IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney...

Area of Science:

• Nephrology
• Immunology
• Toxicology
• Cellular Biology

Background:

• Occupational exposure to trichloroethylene can lead to immune kidney injury and dermatitis.
• Previous research linked C5b-9 complement complex-dependent calcium (Ca2+) overload and ferroptosis to trichloroethylene-induced kidney injury.
• The precise mechanisms of C5b-9-mediated calcium rise and subsequent ferroptosis remained unclear.

Purpose of the Study:

• To investigate the role of inositol trisphosphate receptor (IP3R)-dependent mitochondrial dysfunction in C5b-9-mediated ferroptosis within trichloroethylene-sensitized kidneys.

Main Methods:

• Examined IP3R activation and mitochondrial membrane potential in renal cells from trichloroethylene-sensitized mice and a C5b-9-treated HK-2 cell model.
• Utilized RNA interference (RNAi) targeting IP3R to assess its impact on calcium overload, mitochondrial function, and ferroptosis.
• Employed cyclosporin A, a mitochondrial permeability transition pore inhibitor, to evaluate its protective effects.

Main Results:

• IP3R activation and decreased mitochondrial membrane potential were observed in trichloroethylene-exposed kidney cells, effects antagonized by CD59.
• Silencing IP3R expression mitigated C5b-9-induced calcium overload, mitochondrial dysfunction, and ferroptosis in HK-2 cells.
• Cyclosporin A treatment ameliorated mitochondrial dysfunction and inhibited ferroptosis, confirming the role of the mitochondrial permeability transition pore.

Conclusions:

• IP3R-dependent mitochondrial dysfunction is a key mechanism driving ferroptosis in trichloroethylene-sensitized renal tubular injury.
• Targeting IP3R or the mitochondrial permeability transition pore may offer therapeutic strategies for trichloroethylene-induced kidney damage.