Customized fake Guatemala ID card【visit: hk965.com】【whatsapp:+852 92908202】【telegram:hz99888】Professional production of documents, including passports, visas, driver's licenses, ID cards, green cards, residence cards, various certificates, and utility bills Global shipping, safe and fast. Contact us if needed.,【Customized website: https://hk965.com】,【whatsapp:+852 92908202】【telegram:@hz99888】Customized fake Guatemala ID card,Customized fake Guatemala ID card. . . . . . . . Perceiving and responding to the external environment is one of the most basic characteristics of life phenomena.At the cellular level, the extracellular matrix (Extracellular Matrix) is the main component of the cellular microenvironment. It is composed of various structural and functional molecules secreted by cells, including collagen, hyaluronic acid, and growth and immune factors.Therefore, the extracellular matrix is 鈥嬧€媋lso a direct platform for cells to sense their microenvironment.So, through what molecular pathways will changes in the extracellular matrix specifically affect intracellular homeostasis, and what is the evolutionary basis and physiological significance of such a communication mechanism?On June 27, 2024, Dr. Zhang Hanlin and his collaborators from Professor Andrew Dillin鈥檚 research group at the University of California, Berkeley and Howard Hughes Medical Institute published the article The extracellular matrix integrates mitochondrial homeostasis in Cell, providing an answer to these questions.The authors used genetic and chemical treatments to regulate the extracellular matrix of human fibroblasts, including overexpressing or knocking out hyaluronidase TMEM2, and adding exogenous purified hyaluronidase.After a series of drug stress tests, the authors found that TMEM2-overexpressing cells were more sensitive to mitochondrial stress, while TMEM2-knockout cells showed greater resistance to mitochondrial stress.Further mitochondrial phenotype analysis revealed that TMEM2-mediated extracellular matrix degradation can lead to changes such as decreased mitochondrial function, increased production of reactive oxygen species ROS, loss of mitochondrial inner membrane, and mitochondrial fission (Figure 1).These phenomena indicate that the degradation of hyaluronic acid components in the extracellular matrix can lead to mitochondrial damage and stress response.Figure 1. TMEM2-mediated extracellular matrix degradation leads to changes in mitochondrial structure.(Figure from the paper)To test whether this new extracellular matrix-intracellular mitochondrial communication phenomenon also exists in vivo and in other species, the authors used Caenorhabditiselegans) model overexpressed the human hyaluronic acid hydrolase TMEM2 or the endogenous extracellular matrix hydrolase of nematodes to achieve the degradation of the nematode extracellular matrix, and found that such treatment can also cause similar stress changes in the structure and function of intracellular mitochondria.This suggests that extracellular matrix-mitochondria communication behavior may have an ancient evolutionary basis and have important physiological significance.The author next first explored the molecular mechanism of this communication phenomenon.Using a combination of genetic screening, transcriptome analysis, and targeted cell biology and biochemistry techniques, the authors identified that the TGF-尾 signaling pathway may be involved in mediating signal transduction from the extracellular matrix to mitochondria.As a brief summary, treatment with TGF-尾 ligand (TGF-尾1) can directly reduce the tolerance of cells to mitochondrial stress, with reactions such as increased ROS production and weakened mitochondrial respiratory function.Genetic knockout or drug inhibition of TGF-尾 receptors and downstream transcription factors can increase cells' tolerance to mitochondrial stress.As a more in-depth study of the mechanism, the authors found that TGF-尾1 can promote the expression of a series of mitochondrial fission genes, leading to stress changes in mitochondrial morphology and function.In addition, TGF-尾 is an evolutionarily conserved developmental and immune regulatory pathway, and the authors confirmed that this pathway is also involved in similar regulation of mitochondrial homeostasis in C. elegans.Finally, the authors explore the physiological significance of this newly identified molecular pathway.Transcriptome data analysis showed that degradation of the extracellular matrix can lead to the activation of a series of antiviral-related interferon genes in cultured fibroblasts, and this activation is accompanied by an increase in mitochondrial DNA content in the cytosol.Therefore, the authors believe that TGF-尾-induced mitochondrial damage in this pathway can activate the cGAS-STING pathway in the cytoplasm through the release of mitochondrial DNA to activate the cellular immune response.In order to further verify this immune activation phenomenon under physiological conditions in vivo, the authors used nematode bacterial infection as a model and found that extracellular matrix damage signals can increase the nematode's resistance to pathogenic bacteria through the activation of mitochondrial stress responses.Based on these findings, the authors proposed that this extracellular matrix to mitochondria communication mechanism may initially be a primitive immune response. Cells can stimulate mitochondrial stress and immune responses by sensing extracellular matrix damage, thereby achieving damage repair and resistance to pathogens (Figure 2).Because the activation of this molecular pathway does not depend on the direct recognition of specific pathogen signals, this discovery may have a broader regulatory function in the organism and participate in many physiological processes such as individual development, damage repair, infection immunity, and aging.Figure 2. Schematic diagram summarizing the findings of the paper.(Picture from the paper)Dr. Andrew Dillin is the corresponding author of the paper and is responsible for the supervision, guidance and financial support of the scientific research team.Dr. Zhang Hanlin is the first author of the paper and leads the planning, design, implementation and funding acquisition related to the project.Undergraduate members of the research team, Wu Haolun (who is about to pursue a doctoral degree at Cornell University), Fan Wudi (currently a doctoral candidate at Berkeley), and other collaborators also made important contributions to the completion of the project.In particular, Dr. Zhang Hanlin has long been focused on the molecular basis of biological aging and clinical translation research. He has previously discovered the regulatory mechanism of biological polyamine metabolites on cell homeostasis and immune aging, and successfully conducted clinical trials.Anyone interested in related research is welcome to communicate with the author.Original link:https://www.cell.com/cell/abstract/S0092-8674(24)00638-X