Energy disorders caused by mitochondrial dysfunction contribute to α-amatoxin-induced liver function damage and liver failure

Mushroom toxicity is the main branch of foodborne poisoning, and liver damage caused by amatoxin poisoning accounts for more than 90 % of deaths due to mushroom poisoning. Alpha-amatoxin (alpha-AMA) has been considered the primary toxin from amatoxin-containing mushrooms, which is responsible for hepatotoxicity and death. However, the mechanism underlying liver failure due to alpha-AMA remains unclear. This study constructed animal and cell models. In the animal experiments, we investigated liver injury in BALB/c mice at different time points after alpha-AMA treatment, and explored the process of inflammatory infiltration using immunohistochemistry and western blotting. Then, a metabonomics method based on gas chromatography mass spectrometry (GC-MS) was established to study the effect of alpha-AMA on liver metabonomics. The results showed a significant difference in liver metabolism between the exposed and control mice groups that coincided with pathological and biochemical indicators. Moreover, 20 metabolites and 4 metabolic pathways related to its mechanism of action were identified, which suggested that energy disorders related to mitochondrial dysfunction may be one of the causes of death. The significant changes of trehalose and the fluctuation of LC3-II and sqstm1 p62 protein levels indicated that autophagy was also involved in the damage process, suggesting that autophagy may participate in the clearance process of damaged mitochondria after poisoning. Then, we constructed an alpha-AMA-induced human normal liver cells (L-02 cells) injury model. The above hypothesis was further verified by detecting cell necrosis, mitochondrial reactive oxygen species (mtROS), mitochondrial permeability transition pore (mPTP) opening, mitochondrial membrane potential (Delta psi m), and cellular ATP level. Collectively, our results serve as direct evidence of elevated in vivo hepatic mitochondrial metabolism in alpha-AMA-exposed mice and suggest that mitochondrial dysfunction plays an important role in the early stage of alpha-AMA induced liver failure.

Automated summary

The study revealed that the impact of α-AMA on liver function is mainly through inducing mitochondrial dysfunction, leading to liver damage and failure. Through animal experiments and cell models, it was found that energy metabolism disorders related to mitochondria and the involvement of autophagy process play key roles in α-AMA-induced liver injury.