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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE198348 | GEO | 2022/12/31

REPOSITORIES: GEO

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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

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.

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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

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

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

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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.

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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