A novel mechanism for the protection against acute lung injury by melatonin: mitochondrial quality control of lung epithelial cells is preserved through SIRT3-dependent deacetylation of SOD2
A novel mechanism for the protection against acute lung injury by melatonin: mitochondrial quality control of lung epithelial cells is preserved through SIRT3-dependent deacetylation of SOD2
复制标题
褪黑素预防急性肺损伤的新机制：通过 SIRT3 依赖性 SOD2 脱乙酰作用保留肺上皮细胞的线粒体质量控制
DOI：
10.1007/s00018-022-04628-0
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发表时间：
2022-12-01
影响因子：
8
通讯作者：
Geng, Qing
中科院分区：
文献类型：
--
作者：
Li, Ning;Xiong, Rui;Geng, Qing
脓毒症时肺上皮细胞线粒体质量控制受到干扰，导致线粒体功能异常和急性肺损伤。褪黑素是松果体分泌的主要激素之一，在败血症和心肺疾病中表现出良好的抗氧化作用。然而，褪黑素在脂多糖（LPS）处理的肺上皮细胞中的潜在作用和分子基础尚未被探索和报道。本文通过线粒体质量控制及其可能的分子靶点，研究褪黑素是否对脓毒症诱导的急性肺损伤（ALI）和lps处理的肺上皮细胞具有保护作用。野生型和Sirt3基因敲除小鼠经气管灌注LPS 12 h，建立体内急性肺损伤模型。利用A549肺上皮细胞和原代肺泡II型（AT-II）细胞，通过对Sirt3的小干扰RNA孵育，探讨褪黑素在体外可能的作用。为了确定褪黑激素受体的作用，细胞和小鼠被si Mtnr1b和luzindole处理。褪黑素预处理显著抑制lps处理的肺组织和肺上皮细胞的病理损伤、炎症反应、氧化应激和凋亡。此外，褪黑素还改变了线粒体从裂变到融合的动态过程，抑制了lps处理的肺上皮细胞的线粒体自噬和脂肪酸氧化。然而，SIRT3抑制消除了褪黑素在急性肺损伤中的保护作用。机制上，我们发现褪黑素增加了SIRT3的活性和表达，从而进一步促进了SOD2在K122和K68位点的去乙酰化。更重要的是，在ALI期间，褪黑素通过激活MTNR1B而不是MTNR1A发挥肺保护作用。综上所述，褪黑激素可以通过sirt3依赖的方式使SOD2去乙酰化，从而维持肺上皮细胞的线粒体质量控制，最终减轻败血症诱导的损伤、炎症、氧化应激和凋亡。因此，褪黑素可能在未来作为抗ALI的有希望的候选药物。
The mitochondrial quality control of lung epithelial cells is disturbed during sepsis, which contributes to abnormal mitochondrial function and acute lung injury. Melatonin is one of the primary hormones secreted by the pineal gland, displaying favorable antioxidative actions in sepsis and cardiopulmonary disease. However, the potential roles and molecular basis of melatonin in lipopolysaccharide (LPS)-treated lung epithelial cells have not been explored and reported. Herein, we investigated whether melatonin could protect against sepsis-induced acute lung injury (ALI) and LPS-treated lung epithelial cells through the mitochondrial quality control as well as its possible molecular targets. Wild type and Sirt3 knockout mice were intratracheally instilled with LPS for 12 h to construct an in vivo acute lung injury model. Both A549 lung epithelial cells and primary alveolar type II (AT-II) cells were used to explore the possible roles of melatonin in vitro by incubating with small interfering RNA against Sirt3. To determine the involvement of the melatonin receptor, cells and mice were treated with si Mtnr1b and luzindole. Melatonin pretreatment significantly inhibited pathological injury, inflammatory response, oxidative stress, and apoptosis in LPS-treated lung tissues and LPS-treated lung epithelial cells. Furthermore, melatonin also shifted the dynamic course of mitochondria from fission to fusion, inhibited mitophagy and fatty acid oxidation in LPS-treated lung epithelial cells in vitro and in vivo. However, SIRT3 inhibition abolished the protective roles of melatonin in acute lung injury. Mechanistically, we found that melatonin increased the activity and expression of SIRT3, which further promoted the deacetylation of SOD2 at K122 and K68. More importantly, melatonin exerted pulmonary protection by activating MTNR1B but not MTNR1A during ALI. Collectively, melatonin could preserve the mitochondrial quality control of lung epithelial cells through the deacetylation of SOD2 in a SIRT3-dependent manner, which eventually alleviated sepsis-induced injury, inflammation, oxidative stress, and apoptosis. Thus, melatonin may serve as a promising candidate against ALI in the future.