RESUMEN
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.
Asunto(s)
Lesión Pulmonar Aguda , Melatonina , Sepsis , Sirtuina 3 , Animales , Ratones , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/prevención & control , Células Epiteliales Alveolares , Células Epiteliales , Lipopolisacáridos/farmacología , Melatonina/farmacología , Melatonina/uso terapéutico , Mitocondrias , Sirtuina 3/genéticaRESUMEN
The pollution of soil with heavy metals is an increasingly serious worldwide problem, and cadmium (Cd) has attracted attention because of its high toxicity to almost all plants. Since castor tolerates the accumulation of heavy metals, it has the potential for heavy metal soil remediation. We studied the mechanism of the tolerance of castor to Cd stress treatments at three doses: 300 mg/L, 700 mg/L, and 1,000 mg/L. This research provides new ideas for revealing the defense and detoxification mechanisms of Cd-stressed castor. By combining the results of physiology, differential proteomics and comparative metabolomics, we conducted a comprehensive analysis of the networks that regulate the response of castor to Cd stress. The physiological results mainly emphasize the super-sensitive responses of castor plant roots to Cd stress and the effects of Cd stress on plants' antioxidant system, ATP synthesis and ion homeostasis. We confirmed these results at the protein and metabolite levels. In addition, proteomics and metabolomics indicated that under Cd stress, the expressions of proteins involved in defense and detoxification, energy metabolism and other metabolites such as organic acids and flavonoids were significantly up-regulated. At the same time, proteomics and metabolomics also show that castor plants mainly block the root system's absorption of Cd2+ by enhancing the strength of the cell wall, and inducing programmed cell death in response to the three different doses of Cd stress. In addition, the plasma membrane ATPase encoding gene (RcHA4), which was significantly upregulated in our differential proteomics and RT-qPCR studies, was transgenically overexpressed in wild type Arabidopsis thaliana for functional verification. The results indicated that this gene plays an important role in improving plant Cd tolerance.