PINK1-Parkin-Mediated mitophagy alleviates hepatocyte injury induced by α-amanitin

The death cap mushroom (Amanita phalloides) is one of the most toxic fungi worldwide, with α-amanitin (α-AMA) identified as its primary lethal toxin. Mitophagy selectively eliminates damaged mitochondria via the autophagy pathway and plays a critical role in maintaining mitochondrial quality and cellular homeostasis. However, its function in α-AMA-induced liver injury remains unclear. To elucidate the role and underlying mechanism of mitophagy in α-AMA hepatotoxicity, this study investigated its effects on α-AMA-exposed hepatocytes using both in vitro and in vivo models. The results showed that α-AMA treatment significantly reduced hepatocyte viability and increased reactive oxygen species (ROS) levels, confirming its hepatotoxic effects. Subsequently, mitophagy was activated to assess its functional role. Activation of mitophagy markedly alleviated α-AMA-induced hepatocyte damage. Further mechanistic analysis revealed that mitophagy activation also significantly attenuated oxidative stress and apoptosis—two key pathological processes associated with mitochondrial dysfunction under α-AMA toxicity. In summary, this study provides new evidence that enhancing mitophagy protects hepatocytes against α-AMA-induced injury. These findings highlight mitophagy as a promising therapeutic target for developing treatment strategies against life-threatening α-AMA poisoning. • α-amanitin (α-AMA) induces hepatocyte injury in mice, accompanied by elevated reactive oxygen species (ROS) levels. • Activation of mitophagy significantly mitigates α-AMA-induced hepatocyte injury in mice. • Protection is linked to reduced oxidative stress and mitochondrial dysfunction. • This study reveals for the first time that activating mitophagy is a key protective mechanism against α-AMA hepatotoxicity.