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Published on: May 26, 2023
HIF-1α/BNIP3L-mediated mitophagy is involved in T-2 toxin-induced myocardial injury
Qian Li1, Miao Wang1, Juan Zuo2
1Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
Abstract:
T-2 toxin, the most toxic type A mycotoxin, induces cardiotoxicity and impairs cardiac function. Herein, we investigated the regulatory role of mitophagy in T-2 toxin-induced myocardial injury. Using the Comparative Toxicogenomics Database, we identified 288 rat genes associated with T-2 toxin-induced myocardial injury. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that mitophagy was significantly associated with myocardial injury. Protein-protein interaction network analysis revealed HIF-1α as the core regulatory gene. Rats were exposed to T-2 toxin and assigned to control, low-dose (100 ng/g·bw/day), and high-dose (200 ng/g·bw/day) groups. H9C2 cardiomyocytes were divided into control, low-dose (3 ng/mL), medium-dose (6 ng/mL), and high-dose (12 ng/mL) groups. High-dose T-2 toxin exposure caused significant myocardial damage, increased lactate dehydrogenase and creatine kinase-myocardial band levels, elevated reactive oxygen species (ROS) accumulation, and upregulated HIF-1α expression in the nucleus. Flow cytometry showed that T-2 toxin significantly decreased mitochondrial membrane potential. Transmission electron microscopy revealed mitochondrial swelling, vacuolation, and cristae disruption. Molecular docking and immunofluorescence confirmed direct binding between BNIP3L and LC3. T-2 toxin significantly upregulated HIF-1α, BNIP3L, and LC3 mRNA and protein levels, promoted LC3-I to LC3-II conversion, and suppressed P62 expression in tissues and cells. Immunohistochemistry further confirmed these protein expression trends. Myocardial injury was ameliorated by 2-ME2 by suppressing HIF-1α accumulation and BNIP3L-mediated mitophagy. In summary, T-2 toxin-induced ROS accumulation activated HIF-1α in cardiomyocytes, which regulated BNIP3L-LC3 binding, mediated mitophagy, and ultimately caused myocardial injury.
Insights
T-2 toxin causes heart damage by increasing reactive oxygen species (ROS), activating HIF-1α, and promoting mitophagy. This process impairs cardiac function, but can be mitigated by suppressing HIF-1α and mitophagy.
Area of Science:
- Toxicology
- Cardiology
- Cell Biology
Background:
- T-2 toxin, a potent mycotoxin, is known to induce cardiotoxicity and cardiac dysfunction.
- Mitophagy, the selective degradation of damaged mitochondria, plays a crucial role in cellular homeostasis.
- The specific mechanisms linking T-2 toxin exposure to myocardial injury via mitophagy remain incompletely understood.
Purpose of the Study:
- To investigate the regulatory role of mitophagy in T-2 toxin-induced myocardial injury.
- To identify key molecular players involved in this process.
- To explore potential therapeutic interventions.
Main Methods:
- Bioinformatic analysis (Comparative Toxicogenomics Database, Gene Ontology, KEGG, protein-protein interaction networks) to identify T-2 toxin-associated genes and pathways.
- In vivo studies exposing rats to T-2 toxin and in vitro studies using H9C2 cardiomyocytes.
- Biochemical assays (LDH, CK-MB), ROS measurement, flow cytometry, transmission electron microscopy, molecular docking, immunofluorescence, Western blotting, and immunohistochemistry.
Main Results:
- T-2 toxin exposure led to significant myocardial damage, increased cardiac enzyme levels, elevated ROS, and decreased mitochondrial membrane potential.
- T-2 toxin upregulated the expression of HIF-1α, BNIP3L, and LC3, promoting the conversion of LC3-I to LC3-II and suppressing P62.
- HIF-1α was identified as a core regulatory gene, and its activation was linked to BNIP3L-mediated mitophagy, contributing to myocardial injury.
- Treatment with 2-ME2 ameliorated T-2 toxin-induced myocardial injury by suppressing HIF-1α and BNIP3L-mediated mitophagy.
Conclusions:
- T-2 toxin-induced ROS accumulation activates HIF-1α in cardiomyocytes.
- Activated HIF-1α regulates BNIP3L-LC3 binding, mediating mitophagy and causing myocardial injury.
- Targeting the HIF-1α/BNIP3L/mitophagy axis may offer a therapeutic strategy for T-2 toxin-induced cardiotoxicity.
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