Theranostics 2022; 12(2):976-998. doi:10.7150/thno.63751 This issue Cite

Research Paper

Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation

Rongqing Li1,2#, Xueqin Li1,2#, Jie Zhao1,2#, Fandong Meng3#, Chen Yao1,2, Ensi Bao1,2, Na Sun1,2, Xin Chen1,2, Wanpeng Cheng1,2, Hui Hua1,2, Xiangyang Li1,2, Bo Wang4, Hui Wang1,2, Xiucheng Pan5✉, Hongjuan You1,2✉, Jing Yang1,2✉, Takayuki Ikezoe6

1. Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China.
2. Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
3. Department of Endocrinology, The First Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.
4. Department of Critical Care Medicine, The First Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.
5. Department of Infectious Disease, The First Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, Jiangsu, China.
6. Department of Hematology, Fukushima Medical University, Fukushima, Japan.
# These authors contributed equally to this work.

Citation:
Li R, Li X, Zhao J, Meng F, Yao C, Bao E, Sun N, Chen X, Cheng W, Hua H, Li X, Wang B, Wang H, Pan X, You H, Yang J, Ikezoe T. Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation. Theranostics 2022; 12(2):976-998. doi:10.7150/thno.63751. https://www.thno.org/v12p0976.htm
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Abstract

Graphic abstract

Rationale: We found that a subset of signal transducer and activator of transcription 3 (STAT3) translocated into mitochondria in phagocytes, including macrophages isolated from individuals with sepsis. However, the role of mitochondrial STAT3 in macrophages remains unclear.

Method: To investigate the function of mitochondrial STAT3 in vivo, we generated inducible mitochondrial STAT3 knock-in mice. A cytokine array analysis, a CBA analysis, flow cytometry, immunofluorescence staining and quantification and metabolic analyses in vivo were subsequently performed in an LPS-induced sepsis model. Single-cell RNA sequencing, a microarray analysis, metabolic assays, mass spectrometry and ChIP assays were utilized to gain insight into the mechanisms of mitochondrial STAT3 in metabolic reprogramming in LPS-induced sepsis.

Results: We found that mitochondrial STAT3 induced NF-κB nuclear localization and exacerbated LPS-induced sepsis in parallel with a metabolic switch from mainly using glucose to an increased reliance on fatty acid oxidation (FAO). Moreover, mitochondrial STAT3 abrogated carnitine palmitoyl transferase 1a (CPT1a) ubiquitination and degradation in LPS-treated macrophages. Meanwhile, an interaction between CPT1a and ubiquitin-specific peptidase 50 (USP50) was observed. In contrast, knocking down USP50 decreased CPT1a expression and FAO mediated by mitochondrial STAT3. The ChIP assays revealed that NF-κB bound the USP50 promoter. Curcumin alleviated LPS-mediated sepsis by suppressing the activities of mitochondrial STAT3 and NF-κB.

Conclusion: Our findings reveal that mitochondrial STAT3 could trigger FAO by inducing CPT1a stabilization mediated by USP50 in macrophages, at least partially.

Keywords: mitochondrial STAT3, FAO, CPT1a stabilization, USP50


Citation styles

APA
Li, R., Li, X., Zhao, J., Meng, F., Yao, C., Bao, E., Sun, N., Chen, X., Cheng, W., Hua, H., Li, X., Wang, B., Wang, H., Pan, X., You, H., Yang, J., Ikezoe, T. (2022). Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation. Theranostics, 12(2), 976-998. https://doi.org/10.7150/thno.63751.

ACS
Li, R.; Li, X.; Zhao, J.; Meng, F.; Yao, C.; Bao, E.; Sun, N.; Chen, X.; Cheng, W.; Hua, H.; Li, X.; Wang, B.; Wang, H.; Pan, X.; You, H.; Yang, J.; Ikezoe, T. Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation. Theranostics 2022, 12 (2), 976-998. DOI: 10.7150/thno.63751.

NLM
Li R, Li X, Zhao J, Meng F, Yao C, Bao E, Sun N, Chen X, Cheng W, Hua H, Li X, Wang B, Wang H, Pan X, You H, Yang J, Ikezoe T. Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation. Theranostics 2022; 12(2):976-998. doi:10.7150/thno.63751. https://www.thno.org/v12p0976.htm

CSE
Li R, Li X, Zhao J, Meng F, Yao C, Bao E, Sun N, Chen X, Cheng W, Hua H, Li X, Wang B, Wang H, Pan X, You H, Yang J, Ikezoe T. 2022. Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation. Theranostics. 12(2):976-998.

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