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Aflatoxin B1 Induces Pyroptosis and Apoptosis in Renal Cells by Mediating Mitophagy Dysfunction and Mitochondrial
Xinyu Yao1, Min Gao1, Jing Lu1,2
1College of Food Science and Engineering, Jilin University, Changchun, Jilin 130062, People's Republic of China.
Abstract:
Aflatoxin B1 (AFB1), a potent mycotoxin, induces nephrotoxicity through previously unrecognized crosstalk between pyroptosis and apoptosis. Using in vivo and in vitro renal injury models, we demonstrate that AFB1 impairs mitophagy, leading to an excessive level of reactive oxygen species (ROS) accumulation. This ROS surge triggers lysosomal membrane permeabilization (LMP) and cathepsin B (CTSB)-dependent activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, initiating caspase-1-mediated pyroptosis via gasdermin D N-terminal (GSDMD-N) pore formation. Importantly, AFB1 also induces cardiolipin translocation to the mitochondrial outer membrane, where pyroptosis-derived GSDMD-N is recruited to form mitochondrial pores. This results in cytochrome c (Cyt-c) release and activation of a caspase-dependent noncanonical apoptotic cascade distinct from the classical apoptotic pathway. These findings establish GSDMD-N-mediated mitochondrial damage as a molecular bridge linking pyroptosis to apoptosis in AFB1 nephrotoxicity and highlight GSDMD-N inhibition as a promising therapeutic strategy. Given AFB1's persistence and bioaccumulation in the food chain, these mechanistic insights provide a molecular basis for developing targeted interventions to mitigate its health risks in agricultural production and food safety.
Insights
Aflatoxin B1 (AFB1) causes kidney damage by linking pyroptosis and apoptosis. Inhibiting gasdermin D-N (GSDMD-N) may prevent this toxicity, crucial for food safety.
Area of Science:
- Toxicology
- Cellular Biology
- Pathology
Background:
- Aflatoxin B1 (AFB1) is a prevalent mycotoxin with known toxicity.
- The precise mechanisms of AFB1-induced nephrotoxicity remain incompletely understood.
- Crosstalk between programmed cell death pathways is increasingly recognized in toxicology.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying AFB1-induced nephrotoxicity.
- To investigate the role of pyroptosis and apoptosis in AFB1 renal injury.
- To identify potential therapeutic targets for AFB1 toxicity.
Main Methods:
- In vivo and in vitro renal injury models were utilized.
- Analysis of mitophagy, reactive oxygen species (ROS) levels, and lysosomal membrane permeabilization (LMP).
- Investigated inflammasome activation (NLRP3, caspase-1), pyroptosis (GSDMD-N), and apoptosis (cytochrome c release).
Main Results:
- AFB1 impairs mitophagy, increasing ROS accumulation and triggering lysosomal damage.
- ROS surge activates the NLRP3 inflammasome, leading to caspase-1-mediated pyroptosis via GSDMD-N.
- GSDMD-N forms mitochondrial pores, causing cytochrome c release and a noncanonical apoptotic cascade.
Conclusions:
- AFB1 nephrotoxicity involves a novel crosstalk between pyroptosis and apoptosis, bridged by GSDMD-N-mediated mitochondrial damage.
- GSDMD-N inhibition presents a potential therapeutic strategy against AFB1 toxicity.
- Understanding these pathways is vital for mitigating AFB1 risks in agriculture and food safety.
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