Mitochondrial dysfunction has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through poorly defined mechanisms. Melatonin supplementation has been found to protect liver function in diabetes and obesity. Here, we intensively explored the role and mechanism of melatonin in the development of NAFLD. We demonstrated that the onset of diet‐induced NAFLD greatly caused NR4A1 upregulation in hepatocytes, leading to the activation of DNA‐PKcs and p53. On the one hand, p53 aided Drp1 migration in the mitochondria and consequently drove mitochondrial fission. On the other hand, p53 repressed Bnip3 transcription and expression, resulting in mitophagy arrest. The excessive fission and deficient mitophagy dramatically mediated mitochondrial dysfunction, including extensive mPTP opening, reduction in mitochondrial potential, oxidative stress, calcium overload, mitochondrial respiratory collapse, and ATP shortage. However, genetic deletion of NR4A1 or DNA‐PKcs could definitively reverse NAFLD progression and the mitochondrial dysfunction. Similarly, melatonin supplementation could robustly reduce the damage to liver and mitochondrial structure and function in NAFLD. Mechanistically, melatonin halted fission but recovered mitophagy via blockade of NR4A1/DNA‐PKcs/p53 pathway, finally improving mitochondrial and liver function in the setting of NAFLD. Our results identify NR4A1/DNA‐PKcs/p53 pathway as the novel molecular mechanism underlying the pathogenesis of NAFLD via regulation of Drp1‐mediated mitochondrial fission and Bnip3‐related mitophagy. Meanwhile, we also confirm that melatonin has the ability to cut off the NR4A1/DNA‐PKcs/p53 pathway, which confers a protective advantage to hepatocytes and mitochondria. The manipulation of NR4A1/DNA‐PKcs/p53 pathway by melatonin highlights a new entry point for treating NAFLD.

中文翻译：

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褪黑素对脂肪肝的影响：NR4A1 / DNA‐PKcs / p53途径，线粒体裂变和线粒体吞噬的作用

线粒体功能障碍已通过定义不明确的机制参与了非酒精性脂肪肝疾病（NAFLD）的发病机理。已经发现补充褪黑激素可以保护糖尿病和肥胖症的肝功能。在这里，我们深入研究了褪黑激素在NAFLD发生中的作用和机制。我们证明饮食引起的NAFLD的发作极大地引起了肝细胞中NR4A1的上调，从而导致DNA-PKcs和p53的激活。一方面，p53促进了Drp1在线粒体中的迁移，从而促进了线粒体的裂变。另一方面，p53抑制了Bnip3转录和表达，导致线粒体停滞。过度裂变和线粒体功能不足会极大地介导线粒体功能障碍，包括广泛的mPTP开放，线粒体电位降低，氧化应激，钙超载，线粒体呼吸衰竭和ATP缺乏。但是，NR4A1或DNA-PKcs的基因缺失可以最终逆转NAFLD的进展和线粒体功能障碍。同样，补充褪黑激素可以有效减少NAFLD对肝脏和线粒体结构与功能的损害。从机制上讲，褪黑素阻止了裂变，但通过阻断NR4A1 / DNA-PKcs / p53途径恢复了线粒体吞噬，最终改善了NAFLD的线粒体和肝功能。我们的结果确定了NR4A1 / DNA‐PKcs / p53途径是通过调节Drp1介导的线粒体裂变和Bnip3相关的细胞吞噬作用而成为NAFLD发病机理的新分子机制。同时，我们还证实褪黑激素具有切断NR4A1 / DNA-PKcs / p53途径的能力，赋予肝细胞和线粒体保护性优势。褪黑素对NR4A1 / DNA-PKcs / p53途径的操纵突显了治疗NAFLD的新切入点。