Targeting Metabolic Dysfunction in Cystinosis Proximal Tubular Epithelial Cells

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Background: Cystinosis is a rare, incurable lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal cystine transporter cystinosin. These mutations cause cystine accumulation in lysosomes throughout the body, prominently affecting the kidneys from early stages. Although cysteamine effectively reduces cystine accumulation, it does not reverse renal Fanconi syndrome or halt progression to end-stage renal disease, indicating that additional mechanisms contribute to renal pathology. This study aims to define the metabolic disturbances occurring in cystinosis proximal tubular epithelial cells (PTECs) derived from patients, with the ultimate goal of identifying clinically actionable metabolic targets. Methods: We utilized immortalized cystinosis PTECs derived from patients carrying the common 57 kb deletion in the CTNS gene, alongside healthy control cells. Metabolic flux was evaluated using stable isotope-labeled tracers (glucose, glutamine, cystine, and oleic acid). Cell viability and intracellular ATP levels were quantified through both biochemical assays and Seahorse XF Analyzer. Mitochondrial respiratory function and glycolysis were assessed using Seahorse metabolic profiling. Results: Cystinosis PTECs exhibited profound metabolic dysfunction, including significantly reduced metabolite flux into glycolysis and the tricarboxylic acid (TCA) cycle. Specifically, basal mitochondrial respiration and spare respiratory capacity were decreased, along with extracellular acidification rate (ECAR). Glycolytic performance was impaired, characterized by decreased basal and compensatory glycolytic responses. Notably, pharmacological targeting using a compound currently in clinical trials, restored basal mitochondrial respiration, ATP production, and glycolytic function in cystinosis PTECs. Conclusion: These results establish mitochondrial and glycolytic dysfunction as central pathogenic mechanisms driving PTEC impairment in cystinosis. Targeting these metabolic pathways offers a novel therapeutic approach with significant translational potential. Ongoing studies evaluating repurposed, clinically relevant compounds may accelerate the translation of these findings into effective treatments for cystinosis.

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