Citrinin induces renal PANoptosis by mediating mitochondrial dysfunction through the GSDMD-N/DRP1 pathway

Area of Science:

• Toxicology
• Cell Biology
• Nephrology

Background:

• Citrinin (CTN) is a nephrotoxic mycotoxin found in food, linked to Balkan endemic nephropathy (BEN).
• The precise molecular mechanisms of CTN-induced kidney damage are not fully understood.
• PANoptosis, a novel cell death pathway integrating pyroptosis, apoptosis, and necroptosis, is implicated in kidney diseases.

Purpose of the Study:

• To investigate the molecular mechanisms of CTN-induced nephrotoxicity.
• To determine if CTN induces PANoptosis in kidney cells.
• To elucidate the role of mitochondrial dysfunction and the GSDMD-N/DRP1 pathway in CTN-induced kidney injury.

Main Methods:

• In vivo (KM mice) and in vitro (TCMK-1 cells) models of CTN exposure.
• Assessment of pyroptotic, apoptotic, and necroptotic markers.
• Mitochondrial function analysis, including DRP1 activity, ROS generation, and cytochrome c release.
• Pharmacological inhibition of DRP1 (Mdivi-1), mtROS (Mito-TEMPO), and GSDMD-N (disulfiram).
• Molecular docking and Co-immunoprecipitation (Co-IP) assays.

Main Results:

• CTN exposure activated pyroptosis, apoptosis, and necroptosis, indicating PANoptosis induction.
• CTN caused mitochondrial damage, DRP1 upregulation, increased mitochondrial ROS (mtROS), and cytochrome c release.
• Inhibition of DRP1, mtROS, or GSDMD-N attenuated CTN-induced mitochondrial dysfunction and PANoptosis.
• GSDMD-N and DRP1 were found to directly interact.

Conclusions:

• CTN induces PANoptosis in kidney cells via GSDMD-N/DRP1-mediated mitochondrial dysfunction.
• Mitochondrial damage, mtROS, and cytochrome c are key mediators in CTN-induced cell death.
• Targeting the GSDMD-N/DRP1 pathway offers a potential therapeutic strategy for CTN-induced nephrotoxicity.