Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages
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PROVIDER: PRJNA1218688 | ENA |
REPOSITORIES: ENA
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Project description:Lung tissue-resident macrophages (TRMs), including alveolar macrophages (AMs) and interstitial macrophages (IMs), are pivotal in maintaining both immune defense and tissue homeostasis. Although the distinct functional roles of these macrophage populations are well recognized, the specific metabolic pathways that support their functions are not fully understood. Comparative RNA sequencing analysis identified Sdha, a key enzyme in mitochondrial metabolism, as one of the most highly expressed and differentially regulated genes involved in metabolic pathways in AMs relative to IMs. This finding led us to investigate the role of succinate dehydrogenase complex subunit A (SDHA) in regulating AM metabolism and function. Here, we demonstrated that SDHA is crucial for maintaining AM homeostasis. Deletion of SDHA resulted in a significant reduction in AM populations without affecting IMs, highlighting an AM-specific requirement for SDHA. In the absence of SDHA, AMs underwent metabolic reprogramming towards glycolysis compared with IMs, along with significant transcriptional changes and cell death. Furthermore, SDHA-deficient AMs showed lipid accumulation and increased endoplasmic reticulum (ER) stress. These findings establish SDHA as a crucial regulator of AM metabolism and underscore the importance of maintaining metabolic integrity for AM function and survival within the lung microenvironment.
2025-02-07 | GSE288614 | GEO
Project description:Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumours arising in the adrenal medulla and paraganglia of the autonomous nervous system, respectively. Malignant PCC/PGL are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Gene expression changes associated with SDHB inactivation were investigated in a two genetically defined murine cellular models. These models were generated by Cre-mediated recombination in spontaneously immortalized mouse chromaffin cells (imCCs) and adrenal fibroblasts (MAFs).
2015-11-04 | E-MTAB-3403 | biostudies-arrayexpress
Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.
2016-07-01 | GSE82043 | GEO
Project description:The apicomplexan parasite Toxoplasma gondii has a divergent mitochondrial electron transport chain (mETC). Succinate dehydrogenase (SDH), the second complex in the mETC and an enzyme in the TCA cycle, has 4 subunits in common model organisms, but Toxoplasma has a 9 subunit SDH complex. We performed immunoprecipitation of SDH, via an HA epitope tagged SDHB subunit, and the unrelated Complex III and analysed the elution via LFQ mass spectrometry, to confirm the composition of the divergent Toxoplasma gondii SDH complex.
2023-12-27 | PXD047027 | Pride
Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.
2016-07-01 | E-GEOD-82043 | biostudies-arrayexpress
Project description:Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation
| PRJNA1039834 | ENA
Project description:Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct microenvironment-associated metabolic processes. Here, we identified SDH deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to a wide range of anti-cancer therapies. Mechanistically, succinate promoted the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function was mediated by succinate-triggered upregulation of UBC12 phosphorylation, which impaired its E2 function in cullins neddylation. Notably, decreasing succinate levels by fludarabine could effectively restore the drug sensitivity of SDH-deficient AML PDX. Together, we uncover a novel function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.
2024-08-27 | GSE247623 | GEO
Project description:Background; Mitochondrial respiration is an important and widely conserved cellular function in eukaryotic cells. The succinate dehydrogenase complex (SDH-complex) plays an important role in respiration as it connects the mitochondrial respiratory chain to the tricarboxylic acid (TCA) cycle where it catalyzes the oxidation of succinate to fumarate. Cellular response to the SDH-complex dysfunction (i.e. impaired respiration) thus has important implications not only for biotechnological applications but also for understanding cellular physiology underlying metabolic diseases such as diabetes. We therefore explored the physiological and transcriptional response of Saccharomyces cerevisiae to the deletion of SDH3, that codes for an essential subunit of the SDH-complex. Results; Although the SDH-complex has no direct role in transcriptional regulation and the flux through the corresponding reaction under the studied conditions is very low, deletion of SDH3 resulted in significant changes in the expression of several genes involved in various cellular processes ranging from metabolism to the cell-cycle. By using various bioinformatics tools we explored the organization of these transcriptional changes in the metabolic and other cellular functional interaction networks. Conclusions; Our results show that the transcriptional regulatory response resulting from the impaired respiratory function is linked to several different parts of the metabolism, including fatty acid and sterol metabolism. Experiment Overall Design: Two replicates for sdh3 deletion mutants. Reference strain transcriptome data: Westergaard SL et al., FEMS Yeast Res 2004, 5: 193-204.
2009-01-13 | E-GEOD-13924 | biostudies-arrayexpress
Project description:Background Mitochondrial respiration is an important and widely conserved cellular function in eukaryotic cells. The succinate dehydrogenase complex (SDH-complex) plays an important role in respiration as it connects the mitochondrial respiratory chain to the tricarboxylic acid (TCA) cycle where it catalyzes the oxidation of succinate to fumarate. Cellular response to the SDH-complex dysfunction (i.e. impaired respiration) thus has important implications not only for biotechnological applications but also for understanding cellular physiology underlying metabolic diseases such as diabetes. We therefore explored the physiological and transcriptional response of Saccharomyces cerevisiae to the deletion of SDH3, that codes for an essential subunit of the SDH-complex. Results Although the SDH-complex has no direct role in transcriptional regulation and the flux through the corresponding reaction under the studied conditions is very low, deletion of SDH3 resulted in significant changes in the expression of several genes involved in various cellular processes ranging from metabolism to the cell-cycle. By using various bioinformatics tools we explored the organization of these transcriptional changes in the metabolic and other cellular functional interaction networks. Conclusions Our results show that the transcriptional regulatory response resulting from the impaired respiratory function is linked to several different parts of the metabolism, including fatty acid and sterol metabolism.
2008-12-16 | GSE13924 | GEO
Project description:Heterozygosity for loss‐of‐function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional Sdhx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. Here we characterize two available murine SDH-loss cell lines, one representing PPGL-susceptible chromaffin cells and the other PPGL-resistant fibroblasts. Consistent with previous analyses, we find strikingly different effects of SDH loss in these two cellular contexts, including evidence of residual Complex I activity only in SDH-loss immortalized mouse chromaffin cells. This work supports the hypothesis that chromaffin cells may uniquely tolerate SDH loss and sets the stage for analyses of unique vulnerabilities in SDH-loss chromaffin cells.
2025-01-02 | GSE263778 | GEO