Mitochondrial PGAM5−Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses
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ABSTRACT:
PROVIDER: PRJNA985681 | ENA |
REPOSITORIES: ENA
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Project description:Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-kB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling might be a link between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.
2023-06-20 | GSE235306 | GEO
Project description:Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development.
2024-11-05 | GSE249865 | GEO
Project description:PGAM5 is a mitochondria-localized protein phosphatase. To analyze the effect on gene expression profiles by PGAM5 in iBAT, RNA-seq analysis was performed.
2019-10-12 | GSE138782 | GEO
Project description:Although up to 80% small-cell lung cancer (SCLC) patients response good for first-line chemotherapy regimen, most patients develop recurrence of the disease within weeks to months. Here, we report cytostatic effect of Leflu and Teri on SCLC cell proliferation through inhibition of DRP1 phosphorylation at Ser616 and decreased mitochondrial fragmentation. When administered together, Teri and carboplatin (Carbo) acted synergistically to significantly inhibit cell proliferation and DRP1 phosphorylation, reduce abundance of intermediates in pyrimidine de novo pathway, and increase apoptosis and DNA damage. Combination of Leflu&Carbo has anti-tumorigenic effect in vivo. Additionally, lurbinectedin (Lur) and Teri potently and synergistically inhibited spheroid growth, and depleted uridine and DRP1 phosphorylation in mouse tumors. Our results suggest combinations of Carbo and Lur with Teri or Leflu are efficacious and underscore how the relationship between DRP1/DHODH and mitochondrial plasticity serves as a potential therapeutic target to validate these treatment strategies in SCLC clinical trials.
2024-05-22 | GSE267928 | GEO
Project description:Purpose:to verify Drp1-mediated biological pathways under physiological and ischemia conditions.Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners. Methods:C57BL/6 mice and Drp1 knockdown mice were used for ischemia treatment. Right femoral arteries were catheterized with polyethylene catheters for bleeding 50% of total blood volume (≈7% of weight). The ischemia time started to calculate after the model was established. A laparotomy was then carried out to obtain superior mesenteric artery tissues (SMAs) for transcriptome analysis. Series-Cluster analysis was performed to identify the global trends of mitochondrial DEGs after Drp1 knockdown. Gene ontology (GO) analysis was performed to facilitate elucidating the biological process (BP), molecular function (MF) and cellular component (CC) of unique genes in the significant or representative profiles. Results:In addition to its traditional roles in GTPase regulation and mitochondrial fission, Drp1 may also regulate actin cytoskeleton and the movement of microtubules. Besides, Drp1 may participate in the regulation of morphology and functions of other organelles, including endoplasmic reticulum, peroxisome, phagolysosome, etc. As for general organ functions, Drp1 may regulate vascular constriction and dilation. These consequences indicated the important role of Drp1 in ischemia-induced cellular regulation. Conclusions: Drp1 deficiency proves the important role of Drp1 in ischemia-induced biomedical processes through multiple potential fission-independent manners.
2020-04-29 | GSE124096 | GEO
Project description:To decipher the contribution of STAT3, IRF1 and PGAM5 to androgen-responsive gene expression, effect of siRNA-mediated silencing of STAT3, IRF1 and PGAM5 on expression of androgen-dependent genes was studied.
2017-05-01 | GSE81780 | GEO
Project description:In cells, mitochondria undergo constant fusion and fission. An essential factor for fission is the mammalian dynamin-related protein 1 (Drp1). Dysregulation of Drp1 has been linked to neurodegenerative diseases including Parkinson’s as well as cardiovascular diseases and cancer. Here, we developed nanobodies (Nbs) for proteomics, advanced microscopy and live cell imaging of Drp1. To specifically enrich endogenous Drp1 with interacting proteins for proteomics, we functionalized high-affinity Nbs as capture matrices. Considering the wide range of research applications, the presented Nb toolset will open up new possibilities for advanced functional studies of Drp1 in disease-relevant models.
2024-05-29 | PXD051737 | Pride
Project description:Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development.
2024-11-05 | GSE248431 | GEO
Project description:This study demonstrated that circadian gene clock plays an important role in the regulation of mitochondrial homeostasis. In this process, CLOCK interacts with PUF60 and affects the mRNA stability of Drp1.
2022-03-31 | PXD032057 |
Project description:To investigate the function of mitochondrial fission protein DRP1 in the development of alcoholic liver disease, we generated liver-specific Dnm1l KO mice using Alb-Cre/loxP system. These mice were subjected to Gao-Binge alcohol model. We then performed RNA sequensing analysis using the liver tissue. Gene expression profiling analysis was conducted using data obtained from RNA-seq of 4 different groups.
2022-07-01 | GSE207074 | GEO