Drp1-mediated mitochondrial fission promotes carbon tetrachloride-induced hepatic fibrogenesis in mice

Abstract

Background Mitochondrial dynamics is essential for the maintenance of healthy mitochondrial network. Emerging evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of hepatic fibrogenesis following chronic liver injury. However, the role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in the context of liver fibrosis remains unclear. Methods and Results In this study, C57BL/6 mice were used to establish a model of liver fibrosis via oral gavage with CCl4 treatment for 8 weeks. Furthermore, mitochondrial fission intervention experiments were achieved by the mitochondrial division inhibitor 1 (Mdivi-1). The results demonstrated that chronic CCl4 exposure resulted in severe hepatic fibrogenesis and mitochondrial damage. By contrast, pharmacological inhibition of mitochondrial division by Mdivi-1 substantially reduced the changes of mitochondrial dynamics and finally prevented the deposition of extracellular matrix proteins. Mechanistically, excessive mitochondrial fission may activate hepatic stellate cells through RIPK1-MLKL-dependent hepatocyte death, which ultimately promotes liver fibrosis. Conclusion Our study imply that inhibiting Drp1-mediated mitochondrial fission attenuates CCl4-induced liver fibrosis and may serve as a therapeutic target for retarding progression of chronic liver disease.

Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice

“…We found that the voltage-dependent anion channel lying in the mitochondrial outer membrane contributes to radiation-induced mtDNA release, which can be blocked by the VDAC1 inhibitor DIDS. Mitochondrion is an important organelle of eukaryotic cells, and also acts as a target for various environmental factors [ 37 , 38 , 39 , 40 , 41 ]. Some damage stresses, such as H 2 O 2 , high glucose, LPS, and IR, were reported to increase mtDNA release into the cytosol [ 41 , 42 , 43 , 44 , 45 , 46 ].…”

Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease—Oxidative Stress and Inflammation Relevance

“…A key factor in the mitochondrial fission process is the activity of dynamin-related protein 1 (DRP1), which acts strictly on apoptosis by mediating the process of fission [ 112 ]. It was suggested that the loss of liver DRP1 may enhance the inflammatory response [ 112 ], and its phosphorylation, as a consequence of ROS products, encourages the fission process [ 113 ]. Moreover, findings from 2022 highlighted that excessive mitochondrial fission may make a certain contribution to the progression of NAFLD, while the inhibition of this process was correlated to a decrease in hepatic injuries and endoplasmic reticulum (ER) stress [ 106 ].…”

Evaluation of the efficacy of mitochondrial fission inhibitor (Mdivi-1) using non-alcoholic steatohepatitis (NASH) liver organoids

“…For example, excessive DRP1-triggered mitochondrial fission takes part in apoptosis in various pathological conditions, and thus it has emerged as a promising therapeutic target. A recent study revealed that DRP1-mediated mitochondrial fission promotes carbon tetrachloride-induced liver fibrosis and may function as a therapeutic target for retarding the progression of chronic liver disease ( Shan et al, 2022 ). Mitochondrial division inhibitor 1 (Mdivi-1) has been revealed to play a valuable role in various diseases by inhibiting DRP1-mediated mitochondrial fission ( Deng et al, 2021 ; Ding et al, 2022 ).…”