Browse
Submit Data
Databases
API
Help

Dataset Information

13 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport.

ABSTRACT: Tumor necrosis factor (TNF) is a critical host resistance factor against tuberculosis. However, excess TNF produces susceptibility by increasing mitochondrial reactive oxygen species (mROS), which initiate a signaling cascade to cause pathogenic necrosis of mycobacterium-infected macrophages. In zebrafish, we identified the mechanism of TNF-induced mROS in tuberculosis. Excess TNF in mycobacterium-infected macrophages elevates mROS production by reverse electron transport (RET) through complex I. TNF-activated cellular glutamine uptake leads to an increased concentration of succinate, a Krebs cycle intermediate. Oxidation of this elevated succinate by complex II drives RET, thereby generating the mROS superoxide at complex I. The complex I inhibitor metformin, a widely used antidiabetic drug, prevents TNF-induced mROS and necrosis of Mycobacterium tuberculosis-infected zebrafish and human macrophages; metformin may therefore be useful in tuberculosis therapy.

SUBMITTER: Roca FJ

PROVIDER: S-EPMC7612974 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan.

Project description:Increased production of reactive oxygen species (ROS) has long been considered a cause of aging. However, recent studies have implicated ROS as essential secondary messengers. Here we show that the site of ROS production significantly contributes to their apparent dual nature. We report that ROS increase with age as mitochondrial function deteriorates. However, we also demonstrate that increasing ROS production specifically through respiratory complex I reverse electron transport extends Drosophila lifespan. Reverse electron transport rescued pathogenesis induced by severe oxidative stress, highlighting the importance of the site of ROS production in signaling. Furthermore, preventing ubiquinone reduction, through knockdown of PINK1, shortens lifespan and accelerates aging; phenotypes that are rescued by increasing reverse electron transport. These results illustrate that the source of a ROS signal is vital in determining its effects on cellular physiology and establish that manipulation of ubiquinone redox state is a valid strategy to delay aging.

| S-EPMC4835580 | biostudies-literature

TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis through a Mitochondrial-Lysosomal-Endoplasmic Reticulum Circuit.

Project description:Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.

| S-EPMC6736209 | biostudies-literature

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

Project description:Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of Complex I (CI) and II (CII), the gatekeepers for initiating electron flow, remains unclear. Here, we report that loss of CII, but not CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex I-antigen processing and presentation (MHC-APP) genes that is independent of interferon signaling. Furthermore, knock-out of MCJ, to promote electron entry preferentially via CI, provides proof-of-concept of ETC rewiring to achieve anti-tumor responses without side effects associated with an overall reduction in mitochondrial respiration in non-cancer cells. Our results hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

2024-05-01 | GSE235311 | GEO

Vanadium Dioxide Nanocoating Induces Tumor Cell Death through Mitochondrial Electron Transport Chain Interruption.

Project description:A biomaterials surface enabling the induction of tumor cell death is particularly desirable for implantable biomedical devices that directly contact tumor tissues. However, this specific antitumor feature is rarely found. Consequently, an antitumor-cell nanocoating comprised of vanadium dioxide (VO2) prepared by customized reactive magnetron sputtering has been proposed, and its antitumor-growth capability has been demonstrated using human cholangiocarcinoma cells. The results reveal that the VO2 nanocoating is able to interrupt the mitochondrial electron transport chain and then elevate the intracellular reactive oxygen species levels, leading to the collapse of the mitochondrial membrane potential and the destruction of cell redox homeostasis. Indeed, this chain reaction can effectively trigger oxidative damage in the cholangiocarcinoma cells. Additionally, this study has provided new insights into designing a tumor-cell-inhibited biomaterial surface, which is modulated by the mechanism of mitochondria-targeting tumor cell death.

| S-EPMC6436600 | biostudies-literature

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-31 | GSE198348 | GEO

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [bulk RNA-seq]

Project description:Loss of antigen presentation by MHCI is a common mechanism of tumor immune evasion. Mitochondrial oxidative phosphorylation (OXPHOS) capacity influences MHCI expression, but the underlying molecular mechanisms remain unclear. Here, we demonstrate that the relative flow of electrons through complex I or II of the mitochondrial electron transport chain (ETC) regulates MHCI expression and antigen presentation in cancer cells. Specifically, reducing electron flow from complex II increases mitochondrial succinate which activates transcription of MHCI and antigen processing and presentation (APP) genes. These phenotypes are independent of the interferon (IFN) signaling pathway and driven by succinate-mediated enzymatic inhibition of lysine-specific demethylases, KDM5A/B and destabilization of polycomb repressor complex 2 (PRC2). Finally, knockout of the mitochondrial Complex I inhibitor protein, MCJ, preferentially reduces electron flow through Complex II and increases succinate which drives an enhanced antigen-dependent CD8+ T cell response to mouse melanoma tumors in vivo. These findings suggest that the mitochondrial ETC can be manipulated therapeutically to enhance antitumor immune responses independently of IFNγ.

2022-12-31 | GSE198346 | GEO

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Project description:The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of NLRP3 inflammasome through multiple mechanisms including generation of mitochondrial ROS. Here we report that mitochondrial electron transport chain (ETC) complexes I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase (AOX), which can respectively complement the functional loss of mitochondrial complex I or III, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP but a ROS independent mechanism.

2022-03-09 | GSE197606 | GEO

Soluble ST2 induces cardiac contractile dysfunction by repressing mitochondrial electron transport chain genes in cardiomyocytes during fulminant myocarditis

Project description:Fulminant myocarditis (FM) is an acute fatal disease characterised by myocardial inflammation. Our previous study identified soluble growth stimulation- expressed gene 2 (sST2) as a sensitive and specific biomarker for early diagnosis of FM. However, its function in FM remains unclear.In the present study, we observed a marked elevation of sST2 in the plasma and hearts of mice with FM induced by coxsackievirus B3 (CVB3) and explored the main cellular sources of sST2 in FM. Moreover, using recombinant sST2 protein administration and unbiased transcriptomics analyses, we investigated the role and underlying mechanisms of sST2 in FM. Importantly, we found that sST2 has a novel non-classical function in cardiomyocytes, other than acting as an IL-33 decoy receptor. These findings reveal a novel role and action mechanism of sST2 in FM and suggest that sST2 may be a potential therapeutic target for FM.

2024-03-24 | GSE261940 | GEO

Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [scRNA-seq and scTCR-seq]

Project description:The aim of the study is to analyze and compare the transcriptional profiles and clonotypes at a single cell level of tumor-infiltrating lymphocytes from subcutaneous mouse YUMM melanoma model.

2022-12-31 | GSE198347 | GEO

Inhibition of the mitochondrial electron transport chain by antimycin A in Arabidopsis thaliana

Project description:Plant mitochondria signal to the nucleus leading to altered transcription of nuclear genes by a process called mitochondrial retrograde regulation (MRR). MRR is implicated in metabolic homeostasis and responses to stress conditions. Transcriptional consequences on nuclear gene expression of mitochondrial perturbations were examined by a microarray analyses. Expression of 1316 was altered by antimycin A (AA) inhibition of the cytochrome respiratory pathway in leaves of soil grown Arabidopsis plants in the dark for 6 hours. Functional gene category (MapMan) and cluster analyses showed that genes with expression levels affected by perturbation from AA or MFA inhibition were most similarly affected by biotic stresses such as pathogens, not oxidative stresses. Overall, the data provide further evidence for the presence of mtROS-independent MRR signaling, and support the proposed involvement of MRR and mitochondrial function in plant responses to biotic stress. Three independent (bio-replicate) experiments were done using three independent plant samples and independent chemicals in the treatments. For each, approximately 30 plants were used for the treated sample and about 30 plants were used as the control treated sample. Plants were treated with 20 uM antimycin A in 0.01% Tween 20 and incubated in the dark at room temperature (25C) for 6 hours. RNA was isolated from the inhibitor treated and control treated plants and used for microarray experiments. For each independent (bio-replicate) experiment, two microarrays were utilized using Cy3 and Cy5 dye-labeled samples and dye swapping was incorporated- so, minimum of 2 microarrays for each of 3 independent experiments (6 microarrays). In addition, two of the microarrays were duplicated so that a total of 8 slides were used in the data analyses.

2013-01-01 | E-GEOD-29204 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data