Epidermal growth factor receptor promotes high-fructose nonalcoholic fatty liver disease by inducing mitochondrial fission in zebrafish.

Mitochondrial function has a pivotal role in the pathogenesis of NAFLD. Mitochondrial dynamics is a foundational activity underlying the maintenance of mitochondrial function in bioenergetics, the maintenance of MtDNA, calcium homeostasis, reactive oxygen species metabolism, and quality control. Loss of mitochondrial plasticity in terms of functions, morphology and dynamics may also be the critical switch from NAFLD/NASH to HCC. However, the cause of mitochondrial fission in NAFLD remains unclear. Recent studies have reported that EGFR can bind to Mfn1 and interfere with its polymerization. In this study, we investigated whether EGFR binds to Mfn1 in NAFLD, and whether reducing their binding can improve NAFLD in zebrafish model. Our results demonstrated that EGFR was activated in hepatocytes from high fructose (HF)-induced NAFLD zebrafish and interfered with Mfn1 polymerization, leading to reduction of MtDNA. Suppression of EGFR activation or mitochondrial translocation significantly improved mitochondrial morphology and increased mitochondrial DNA, ultimately preventing hepatic steatosis. In conclusion, these results suggest that EGFR binding to Mfn1 plays an important role in NAFLD zebrafish model and that inhibition of their binding could be a potential therapeutic target.