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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
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
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
Project description:Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Antigen Presentation and Immunogenicity [bulk RNA-seq]
| PRJNA814674 | ENA
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
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
Project description:PurposeDespite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry.ResultsWe show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNγ-independent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic non-heat shock-inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy.ConclusionsThese highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.See related commentary by Srivastava and Callahan, p. 6277.
| S-EPMC6825536 | biostudies-literature
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
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.
2013-01-01 | GSE29204 | GEO
Project description:Respiration is one of the most vital and basic features of living organisms. In mammals, respiration is accomplished by respiratory chain complexes located on the mitochondrial inner membrane. In the past century, scientists put tremendous efforts in understanding these complexes, but failed to solve the high resolution structure until recently. In 2016, three research groups reported the structure of respiratory chain supercomplex from different species, and fortunately the structure solved by our group has the highest resolution. In this review, we will compare the recently solved structures of respirasome, probe into the relationship between cristae shape and respiratory chain organization, and discuss the highly disputed issues afterwards. Besides, our group reported the first high resolution structure of respirasome and medium resolution structure of megacomplex from cultured human cells this year. Definitely, these supercomplex structures will provide precious information for conquering the mitochondrial malfunction diseases.
| S-EPMC6138618 | biostudies-literature