PUBLICATION
Targeting oxidative stress-induced lipid peroxidation enhances podocyte function in cystinosis
- Authors
- Berlingerio, S.P., Bondue, T., Tassinari, S., Siegerist, F., Ferrulli, A., Lismont, C., Cairoli, S., Goffredo, B.M., Ghesquière, B., Fransen, M., Endlich, N., Oliveira Arcolino, F., Bussolati, B., van den Heuvel, L., Levtchenko, E.
- ID
- ZDB-PUB-250221-17
- Date
- 2025
- Source
- Journal of translational medicine 23: 206206 (Journal)
- Registered Authors
- Keywords
- ctns −/− [Tg(fabp10a:gc-EGFP)] zebrafish larvae model, Cystinosis, Ferroptosis, Lipid peroxidation, Liproxstatin-1, MitoTEMPO, Mitochondrial oxidative stress, Podocyte
- MeSH Terms
-
- Humans
- Podocytes*/metabolism
- Podocytes*/pathology
- Ferroptosis
- Lipid Peroxidation*
- Cystinosis*/metabolism
- Cystinosis*/pathology
- Zebrafish*
- Oxidative Stress*
- Reactive Oxygen Species/metabolism
- Amino Acid Transport Systems, Neutral*/genetics
- Amino Acid Transport Systems, Neutral*/metabolism
- Animals
- Mitochondria/metabolism
- PubMed
- 39980044 Full text @ J Transl Med
Citation
Berlingerio, S.P., Bondue, T., Tassinari, S., Siegerist, F., Ferrulli, A., Lismont, C., Cairoli, S., Goffredo, B.M., Ghesquière, B., Fransen, M., Endlich, N., Oliveira Arcolino, F., Bussolati, B., van den Heuvel, L., Levtchenko, E. (2025) Targeting oxidative stress-induced lipid peroxidation enhances podocyte function in cystinosis. Journal of translational medicine. 23:206206.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping