1. PGC-1α loss promotes mitochondrial protein lactylation in acetaminophen-induced liver injury via the LDHB-lactate axis.
- Author
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Hong W, Zeng X, Wang H, Tan X, Tian Y, Hu H, Ashrafizadeh M, Sethi G, Huang H, and Duan C
- Subjects
- Animals, Mice, Humans, Male, Lactic Acid metabolism, Mitochondrial Proteins metabolism, Mitochondrial Proteins genetics, Cell Line, Mitochondria, Liver metabolism, Mitochondria, Liver drug effects, Sirtuin 1 metabolism, Sirtuin 1 genetics, Isoenzymes, Acetaminophen, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury pathology, Mice, Inbred C57BL, L-Lactate Dehydrogenase metabolism
- Abstract
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-1α 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-1α were overexpressed in vitro via lentiviral transfection to establish stable cell lines. The results showed that APAP treatment decreased SIRT1/PGC-1α/LDHB expression and increased protein lactylation, mitochondrial lactate levels, and pathological damage in liver mitochondria. PGC-1α upregulation or activation ameliorated APAP-induced damage in the cells and liver. Furthermore, PGC-1α overexpression increased LDHB synthesis, reduced lactylation, and induced a switch from lactate to pyruvate production. These results suggest that PGC-1α and LDHB play a role in APAP-induced liver injury by regulating mitochondrial quality control and lactate metabolic reprogramming. Therefore, the PGC-1α/LDHB axis is a potential therapeutic target for APAP-induced liver injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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