PGC-1 α loss promotes mitochondrial protein lactylation in acetaminophen-induced liver injury via the LDHB-lactate axis

作者全名：Hong, Weilong; Zeng, Xue; Wang, Houping; Tan, Xuxin; Tian, Yu; Hu, Hongtao; Ashrafizadeh, Milad; Sethi, Gautam; Huang, He; Duan, Chenyang

作者地址：[Hong, Weilong; Zeng, Xue; Wang, Houping; Tan, Xuxin; Huang, He; Duan, Chenyang] Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 2, 76 Linjiang Rd, Chongqing 400010, Peoples R China; [Zeng, Xue] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400010, Peoples R China; [Tian, Yu] Guangdong Med Univ, Huizhou Cent Peoples Hosp, Res Ctr, Huizhou 516008, Peoples R China; [Hu, Hongtao] Weifang Med Coll, Affiliated Hosp, Dept Orthoped Surg, Weifang 261000, Shandong, Peoples R China; [Ashrafizadeh, Milad] Fudan Univ, Shanghai Inst Cardiovasc Dis, Zhongshan Hosp, Shanghai 200032, Peoples R China; [Ashrafizadeh, Milad] Shandong First Med Univ, Shandong Canc Hosp & Inst, Dept Radiat Oncol, Jinan, Shandong, Peoples R China; [Ashrafizadeh, Milad] Shandong Acad Med Sci, Jinan 250000, Shandong, Peoples R China; [Sethi, Gautam] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore; [Sethi, Gautam] Natl Univ Singapore, NUS Ctr Canc Res, Yong Loo Lin Sch Med, Singapore, Singapore

通信作者：Huang, H; Duan, CY (通讯作者)，Chongqing Med Univ, Dept Anesthesiol, Affiliated Hosp 2, 76 Linjiang Rd, Chongqing 400010, Peoples R China.; Sethi, G (通讯作者)，Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore.; Sethi, G (通讯作者)，Natl Univ Singapore, NUS Ctr Canc Res, Yong Loo Lin Sch Med, Singapore, Singapore.

来源：PHARMACOLOGICAL RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001249044900001

JCR分区：Q1

影响因子：9.1

年份：2024

卷号：205

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：PGC-1 alpha; LDHB; Mitochondrial quality control; APAP; Acute liver injury

摘要：Coronavirus disease 2019 (COVID-19) affected people worldwide, and fever is one of the major symptoms of this disease. Although Acetaminophen (APAP) is a common fever-reducing medication, it can also mediate liver injury. However, the role of PGC-1 alpha in regulating mitochondrial quality control by lactate dehydrogenase B (LDHB), a vital enzyme catalyzing the conversion of lactate to pyruvate, in APAP-induced hepatotoxicity, is unclear. Here, gene expression omnibus data of patients with APAP-induced liver injury were used to explore gene expression profiles. AML12 cells and C57/BL6 mice were used to establish models of APAP-induced acute liver injury. SIRT1 and PGC-1 alpha were overexpressed in vitro via lentiviral transfection to establish stable cell lines. The results showed that APAP treatment decreased SIRT1/PGC-1 alpha/LDHB expression and increased protein lactylation, mitochondrial lactate levels, and pathological damage in liver mitochondria. PGC-1 alpha upregulation or activation ameliorated APAP-induced damage in the cells and liver. Furthermore, PGC-1 alpha overexpression increased LDHB synthesis, reduced lactylation, and induced a switch from lactate to pyruvate production. These results suggest that PGC-1 alpha and LDHB play a role in APAP-induced liver injury by regulating mitochondrial quality control and lactate metabolic reprogramming. Therefore, the PGC-1 alpha/LDHB axis is a potential therapeutic target for APAP-induced liver injury.

基金机构：National Natural Science Foundation of China [82272252, 82372192]; Science and technology project of Tibet Autonomous Region [XZ202102YD0028C]; General project of Chongqing Natural Science Foundation [CSTB2022NSCQ-MSX1665]; Emergency Special project for COVID-19 treatment [2023IIT XG02]

基金资助正文：This work was supported by the National Natural Science Foundation of China (No. 82272252 and 82372192) , Science and technology project of Tibet Autonomous Region (XZ202102YD0028C) , General project of Chongqing Natural Science Foundation (CSTB2022NSCQ-MSX1665) and Emergency Special project for COVID-19 treatment (2023IIT XG02) .