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Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation

ABSTRACT: Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation

PROVIDER: PRJNA1039834 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26815481_1.fastq.gz	Fastqsanger.gz
	SRR26815481_2.fastq.gz	Fastqsanger.gz
	SRR26815482_1.fastq.gz	Fastqsanger.gz
	SRR26815482_2.fastq.gz	Fastqsanger.gz
	SRR26815483_1.fastq.gz	Fastqsanger.gz

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Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation

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

Transcriptional Regulation by Cullin Ubiquitin Ligases

Project description:Transcriptional Regulation by Cullin Ubiquitin Ligases

| PRJNA614537 | ENA

SDH deficiency-driven succinate accumulation dictates the drug resistance of AML through regulating p-UBC12/cullin activity

2024-08-28 | PXD047175 | Pride

SDH deficiency-driven succinate accumulation dictates the drug resistance of AML through regulating p-UBC12/cullin activity

2024-08-28 | PXD053722 | Pride

Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation.

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 metabolic processes. Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to various anti-cancer therapies. Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function is mediated by succinate-triggered upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation. Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the 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.

| S-EPMC11560925 | biostudies-literature

Gene expression profiling of mouse cells deficient for succinate dehydrogenase

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

Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

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

Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages

Project description:Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages

| PRJNA1218688 | ENA

Immunoprecipitation of Toxoplasma gondii succinate dehydrogenase complex

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

Succinate Dehydrogenase Regulates Homeostasis and Metabolic Integrity of Alveolar Macrophages

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

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