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

Area of Science:

• Nephrology
• Genetics
• Cell Biology

Background:

• Cystinosis is a rare lysosomal storage disease due to CTNS gene mutations, leading to cystine buildup.
• Patients exhibit podocyte damage, proteinuria, and focal segmental glomerulosclerosis (FSGS).
• Current treatments don't reverse glomerular injury or prevent podocyte loss, indicating other mechanisms are involved.

Purpose of the Study:

• Investigate podocyte dysfunction in cystinosis beyond cystine accumulation.
• Identify novel pathogenic mechanisms contributing to kidney damage in cystinosis.
• Explore potential therapeutic targets for cystinosis-related podocytopathies.

Main Methods:

• Utilized patient-derived cystinosis and control podocytes, alongside a novel zebrafish model.
• Employed permeability assays, metabolomic analysis, flow cytometry, and redox-sensing probes.
• Assessed mitochondrial function, reactive oxygen species (ROS), and lipid peroxidation.

Main Results:

• Cystinosis podocytes exhibit increased ferroptosis driven by mitochondrial ROS and lipid peroxidation.
• Observed fragmented mitochondria, impaired TCA cycle, and altered energy metabolism in cystinosis cells.
• Inhibition of mitochondrial ROS and lipid peroxidation improved podocyte function and reduced proteinuria in vivo.

Conclusions:

• Mitochondrial ROS-induced lipid peroxidation and ferroptosis contribute to podocyte injury and detachment in cystinosis.
• Cystinosis is identified as a podocytopathy linked to mitochondrial dysfunction.
• Lipid peroxidation represents a potential therapeutic vulnerability for cystinosis podocytes.