RNA sequencing analysis in ESCC cells with Drp1 overexpression or TFAM deficiency
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE182710 | GEO | 2022/03/02
REPOSITORIES: GEO
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Project description:RNA sequencing analysis in ESCC cells with Drp1 overexpression or TFAM deficiency
| PRJNA757454 | ENA
Project description:Background & Aims Mitochondrial dysfunction and mtDNA stress-mediated inflammasome activation play critical roles in the pathogenesis of dry eye disease (DED). Mitochondrial transcription factor A (TFAM) is essential for regulating mtDNA stability and mitochondrial homeostasis. However, the mechanism underling TFAM to infuence DED progression is largely unknown. As a cytosolic DNA sensor, absent in melanoma 2 (AIM2) may contribute to the development of DED. Therefore, we aimed to explore whether the role of TFAM is associated with AIM2 inflammasome activation in DED. Methods The changes in inflammation, mitochondrial function, mtDNA homeostasis and TFAM expression were analyzed in the corneas of DED mice in vivo and in HCECs under oxidative stress in vitro. The effects of TFAM knockout on mtDNA homeostasis, mitochondrial respiration and cytokine release were also investigated in HCECs. The mechanism was analyzed by RNA sequencing in the corneas of DED mice, which was further verified by the HCECs with TFAM depletion. Results We found that the corneas of DED mice and HCECs under oxidative stress exhibited inflammation, mitochondrial damage and mtDNA maintenance disruption , which were highly associated with significantly reduced TFAM protein levels. Furthermore, we demonstrated that silencing of TFAM in HCECs suppressed mitochondrial respiratory capacity, induced mtDNA released into the cytosol and triggered cytokine release. Mechanistically, cytosolic mtDNA accumulation caused by TFAM depletion activated the AIM2 inflammasome and facilitated inflammation, thereby driving DED progression. Conclusions Our findings elucidate that TFAM deficiency induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the AIM2 inflammasome, triggers inflammatory responses and promotes DED progression. TFAM pathway may provide a novel therapeutic strategy for DED.
2024-06-18 | GSE252984 | GEO
Project description:SIRT3 is a NAD+-dependent mitochondrial protein deacetylase participating in the regulation of central metabolism and mitochondrial proteostasis. SIRT3 is downregulated in clear cell renal cell carcinoma (ccRCC), a main type of renal cancers, but the function of SIRT3 in tumorigenesis and development of ccRCC remains unknown. In this study, we established a SIRT3 overexpressed cell line to explore the changes of proteomics and metabolomics regulated by SIRT3 expression. Both the results of quantitative proteomics, metabolomics and acetylome showed overexpression of SIRT3 increased mitochondrial biogenesis and reversed the mitochondrial dysfunctions in ccRCC. We found SIRT3 could increase the activity of TFAM through modulation of TFAM transcription, degradation and acetylation level. The acetylation of TFAM K154 decreased while TFAM protein expression increased after SIRT3 overexpression. Further study revealed that SIRT3 could bind with TFAM, and decrease the acetylation of TFAM, promoting TFAM activity in mitochondrial biogenesis. Overall, our results present a new mechanism of SIRT3 in regulating mitochondrial functions, and the downregulation of SIRT3 in ccRCC lowers the activity of TFAM, subsequently inhibits the transcription of mitochondrial genes and mitochondrial biogenesis.
2018-08-14 | PXD009110 | Pride
Project description:ChIP-seq data characterizing the occupancy of TFAM over the mitochondrial and nuclear genomes in HeLa cells. Characterization of mitochondrial and nuclear genome-wide TFAM binding in HeLa cells
2013-09-21 | E-GEOD-48176 | biostudies-arrayexpress
Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.
2015-01-26 | E-GEOD-63767 | biostudies-arrayexpress
Project description:Objectives: The transcription factor TFAM is controlling the transcription of core proteins required for mitochondrial homeostasis. The aim of the current study was to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function and to evaluate the consequences for fibroblast activation. Methods: The expression of TFAM was analyzed by immunofluorescence and Western blot. The effects of TFAM knockout were investigated in cultured fibroblasts and in bleomycin-induced skin and lung fibrosis and in TβRIact-induced skin fibrosis. Results: The expression of TFAM was downregulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The downregulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mtDNA, accumulation of deletions in mtDNA, metabolic alterations with impaired OXPHOS and release of the mitokine GDF15. Chronic, but not acute exposure of normal fibroblasts to TGFβ mimicked the finding in SSc fibroblasts with downregulation of TFAM and accumulation of mitochondrial damage. Downregulation of TFAM promotes fibroblast activation with upregulation of fibrosis-relevant GO-terms in RNASeq. Mice with fibroblast-specific knockout of TFAM are prone to fibrotic tissue remodeling with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and TβRIact-overexpression. TFAM knockout fosters SMAD3 signaling to promote fibroblast activation. Conclusions: Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
2021-12-21 | GSE184356 | GEO
Project description:Gene expression analysis of 2-month-old Ctrl and Tfam-SCKO mice. At this age mitochondrial function is disrupted in the Schwann cells of Tfam-SCKO mice ,but their nerves display only very limited pathology. Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells, SCs) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response through actions of heme-regulated inhibitor kinase (HRI), and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines, an intermediate of fatty acid b-oxidation. Importantly, we show that acylcarnitines are released from SCs and induce axonal degeneration. A maladaptive integrated stress response as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies. Total RNA samples were prepared by isolating and pooling RNA from three different 2-month-old MPZ-Tfam KO and Ctrl mice. 2 replicates per genotype were used in this experiment and they were prepared entirely independently.
2013-03-13 | E-GEOD-44605 | biostudies-arrayexpress
Project description:Langerhans cells (LCs) are skin-resident professional antigen-presenting dendritic cells (DCs) to maintain skin homeostasis. The number and function of LCs are significantly reduced during the skin aging processes, which is closely related to the aging-associated skin disorders. However, the reasons underlying the changes of LC features with age are uncertain. Mitochondria are well known to be the main powerhouse to regulate cell fitness and function, and a decline in mitochondrial quality and activity was associated with normal aging and correlated with the development of a wide range of age-related diseases. So far, it is unknown if mitochondrial abnormality is involved in skin disorders by regulating LC homeostasis. The mitochondrial transcription factor A (Tfam) acts as a nuclear-encoded transcription factor and plays a critical role in mitochondrial stabilization. To explore the role of mitochondrial quality in LC homeostasis, we generated the mice with conditional deletion of Tfam in LC lineage. We found that Tfam-deficient LCs exhibits mitochondrial abnormality including morphology and membrane permeability of mitochondria, decreased cell number as well as maturation, whereas increased phagocytosis and inflammatory response of LCs. Interestingly, age-LCs from human skin have lower Tfam expression compared to young-LCs, and have the similar features with Tfam-deficient LCs analyzed by scRNA sequence (HRA000395). Thus, our data highlight that Tfam-mediated mitochondrial stability is essential for epidermal LC maintenance and function, which might be explain the states of increased susceptible to skin infections and rising incidence of cutaneous tumor in the elder. This is the first time to investigate the effect of mitochondria abnormality on LC homeostasis, which might be helpful for therapeutic interventions in aging-associated skin pathologies.
2022-08-13 | GSE202351 | 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:The Dynamin-related GTPase, Drp1 (encoded by Dnm1l) plays a central role in mitochondrial fission and is requisite for numerous cellular processes however its role in oxidative metabolism remains unclear. Herein, we show that among human tissues, skeletal muscle exhibits the strongest correlations with the DNM1L gene. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and accumulation of intramyocellular lipids along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced Complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2, normalized Complex II activity and lipid oxidation in Drp1-KD myocytes. Drp1 appears critical in maintaining mitochondrial Complex II assembly and fatty acid oxidation, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle lipid metabolism which is of clinical significance in combatting metabolic diseases.
2024-01-26 | GSE248081 | GEO