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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

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Abstract

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.

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The data and material that support the findings of this study are available upon request to the corresponding authors.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81770095, 81700093, 81901952, 8210082163), the Fundamental Research Funds for the Central Universities (No. 2042021kf0081) and Science Fund for Creative Research Groups of the Natural Science Foundation of Hubei Province (No. 2020CFA027).

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  1. Li Ning, Xiong Rui and Li Guorui have contributed equally to this work.

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  1. Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China

    Li Ning, Xiong Rui, Li Guorui, Fu Tinglv, Li Donghang, Xu Chenzhen & Geng Qing

  2. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Wu Xiaojing

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Contributions

LN, XR and LG contributed equally to this work. LN, XR and LG designed, performed research, analyzed data and wrote the paper. FT, LD and XC performed experiments, analyzed data. WX and GQ helped to design experiments and reviewed the data. LN, WX and GQ helped to design the research, analyzed data and reviewed the manuscript.

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Correspondence to Wu Xiaojing or Geng Qing.

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Ning, L., Rui, X., Guorui, L. et al. 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. Cell. Mol. Life Sci. 79, 610 (2022). https://doi.org/10.1007/s00018-022-04628-0

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