Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the United States and APAP-induced hepatotoxicity is initiated by formation of a reactive metabolite which depletes hepatic glutathione and forms protein adducts. Studies over the years have established the critical role of c-Jun N terminal kinase (JNK) and its mitochondrial translocation, as well as mitochondrial oxidant stress and subsequent induction of the mitochondrial permeability transition in APAP pathophysiology. However, it is now evident that mitochondrial responses to APAP overdose are more nuanced than appreciated earlier, with multiple levels of control, for example, to dose of APAP. In addition, mitochondrial dynamics, as well as the organelle's importance in recovery and regeneration after APAP-induced liver injury is also being recognized, which are exciting new areas with significant therapeutic potential. Thus, this review examines the temporal course of hepatocyte mitochondrial responses to an APAP overdose with an emphasis on mechanistic response to various trigger checkpoints such as NAPQI-mitochondrial protein adduct formation and activated JNK translocation. Mitochondrial dynamics, the organelle's role in recovery after APAP and emerging areas of research which promise to provide further insight into modulation of APAP pathophysiology by these fascinating organelles will also be discussed.

中文翻译：

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通过对乙酰氨基酚肝毒性的线粒体旅程。

对乙酰氨基酚（APAP）过量是美国急性肝衰竭的主要原因，并且APAP诱导的肝毒性是由形成反应性代谢产物而引起的，该代谢产物消耗肝谷胱甘肽并形成蛋白质加合物。多年来的研究已经确定了c-Jun N末端激酶（JNK）及其线粒体易位，线粒体氧化应激以及随后诱导线粒体通透性转变在APAP病理生理学中的关键作用。但是，现在明显的是，线粒体对APAP过量的反应比以前意识到的更为细微，具有多个水平的控制，例如对APAP的剂量。此外，还认识到线粒体动力学以及细胞器在APAP诱发的肝损伤后恢复和再生中的重要性，这是令人兴奋的具有重大治疗潜力的新领域。因此，本综述探讨了肝细胞对APAP过量的线粒体反应的时程，重点是对各种触发检查点（如NAPQI-线粒体蛋白加合物形成和活化的JNK易位）的机械反应。还将讨论线粒体动力学，细胞器在APAP后恢复中的作用以及新兴的研究领域，这些领域有望为这些引人入胜的细胞器对APAP病理生理的调节提供进一步的见解。这篇综述探讨了肝细胞对APAP过量的线粒体反应的时程，重点是对各种触发检查点（如NAPQI-线粒体蛋白质加合物形成和活化的JNK易位）的机械反应。还将讨论线粒体动力学，细胞器在APAP后恢复中的作用以及新兴的研究领域，这些领域有望为这些引人入胜的细胞器对APAP病理生理的调节提供进一步的见解。这篇综述探讨了肝细胞对APAP过量的线粒体反应的时程，重点是对各种触发检查点（如NAPQI-线粒体蛋白质加合物形成和活化的JNK易位）的机械反应。还将讨论线粒体动力学，细胞器在APAP后恢复中的作用以及新兴的研究领域，这些领域有望为这些引人入胜的细胞器对APAP病理生理的调节提供进一步的见解。