Liver diseases, including hepatitis B, hepatitis C, non-alcoholic and alcoholic steatohepatitis and related liver diseases such as fibrosis, cirrhosis, liver failure and hepatocellular carcinoma, are one of the leading causes of illness and death in the world . Despite extensive research into the pathogenesis of various liver diseases, there are still no effective treatments for end-stage liver disease. Therefore, it is crucial to better understand the molecular mechanisms of liver disease and develop potential therapeutic targets.
Mitochondria regulate cell necroptosis
Necroptosis is a common, regulated form of programmed cell necrosis in the liver. Its activation does not depend on caspases and has common characteristics of necrosis and apoptosis. A review published by Academician Li Lanjuan's team from Zhejiang University School of Medicine in IJMS reviewed numerous molecular mechanisms by which mitochondria mediate necroptosis, and discussed its role in various liver diseases and potential clinical research, providing a basis for future research. Research on the pathophysiology of liver disease and its treatment provides insights.
Although the specific mechanism of necroptosis induced by the necrosome complex is still unclear, some studies have shown that the generation of ROS is closely related to cell necroptosis. For example, in some cells ROS can promote RIPK1 autophosphorylation; In addition, as shown in Figure 1, the dual function of mitochondrial PGAM5 plays an important role in cell necroptosis; as shown in Figure 2, in the tumor necrosis factor induction pathway, phosphorylated RIPK3 can directly increase the activity of some metabolic enzymes , for example: glutamate ammonia ligase (GLUL) and glutamate dehydrogenase 1 (GLUD1) induce cell necroptosis; at the same time, the author also summarized the mitochondrial permeability transition pore and cyclophilin protein D, B cells The lymphoma 2 (BCL-2) protein family and other mitochondrial mechanisms regulate cell necroptosis; the above mechanisms indicate that mitochondria and their metabolism play an important regulatory role in the cell necroptosis process.
Mitochondrial mechanism of necroptosis in liver disease
Mitochondrial dysfunction is related to acute liver injury. The authors first discussed the mitochondrial mechanism of necroptosis in acute liver injury. For example, when Listeria monocytogenes infection causes acute liver injury in mice, RIPK1/RIPK3/MLKL signaling The pathway is activated, subsequently leading to necroptosis and liver damage; knocking out the RIPK1 gene can alleviate mitochondrial dysfunction and necroptosis in the liver tissue of infected mice.
Subsequently, the authors discussed the mechanism of mitochondrial necroptosis in chronic liver disease. Although numerous studies have demonstrated a clear link between apoptosis and chronic liver disease, the occurrence of necroptosis and its impact on chronic liver disease are controversial. This contradiction lies in the fact that theoretically the occurrence of necroptosis depends on RIPK3, but the expression of RIPK3 has not been detected in primary mouse hepatocytes. Nonetheless, an increasing number of studies at the liver level reflect that mitochondrial dysfunction may contribute to chronic liver disease. In addition, many studies have shown that necroptosis occurs in liver cancer cells through mitochondria-related signaling pathways. N-terminal kinase (JNK), BAX, BAK and other proteins play an important role in regulating mitochondrial necroptosis in liver cancer cells.
Analysis conclusion
In various liver diseases, mitochondria are multifaceted regulators of the necroptosis pathway, playing multiple functions such as promoting inflammation, enhancing immune responses, and regulating disease progression. Necroptosis leads to mitochondrial dysfunction through the PIPK1/PIPK3/MLKL pathway. With the advancement of gene editing technology, it is becoming feasible to correct important mutated genes in mitochondria-mediated pathways and thereby improve the progression of certain liver diseases. However, scientists still have much work to do before they can identify safe and effective inhibitors or drugs that improve mitochondrial function.
Research prospects
Mitochondria play an important regulatory role in cell necroptosis, which implies that targeted inhibition of mitochondria-induced apoptosis/necrosis pathways has great prospects for the prevention and treatment of liver diseases. As the academic community has discovered, in non-alcoholic fatty liver disease, the necroptosis pathway is activated, and inhibiting RIPK1 can improve the characteristics of non-alcoholic steatohepatitis in mice fed high-fat diet. Although some progress has been made in the mitochondrial necroptosis mechanism of various liver diseases, current research is mostly completed in animal models of liver diseases, which cannot fully reflect all the characteristics of human liver diseases. Many approaches to target mitochondrial disorders to treat liver disease have been reported, but many nonspecific responses still exist, so it is necessary to develop and test small molecule targets that target specific steps in the mitochondrial-mediated cell death signaling pathway.
