Tfam-deficiency mediated mitochondrial disorder affects Langerhans cell maintenance and function
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ABSTRACT:
PROVIDER: PRJNA835509 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19107758_1.fastq.gz | Fastqsanger.gz | |||
| SRR19107758_2.fastq.gz | Fastqsanger.gz | |||
| SRR19107759_1.fastq.gz | Fastqsanger.gz | |||
| SRR19107759_2.fastq.gz | Fastqsanger.gz | |||
| SRR19107760_1.fastq.gz | Fastqsanger.gz |
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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:In this report, we showed that TFAM deficiency caused impaired AM mitochondrial fitness, altered metabolism and defective lipid catabolic responses, leading to diminished AM quantity and altered AM phenotypes. We demonstrated that TFAM deficiency did not impair AM differentiation from their precursors, but caused reduced AM maintenance. RNA-seq experiment revealed that TFAM deficiency caused impaired AM self-renewal capability. We showed that TFAM deficiency in AMs caused impaired clearance of respiratory debris, surfactant and enhanced susceptibility to severe influenza virus infection. Finally, we found that influenza infection resulted in disruption of TFAM-mediated mitochondrial fitness and metabolism in AMs.
2021-11-07 | GSE188279 | GEO
Project description:Regulatory T cells (Tregs) are pivotal for immune suppression. Cellular metabolism is important for Treg homeostasis and function. However, the exact role of mitochondrial respiration in Tregs remains elusive. Mitochondrial transcription factor A (Tfam) is essential for mitochondrial respiration and controls mitochondrial DNA replication, transcription and packaging. Here we show that genetic ablation of Tfam in Tregs impairs Treg maintenance in non-lymphoid tissues at the steady state and in tumor. Tfam-deficient Tregs have reduced proliferation and Foxp3 expression upon glucose deprivation in vitro. Tfam deficiency preferentially affects gene activation in Tregs through regulation of DNA methylation. Tfam-deficient Tregs have enhanced methylation at TSDR of Foxp3 locus. Deletion of Tfam in Tregs affects Treg homing and maintenance, resulting in tissue inflammation in colitis, but enhances tumor rejection. Thus, our work reveals a critical role for Tfam-mediated Treg respiration in regulation of inflammation and anti-tumor immunity.
2020-04-13 | GSE131883 | GEO
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:TFAM-dependent mitochondrial metabolism is required for alveolar macrophages maintenance and homeostasis
| PRJNA778190 | ENA
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: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:The goal of this study was to compare the gene expression profiles of WT, Tfam+/-, Zbp1-/- and Tfam+/-Zbp1-/- MEFs.
2023-01-28 | GSE223553 | 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