Journal Article

Targeting oxidative stress-induced lipid peroxidation enhances podocyte function in cystinosis

Ghesquière, Bart, Cairoli, Sara, Tassinari, Sarah, Bondue, Tjessa, Ferrulli, Angela, Endlich, Nicole, Goffredo, Bianca Maria, Berlingerio, Sante Princiero, Levtchenko, Elena, Siegerist, Florian, Fransen, Marc, Oliveira Arcolino, Fanny, Bussolati, Benedetta, Lismont, Celien, van den Heuvel, Lambertus

2025

Overview

Background Cystinosis is a rare, incurable lysosomal storage disease caused by mutations in the CTNS gene encoding the cystine transporter cystinosin, which leads to lysosomal cystine accumulation in all cells of the body. Patients with cystinosis display signs of podocyte damage characterized by extensive loss of podocytes into the urine at early disease stages, glomerular proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) lesions. Although standard treatment with cysteamine decreases cellular cystine levels, it neither reverses glomerular injury nor prevents the loss of podocytes. Thus, pathogenic mechanisms other than cystine accumulation are involved in podocyte dysfunction in cystinosis. Methods We used immortalized patient-derived cystinosis, healthy, and CTNS knockdown podocytes to investigate podocyte dysfunction in cystinosis. The results were validated in our newly in-house developed fluorescent ctns −/− [Tg(fabp10a:gc-EGFP)] zebrafish larvae model. To understand impaired podocyte functionality, static and dynamic permeability assays, tracer-metabolomic analysis, flow cytometry, western blot, and chemical and dynamic redox-sensing fluorescent probes were used. Results In the current study, we discovered that cystinosis podocytes demonstrate increased ferroptotic cell death caused by mitochondrial reactive oxygen species (ROS)-driven membrane lipid peroxidation. Moreover, cystinosis cells present a fragmented mitochondrial network with impaired tricarboxylic acid cycle (TCA) cycle and energy metabolism. Targeting mitochondrial ROS and lipid peroxidation improved podocyte function in vitro and rescued proteinuria in vivo in cystinosis zebrafish larvae. Conclusions Mitochondrial ROS contribute to podocyte injury in cystinosis by driving lipid peroxidation and ferroptosis, which in turn lead to podocyte detachment. This finding adds cystinosis to the list of podocytopathies associated with mitochondrial dysfunction. The identified mechanisms reveal new therapeutic targets and highlight lipid peroxidation as an exploitable vulnerability of cystinosis podocytes.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Amino Acid Transport Systems, Neutral - metabolism / Animals / Biomedical and Life Sciences / Biomedicine / Care and treatment / Cell death / Cellular Metabolism Therapy / ctns −/− [Tg(fabp10a:gc-EGFP)] zebrafish larvae model / Cysteine / Cystine / Cystinosis / Cystinosis - metabolism / Cystinosis - pathology / Cystinosis - physiopathology / Danio rerio / Developmental stages / Diagnosis / Energy metabolism / Ethylenediaminetetraacetic acid / Experiments / Ferroptosis / Flow cytometry / Fluorescent indicators / Gene Knockdown Techniques / Gene mutations / Genes / Genetic aspects / Glucose / Health aspects / Humans / Kidneys / Kinases / Larva - metabolism / Lipid peroxidation / Lipid Peroxidation - drug effects / Lipids / Lysosomal storage diseases / Medicine/Public Health / Metabolism / Metabolites / Metabolomics / Methylene blue / Mitochondria / Mitochondria - metabolism / Mitochondrial oxidative stress / Mutation / Oxidative stress / Oxidative Stress - drug effects / Penicillin / Permeability / Podocyte / Podocytes - drug effects / Podocytes - metabolism / Podocytes - pathology / Proteins / Proteinuria / Reactive oxygen species / Reactive Oxygen Species - metabolism / Software / Statistical analysis / Telomerase / Therapeutic targets / Tracers (Chemistry) / Tricarboxylic acid cycle / Urine / Zebrafish