Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis

Su, Ying; Hou, Changbo; Wang, Meili; Ren, Kehan; Zhou, Danmei; Liu, Xiaoli; Zhao, Shanyu; Liu, Xiuping

doi:10.1016/j.biocel.2023.106375

Cited by 9 publications

(2 citation statements)

References 56 publications

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“…It exerts its effects by activating AMPK, which, in turn, inhibits Drp1-mediated mitochondrial fission [ 199 , 200 ]. Interestingly, several recent studies have shown that metformin improves mitochondrial respiration by increasing mitochondrial fission through AMPK-Mff signaling [ 201 ], or by phosphorylating AMPK/Drp1 Ser616 [ 202 ]. Nevertheless, in patients with T2DM, metformin restored mitochondrial fission/fusion balance and improved mitochondrial function [ 203 ].…”

Section: Target Mitochondrial Fission For Antioxidants In Metabolic D...mentioning

confidence: 99%

Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies

Wang

Zhang

et al. 2023

Antioxidants

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Mitochondrial fission is a crucial process in maintaining metabolic homeostasis in normal physiology and under conditions of stress. Its dysregulation has been associated with several metabolic diseases, including, but not limited to, obesity, type 2 diabetes (T2DM), and cardiovascular diseases. Reactive oxygen species (ROS) serve a vital role in the genesis of these conditions, and mitochondria are both the main sites of ROS production and the primary targets of ROS. In this review, we explore the physiological and pathological roles of mitochondrial fission, its regulation by dynamin-related protein 1 (Drp1), and the interplay between ROS and mitochondria in health and metabolic diseases. We also discuss the potential therapeutic strategies of targeting mitochondrial fission through antioxidant treatments for ROS-induced conditions, including the effects of lifestyle interventions, dietary supplements, and chemicals, such as mitochondrial division inhibitor-1 (Mdivi-1) and other mitochondrial fission inhibitors, as well as certain commonly used drugs for metabolic diseases. This review highlights the importance of understanding the role of mitochondrial fission in health and metabolic diseases, and the potential of targeting mitochondrial fission as a therapeutic approach to protecting against these conditions.

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Section: Target Mitochondrial Fission For Antioxidants In Metabolic D...mentioning

confidence: 99%

Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies

Wang

Zhang

et al. 2023

Antioxidants

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“…This protective potential is closely related to the activation of Nrf2 signaling. Su et al (2023) demonstrated that AMPK/DRP1 phosphorylation in hepatic stellate cells induces mitochondrial fission and decreases the expression of α-smooth muscle actin and collagen.…”

Section: Introductionmentioning

confidence: 99%

Influence of doxorubicin on the extracellular matrix of the liver of rats under conditions of chronic alcoholic hepatitis

Mykytenko,

Akimov,

Yeroshenko

et al. 2023

Regul. Mech. Biosyst.

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The liver has a high regenerative potential that is dependent on many factors, in particular adenosine monophosphate kinase signaling, however, long-term alteration, such as daily alcohol consumption, turns regeneration into a chronic disease such as fibrosis, the end stage of which is cirrhosis. Hepatic extracellular matrix proteins are important triggers of enhanced stellate cell function during the progression of liver fibrosis. The experiments were performed on Wistar rats divided into four groups: control group; doxorubicin injection group (1.25 mg/kg); chronic alcohol hepatitis group; injection of doxorubicin during alcoholic hepatitis group, where we studied the total concentration of glycosaminoglycans, concentration of heparin-heparan, keratan-dermatan and chondroitin fractions of glycosaminoglycans, free oxyproline and sialic acids in the liver tissue homogenate. Cells with Mallory-Denk bodies were present in the liver of rats from the alcohol hepatitis group, which consisted of tangled balls of intermediate filaments and showed eosinophilia in the cytoplasm of degenerative hepatocytes. There were also necrotic changes in cells. Sinusoidal capillaries were locally dilated. In the central sections of the liver lobules of rats injected with doxorubicin against the background of chronic alcoholic hepatitis, the central veins were expanded, their endothelium was thinned. Sinusoidal capillaries were locally expanded, there were no blood cells in their lumens. The nuclei of the vast majority of hepatocytes were in a state of karyopyknosis, karyorrhexis, and karyolysis. Mallory-Denk bodies were present in the cytoplasm of cells. Administration of doxorubicin to animals with chronic alcoholic hepatitis leads to an increase in the total concentration of glycosaminoglycans, the concentration of chondroitin sulfates, a decrease in the heparin-heparan fraction of glycosaminoglycans and no changes in concentration of the keratan-dermatan fraction in the liver of rats compared to the control group. In the group of rats injected with doxorubicin against the background of chronic alcoholic hepatitis, the concentrations of total glycosaminoglycans, heparin-heparan fraction, and chondroitin fraction significantly increased, and the content of the keratan-dermatan fraction of glycosaminoglycans significantly decreased compared to animals with chronic alcoholic hepatitis. In rats injected with doxorubicin against the background of chronic alcoholic hepatitis, the content of free oxyproline decreased by 1.25 times, sialic acids – by 1.36 times, compared to the group of animals with chronic alcoholic hepatitis. Administration of ethanol or doxorubicin in combination with ethanol to rats causes morphological changes in the liver that are characteristic of chronic alcoholic hepatitis. Administration of doxorubicin to rats leads to degenerative morphological changes in the liver lobules. The administration of doxorubicin prevents alcohol-induced collagenolysis and the breakdown of glycoproteins, but increases the breakdown of proteoglycans due to an increase in the content of chondroitin and heparin-heparan fractions.

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Emerging therapeutic targets in systemic sclerosis

O’Reilly

2024

J Mol Med

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Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis

Cited by 9 publications

References 56 publications

Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies

Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies

Influence of doxorubicin on the extracellular matrix of the liver of rats under conditions of chronic alcoholic hepatitis

Emerging therapeutic targets in systemic sclerosis

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