Recently, the morbidity and mortality from lung cancer have continued to increase. Mitochondrial dysfunction plays a key role in apoptosis, proliferation, and the bioenergetic reprogramming of cancer cells, especially for energy metabolism. Herein, we investigated the ability of melatonin (MLT) to influence lung cancer growth and explored the association between mitochondrial functions and the progression of lung tumors. The deacetylase, sirtuin 3 (Sirt3), is a pivotal player in maintenance of mitochondrial function, among participating in ATP production by regulating the acetylone and pyruvate dehydrogenase complex (PDH). We initially found that MLT inhibited lung cancer growth in the Lewis mouse model. Similarly, we observed that MLT inhibited the proliferation of lung cancer cells (A549, PC9, and LLC cells), and the underlying mechanism of MLT was related to reprogramming cancer cell metabolism, accompanied by a shift from cytosolic aerobic glycolysis to oxidative phosphorylation (OXPHOS). These changes were accompanied by higher ATP production, an elevated ATP production-coupled oxygen consumption rate (QCR), higher ROS levels, higher mito-ROS levels, and lower lactic acid secretion. Additionally, we observed that MLT improved mitochondrial membrane potential and the activities of complexes Ⅰ and Ⅳ in the electron transport chain. Importantly, we also found and verified that the foregoing changes resulted from activation of Sirt3 and PDH. As a result of these changes, MLT significantly enhanced mitochondrial energy metabolism to reverse the Warburg effect via increasing PDH activity with stimulation of Sirt3. Collectively, these findings suggest the potential use of melatonin as an anti-lung cancer therapy and provide a mechanistic basis for this proposal.

中文翻译：

---

褪黑激素通过刺激 SIRT3/PDH 轴逆转 Warburg 效应来抑制肺癌的发展

近年来，肺癌的发病率和死亡率持续上升。线粒体功能障碍在癌细胞的凋亡、增殖和生物能量重编程中起关键作用，尤其是在能量代谢方面。在此，我们研究了褪黑激素 (MLT) 影响肺癌生长的能力，并探讨了线粒体功能与肺肿瘤进展之间的关联。去乙酰化酶，sirtuin 3 (Sirt3)，是维持线粒体功能的关键参与者，通过调节乙酰酮和丙酮酸脱氢酶复合物 (PDH) 参与 ATP 的产生。我们最初发现 MLT 在 Lewis 小鼠模型中抑制了肺癌的生长。同样，我们观察到 MLT 抑制肺癌细胞（A549、PC9 和 LLC 细胞）的增殖，MLT 的潜在机制与重编程癌细胞代谢有关，伴随着从细胞溶质有氧糖酵解到氧化磷酸化 (OXPHOS) 的转变。这些变化伴随着更高的 ATP 产量、更高的 ATP 产量耦合耗氧率 (QCR)、更高的 ROS 水平、更高的 mito-ROS 水平和更低的乳酸分泌。此外，我们观察到MLT改善了线粒体膜电位和电子传递链中复合物Ⅰ和Ⅳ的活性。重要的是，我们还发现并验证了上述变化是由 Sirt3 和 PDH 的激活引起的。由于这些变化，MLT 显着增强线粒体能量代谢，通过刺激 Sirt3 增加 PDH 活性来逆转 Warburg 效应。集体，