Journal Article

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

Bao, Ensi, Yao, Chen, Meng, Fandong, Wang, Hui, You, Hongjuan, Ikezoe, Takayuki, Li, Xiangyang, Chen, Xin, Pan, Xiucheng, Wang, Bo, Cheng, Wanpeng, Li, Rongqing, Yang, Jing, Li, Xueqin, Hua, Hui, Zhao, Jie, Sun, Na

2022

Overview

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.

• Publisher: Ivyspring International Publisher Pty Ltd,Ivyspring International Publisher
• Subject: 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