Carbon tetrachloride (CCl₄)‐induced liver injury is predominantly caused by free radicals, in which mitochondrial function of hepatocytes is impaired, accompanying with the production of ROS and decreased ATP energy supply in animals intoxicated with CCl₄. Here we explored a novel therapeutic approach, mitochondrial transplantation therapy, for treating the liver injury. The results showed that mitochondria entered hepatocytes through macropinocytosis pathway, and thereby cell viability was recovered in a concentration‐dependent manner. Mitochondrial therapy could increase ATP supply and reduce free radical damage. In liver injury model of mice, mitochondrial therapy significantly improved liver function and prevented tissue fibrogenesis. Transcriptomic data revealed that mitochondrial unfold protein response (UPR^mt), a protective transcriptional response of mitochondria‐to‐nuclear retrograde signaling, would be triggered after mitochondrial administration. Then the anti‐oxidant genes were up‐regulated to scavenge free radicals. The mitochondrial function was rehabilitated through the transcriptional activation of respiratory chain enzyme and mitophage‐associated genes. The protective response re‐balanced the cellular homeostasis, and eventually enhanced stress resistance that is linked to cell survival. The efficacy of mitochondrial transplantation therapy in the animals would suggest a novel approach for treating liver injury caused by toxins.

中文翻译：

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线粒体移植治疗通过清除自由基和保护肝细胞抑制四氯化碳引起的肝损伤


四氯化碳(CCl ₄ )引起的肝损伤主要是由自由基引起的，其中肝细胞线粒体功能受损，伴随着CCl ₄中毒动物体内ROS的产生和ATP供能减少。在这里，我们探索了一种新的治疗方法，即线粒体移植疗法，用于治疗肝损伤。结果表明，线粒体通过巨胞饮途径进入肝细胞，从而以浓度依赖性方式恢复细胞活力。线粒体疗法可以增加 ATP 供应并减少自由基损伤。在小鼠肝损伤模型中，线粒体治疗显着改善肝功能并防止组织纤维化。转录组数据显示，线粒体未折叠蛋白反应（UPR ^mt ）是线粒体到核逆行信号传导的保护性转录反应，在给予线粒体后会被触发。然后抗氧化基因被上调以清除自由基。通过呼吸链酶和线粒体噬菌体相关基因的转录激活来恢复线粒体功能。保护性反应重新平衡了细胞稳态，并最终增强了与细胞存活相关的抗应激能力。线粒体移植疗法在动物身上的功效将为治疗毒素引起的肝损伤提供一种新方法。