Mechanism Study of ROCK1 and Drp1 Binding Promoting Lung Cancer Progression Under Hypoxic Conditions
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ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Yi Zhao
PROVIDER: PXD081032 | iProX | Tue Jul 14 00:00:00 BST 2026
REPOSITORIES: iProX
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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:DEAD box 17 (DDX17) is a typical member of the DEAD box family with transcriptional cofactor activity. Although DDX17 is abundantly expressed in the myocardium, its role in the heart is not fully understood. We generated cardiomyocyte-specific Ddx17-knockout mice and cardiomyocyte-specific Ddx17 transgenic mice and explored the function of DDX17 using various cardiomyocyte injury and heart failure (HF) models. We also validated the correlation between DDX17 expression and cardiac function in myocardial biopsy samples from HF patients. DDX17 was downregulated in myocardial samples from HF mouse models and cardiomyocyte injury models. We found that the cardiomyocyte-specific knockout of DDX17 promotes autophagic flux blockage and cardiomyocyte apoptosis in pathological conditions, resulting in progressive heart dysfunction, thereby leading to maladaptive remodeling and progression of HF. The replenishment of DDX17 in cardiomyocytes protected heart function in pathological conditions. Further studies showed that DDX17 can bind to the transcriptional repressor BCL6 and inhibit the expression of the mitochondrial fission protein DRP1. When DDX17 expression was decreased, the transcriptional repression of BCL6 was reduced, resulting in increased DRP1 expression and mitochondrial fission, which caused autophagy flux blockage and apoptosis in cardiomyocytes, leading to impaired mitochondrial homeostasis and HF. We also verified the clinical correlation of DDX17 expression with cardiac function and DRP1 expression in endomyocardial biopsies from patients with HF. These findings suggest that DDX17 protects cardiac function by promoting mitochondrial homeostasis through the BCL6-DRP1 pathway during HF.
2024-04-07 | GSE157135 | GEO
Project description:Mitotic fission is increased in hyperproliferative, apoptosis-resistant diseases, such as pulmonary arterial hypertension (PAH). PAH’s fissogenic phenotype includes activation of the fission mediator, dynamin related protein 1 (Drp1), which must complex with its adaptor proteins to cause fission. Drp1-induced fission has been therapeutically targeted in experimental PAH. Here we examine the role of two recently discovered, poorly understood, Drp1 adapter proteins, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51) in normal vascular cells and explore the role of their dysregulation in the pathogenesis of PAH. MiDs are increased in PAH PASMC. This accelerates Drp1-mediated mitotic fission, which increases cell proliferation and decreases apoptosis. Silencing MiDs (but not Fis1 or MFF) promotes mitochondrial fusion and G1-phase cell cycle arrest through an ERK1/2 and CDK4-dependent mechanism. Augmenting MiDs in normal cells causes fission and recapitulates the PAH phenotype. MiD upregulation results from decreased microRNA-34a-3p (miR-34a-3p) expression. Circulatory miR34a-3p expression is decreased in PAH patients as well as in preclinical models of PAH. Silencing MiDs or augmenting miR-34a-3p regresses experimental PAH. We used microarrays to identify differences in miR expression in pulmonary artery smooth muscle cells (PASMC) taken from either pulmonary arterial hypertension patients or healthy controls
2018-01-31 | GSE108707 | GEO
Project description:Background: Mitochondrial dysfunction is closely related to ischemic brain injury. Increased expression of dynamin-related protein 1 (Drp1) in neuronal cells plays a crucial role in ischemia/hypoxia-induced mitochondrial damage, and dysregulation of miR-155 expression is implicated in cerebral ischemic injury. However, the mechanistic link between miR-155 dysregulation and Drp1-mediated mitochondrial damage in ischemic/hypoxic neuronal cells remains largely elusive. Methods: Oxygen-glucose deprivation (OGD)-treated Neuro-2a cells were employed to investigate the effects of hypoxia/ischemia on miR-155 expression. The cells transfected with miR-155 mimic and miR-155 inhibitor were used to clarify the the role of miR-155 in OGD-induced mitochondrial damage. The expression levels of PGC-1α, PPARα, PPARβ/δ, PPARγ, ERRα, and Drp1 were assessed using qRT-PCR, Western blotting, and immunofluorescence staining, and their interactions were identified by confocal colocalization and co-immunoprecipitation experiments. Mitochondrial functions were evaluated by measuring ATP content, ROS, MMP, and mPTP opening. Chromatin immunoprecipitation (ChIP) assay was performed to detect the binding of ERRα to the Drp1 promoter. Results: miR-155 expression in OGD-treated neuronal cells exhibited a significant upregulation in a time-dependent manner. Elevated miR-155 induced excessive mitochondrial fission and dysfunction, as evidenced by a decreased ATP content, increased ROS generation, depolarized MMP, and mPTP opening, which is accompanied by a markedly reduced expression of PPAR family members, particularly the PPARγ. Mechanistically, miR-155 weakened the interaction between PGC-1α and PPARγ by suppressing their expressions and thus downregulated ERRα expression, which prevents the binding of ERRα to the Drp1 promoter, thereby relieving the repression of the Drp1 promoter by ERRα. These findings suggest that PGC-1α and ERRα negatively regulate Drp1 expression in neuronal cells. Notably, inhibition of miR-155 could ameliorate mitochondrial dysfunction by improving the OGD-induced dysregulation of PPARγ/PGC-1α/ERRα-Drp1 axis in Neuro-2a cells, providing new insights into the mechanisms of ischemia/hypoxia-induced mitochondrial dysfunction. Conclusion: Our findings reveal a novel mechanism by which miR-155 contributes to mitochondrial damage by driving the ischemia/hypoxia-induced dysregulation of PPARγ/PGC-1α/ERRα-Drp1 axis in neuronal cells, identifying potential new therapeutic targets for the treatment of post-ischemic mitochondrial damage.
2026-07-10 | GSE332777 | GEO
Project description:Dynamin-related protein 1 (DRP1) mediates mitochondrial fission and permits rapid cell cycle progression in hyperproliferative cells by coordinating nuclear and mitochondrial division, a process called mitotic fission. However, DRP1 alone appears insufficient to complete fission and the link between fission and cell cycle progression is unknown.We hypothesize Dynamin 2 (DNM2) interacts with DRP1 to complete mitochondrial fission and regulate cell cycle progression. We show that DNM2 is upregulated in pulmonary arterial smooth muscle cells in human and rodent pulmonary arterial hypertension (PAH PASMC), contributing to disease pathophysiology.
2026-05-01 | GSE327258 | GEO
Project description:Proteomic dentification of FLAG-Drp1 binding protein that is increased after exposure to hypoxic stress in HeLa cells.
2018-10-09 | PXD011317 | JPOST Repository
Project description:Pseudomonas aeruginosa is a Gram-negative, opportunistic bacterium and a major etiological agent in monogenic disease cystic fibrosis (CF). High density colonies of P. aeruginosa are often isolated from hypoxic mucus plugs in respiratory tract of CF patients, indicating high adaptive capacities of the bacterium. Despite the high prevalence and related patient mortality, the protein machinery enabling the bacterium to adapt to this hypoxic environment remains to be fully elucidated. We investigated this by performing both SWATH mass spectrometry and data-dependent SPS-MS3 of TMT labelled peptides to profile the proteomes of two P. aeruginosa CF isolates, PASS2 and PASS3, and a laboratory reference strain, PAO1, grown under hypoxic stress (O2<1%) and aerobic conditions in media that mimics the nutrient components of the CF lung. 3,967 P. aeruginosa proteins were quantitated (FDR <1%) across all three strains, reflecting approximately 71% of predicted ORFs in PAO1 and representing the most comprehensive proteome of clinically relevant P. aeruginosa to date. Comparative analysis revealed 735, 640 and 364 proteins were altered by two-fold or more when comparing low oxygen to aerobic growth in PAO1, PASS2 and PASS3 respectively. Strikingly, under hypoxic stress, all strains showed concurrent increased abundance of proteins required for both aerobic (cbb3-1 and cbb3-2 terminal oxidases) and anaerobic denitrification and arginine fermentation, with the two clinical isolates showing higher relative expression of proteins in these pathways. Additionally, functional annotation revealed that clinical strains portray a unique expression profile of replication, membrane biogenesis and virulence proteins during hypoxia which may endow these bacteria with a survival advantage. These protein profiles illuminate the diversity of P. aeruginosa mechanisms to adapt to low oxygen and shows that CF isolates initiate a robust molecular response to persist under these conditions.
2017-08-29 | PXD007233 | Pride
Project description:Exosomes derived from NSCLC cells under normoxic or hypoxic conditions were compared to identify hypoxic associated enrichment of proteins in exosomes.
2023-03-10 | PXD038587 | Pride
Project description:Aspergillus fumigatus strains CEA10 and srbA mutant expression patterns were compared after exposure to 24h of hypoxic conditions Goal of this study was to find genes that are directly and/or indirectly regulated by the transcription factor srbA, that is know to be crucial for growth under hypoxic conditions Keywords: hypoxic stress response
2008-10-15 | GSE12376 | GEO
Project description:Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.
2020-08-28 | GSE156982 | GEO