Though mitochondrial oxidant stress plays a critical role in the progression of acetaminophen (APAP) overdose-induced liver damage, the influence of mitochondrial bioenergetics on this is not well characterized. This is important, since lifestyle and diet alter hepatic mitochondrial bioenergetics and an understanding of its effects on APAP-induced liver injury is clinically relevant. Pyruvate dehydrogenase (PDH) is critical to mitochondrial bioenergetics, since it controls the rate of generation of reducing equivalents driving respiration, and pyruvate dehydrogenase kinase 4 (PDK4) regulates (inhibits) PDH by phosphorylation. We examined APAP-induced liver injury in PDK4-deficient (PDK4-/-) mice, which would have constitutively active PDH and hence elevated flux through the mitochondrial electron transport chain. PDK4-/- mice showed significant protection against APAP-induced liver injury when compared to wild type (WT) mice as measured by ALT levels and histology. Deficiency of PDK4 did not alter APAP metabolism, with similar APAP-adduct levels in PDK4-/- and WT mice, and no difference in JNK activation and translocation to mitochondria. However, subsequent amplification of mitochondrial dysfunction with release of mitochondrial AIF, peroxynitrite formation and DNA fragmentation were prevented. Interestingly, APAP induced a rapid decline in UCP2 protein levels in PDK4-deficient mice. These data suggest that adaptive changes in mitochondrial bioenergetics induced by enhanced respiratory chain flux in PDK4-/- mice render them highly efficient in handling APAP-induced oxidant stress, probably through modulation of UCP2 levels. Further investigation of these specific adaptive mechanisms would provide better insight into the control exerted by mitochondrial bioenergetics on cellular responses to an APAP overdose.

中文翻译：

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丙酮酸脱氢酶激酶4缺乏的小鼠受到保护，以防止对乙酰氨基酚引起的肝毒性。

尽管线粒体氧化应激在对乙酰氨基酚（APAP）过量引起的肝损伤的进展中起着关键作用，但线粒体生物能量学对此的影响尚不十分清楚。这很重要，因为生活方式和饮食习惯会改变肝线粒体的生物能，并且了解其对APAP诱发的肝损伤的影响在临床上具有相关性。丙酮酸脱氢酶（PDH）对线粒体生物能至关重要，因为它控制着驱动呼吸的还原当量的生成速率，而丙酮酸脱氢酶激酶4（PDK4）通过磷酸化调节（抑制）PDH。我们检查了PDAP4缺陷（PDK4-/-）小鼠中APAP诱导的肝损伤，该小鼠具有组成型活性PDH，因此通过线粒体电子传输链的通量升高。通过ALT水平和组织学测量，与野生型（WT）小鼠相比，PDK4-/-小鼠显示出对APAP诱导的肝损伤的显着保护作用。PDK4的缺乏不会改变APAP的代谢，在PDK4-/-和WT小鼠中APAP加合物的水平相似，并且JNK活化和向线粒体的转运没有差异。然而，随后的线粒体功能障碍随着线粒体AIF的释放，过氧化亚硝酸盐的形成和DNA片段的扩增而被阻止。有趣的是，APAP诱导了PDK4缺陷小鼠的UCP2蛋白水平快速下降。这些数据表明，PDK4-/-小鼠中增强的呼吸链通量引起的线粒体生物能学的适应性变化使它们在处理APAP诱导的氧化应激中非常有效，这可能是通过调节UCP2水平来实现的。