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

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. To investigate the function of mito...

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Published in:Theranostics 2022, Vol.12 (2), p.976-998
Main Authors: Li, Rongqing, Li, Xueqin, Zhao, Jie, Meng, Fandong, Yao, Chen, Bao, Ensi, Sun, Na, Chen, Xin, Cheng, Wanpeng, Hua, Hui, Li, Xiangyang, Wang, Bo, Wang, Hui, Pan, Xiucheng, You, Hongjuan, Yang, Jing, Ikezoe, Takayuki
Format: Article
Language:English
Subjects:
Animals
Carnitine O-Palmitoyltransferase - metabolism
Curcumin - pharmacology
Curcumin - therapeutic use
Fatty Acids - metabolism
Gene expression
Gene Knock-In Techniques
HEK293 Cells
Humans
Lipopolysaccharides - antagonists & inhibitors
Macrophage Activation
Male
Medical research
Metabolism
Mice
Mice, Inbred C57BL
Mitochondria
Mitochondrial Proteins - metabolism
Oxidation-Reduction
Phagocytes
Research Paper
Sepsis
Sepsis - drug therapy
Sepsis - etiology
Sepsis - metabolism
STAT3 Transcription Factor - metabolism
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Summary: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. To investigate the function of mitochondrial STAT3 , we generated inducible mitochondrial STAT3 knock-in mice. A cytokine array analysis, a CBA analysis, flow cytometry, immunofluorescence staining and quantification and metabolic analyses 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. 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. Our findings reveal that mitochondrial STAT3 could trigger FAO by inducing CPT1a stabilization mediated by USP50 in macrophages, at least partially.
ISSN:1838-7640
1838-7640
DOI:10.7150/thno.63751