PP2A attenuates α-amanitin-induced liver injury by promoting autophagy and inhibiting apoptosis in mouse models

Poisoning caused by the mushroom toxin α-amanitin accounts for ∼90 % of food poisoning deaths resulting from mushrooms in China. However, Drosophila melanogaster uses PP2A to mitigate effects of α-amanitin. Our objectives were to test the hypothesis that modulation of PP2A protects mammals against deleterious effects of α-amanitin. In in vitro experiments, α-amanitin significantly suppressed both gene and protein expression of PP2A. Inhibiting PP2A promoted apoptosis induced by α-amanitin while suppressing autophagy. In vivo α-amanitin increased liver coefficient and AST/ALT indexes, plus caused pathological changes, ultrastructural alterations, TUNEL-positive cells, and Cleaved-caspase-3 expression. Inhibiting PP2A activity worsened these end points, but increasing PP2A activity lessened them. Furthermore, α-amanitin reduced feed intake and body weight while increasing health scores and causing concentration-dependent mortality in mice. In contrast, enhancing PP2A significantly mitigated α-amanitin-induced effects on health with 100 % survival. In conclusion, targeting PP2A is a novel therapeutic approach to mitigate α-amanitin toxicity.