Proteomics Unravels Emodin Causes Liver Oxidative Damage Elicited by Mitochondrial Dysfunction

Abstract

Emodin is one of the main active compounds in many Chinese traditional herbs. Due to its potential toxic effect on the liver, the possible injury mechanism needs to be explored. In the present study, we investigated liver injury mechanisms of emodin on rats by the technology of proteomics. Firstly, 4530 proteins were identified from the liver of rats treated with emodin by label free proteomics. Inside, 892 differential proteins were selected, presenting a downward trend. Bioinformatics analysis showed that proteins interfered with by emodin were mainly involved in oxidation-reduction biological processes and mitochondrial metabolic pathways, such as mitochondrial fatty acid b-oxidation, citric acid cycle, and oxidative phosphorylation, which were further confirmed by western blot. The decrease in maximal respiration, ATP production, spare respiratory capacity, and coupling efficiency and increase in proton leakage were detected by seahorse XFe 24 analyzer, which confirmed the damage of mitochondrial function. The down-regulated expressions in antioxidant proteins were verified by western blot and a significant increase of ROS levels were detected in emodin group, which showed that emodin disrupted redox homeostasis in livers. Molecular docking revealed that the main targets of emodin might be acadvl and complex IV. Generally, emodin could induce oxidative stress in livers by directly targeting acadvl/complex IV and inhibiting fatty acid b-oxidation, citric acid cycle, and oxidative phosphorylation taken place in mitochondria.

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

“…In recent years, studies have been conducted using label-free protein identification techniques to analyze differential proteins in different rat disease models [ 36 ]. Moreover, it has provided technical support in analyzing mitochondrial proteins in studies such as rat myocardial injury, liver injury due to mitochondrial dysfunction, renal tubular acidosis, and central nervous system diseases [ 37 , 38 ]. However, the use of the label-free technique for proteomic studies in rat models of pulmonary arterial hypertension is still minimal, primarily through the identification and discovery of the mitochondrial proteome, which can provide new insights to reveal the mechanism of PAH development further, and also, this is one of the important innovations of our study.…”

DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy

“…As the main organs of endogenous ROS production, the mitochondria are extremely vulnerable to ROS [ 32 ]. In liver oxidative stress, damaged mitochondria will further disrupt the redox homeostasis, leading to the production of more ROS, in a vicious cycle [ 33 , 34 ]. Our study found that H 2 O 2 impaired mitochondrial membrane integrity, and increased the mitochondrial membrane permeability, which accompanied the loss of mitochondrial transmembrane potential (ΔΨm).…”

Therapeutic Potential of Emodin for Gastrointestinal Cancers

“…61 In a similar study, rats administered 150 mg/kg of emodin daily for 4 weeks exhibited significant increases in levels of ALT and AST indicating damage to the liver. 62 The mechanisms responsible for emodin-induced hepatotoxicity continue to be unearthed but several studies implicated mitochondria and oxidative stress in playing a role. [61][62][63][64] Indeed, 1500 mg/kg daily dose of emodin for 4 weeks inhibited proton transport and subsequently induced the activation of the mitochondrial apoptosis pathway.…”

“…Emodin at very high doses (150-10 000 mg/kg) down-regulates antioxidant proteins thus suppressing antioxidant defenses that may increase susceptibility to prolonged oxidative stress and excessive ROS production. 62,64,65 Oxidative stress resulting in a prolonged imbalance between the production of ROS with their elimination by antioxidants in the liver can contribute to liver inflammation leading to fibrosis and HCC. 66 Specifically, high dosage of emodin (150 mg/kg, daily, 4 weeks) induced hepatotoxicity by inhibiting antioxidants within the mitochondria, including peroxiredoxins (Prdx), glutathione peroxidases (Gpx), thioredoxin (Trx), and glutaredoxin (Glrx), all of which help in the degradation of free radicals such as ROS.…”