrial functionality and
iron parameters. The patients' fibroblasts showed altered oxidative status, reduced
antioxidant defence, and impaired cytosolic and mitochondrial
aconitase activities compared to control cells. Mitochondrial
iron homeostasis and functionality analysis of patient fibroblasts indicated increased labile
iron pool content and
reactive oxygen species development, altered mitochondrial shape, decreased membrane potential and reduced
ATP levels. Furthermore, analysis of induced neurons, performed at a single cell level, confirmed some of the results obtained in fibroblasts, indicating an altered oxidative status and signs of
mitochondrial dysfunction, possibly due to
iron mishandling. Thus, for the first time, altered biological processes have been identified in vitro in live diseased neurons. Moreover, the obtained induced neurons can be considered a suitable human neuronal model for the identification of candidate therapeutic compounds for this disease.