MITOCHONDRIAL DISFUNCTION ASSOCIATED TO ATP13A2 DEFICIT IN KUFOR-RAKEB SYNDROME

Kufor–Rakeb syndrome (KRS) is a juvenile-onset neurodegenerative disorder characterized by movement abnormalities, cognitive decline, and brain iron accumulation. The disease is caused by homozygous mutations in the ATP13A2 gene, which encodes for ATP13A2 protein, a lysosomal protein involved in polyamine uptake, cation transport, and autophagy. Recent evidence also links ATP13A2 to mitochondrial regulation, however the mechanisms behind this are not well understood. This study aimed to investigate mitochondrial alterations associated with ATP13A2 mutations to better understand the pathogenesis of KRS. To do so, we first used fibroblasts from a KRS patient carrying two novel ATP13A2 mutations, from an asymptomatic sibling carrying one of these mutations in heterozygosity, and from age-matched healthy controls. KRS patient fibroblasts showed reduced cell viability and increased iron accumulation, consistent with KRS brain features. These cells exhibited aberrant accumulation of dysfunctional mitochondria due to defective lysosomal degradation, which reflected in increased mitochondrial ROS production and cell death. In contrast, fibroblasts from the asymptomatic sibling carrying a single heterozygous mutation, displayed partial mitochondrial dysfunction without mitochondrial accumulation, elevated ROS production and cell death, likely due to preserved autophagy activity. These results were replicated using dopaminergic neuron–like cells derived from SH-SY5Y cells with either near-complete ATP13A2 depletion (KD90) or partial ATP13A2 knockdown (KD50).
Together, our findings confirm a close relationship between ATP13A2 protein and mitochondria and identify mitochondrial dysfunction as a key feature of KRS, supporting mitochondria as a potential therapeutic target.