GO:0006105 succinate metabolic process: Metabolic Signaling Hub, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0006105 succinate metabolic process describes all chemical reactions and pathways involving succinate, the dianion of succinic acid and a central intermediate of the TCA cycle.
• Succinate is both a metabolic intermediate and a signaling molecule that links Krebs cycle activity to immunity, inflammation, and cancer.
• Succinate dehydrogenase (SDH) sits at the intersection of succinate oxidation and the electron transport chain, and its inhibition causes succinate accumulation with broad physiological consequences.
• In macrophages, succinate accumulation stabilizes HIF-1alpha and drives a proinflammatory state, while itaconate inhibits SDH to remodel macrophage metabolism.
• Succinate has been increasingly recognized as a signaling molecule in liver diseases, including nonalcoholic fatty liver disease and hepatocellular carcinoma.
• Metabolic pathway engineering in Escherichia coli has been used to optimize non-growth-associated succinate production, demonstrating the biotechnological relevance of this pathway.
Description
Succinate metabolic process (GO:0006105) encompasses the chemical reactions and pathways involving succinate, also known as butanedioate or ethane dicarboxylate, the dianion of succinic acid. Succinate is a dicarboxylic acid intermediate of the tricarboxylic acid (TCA) cycle and a key node connecting oxidative phosphorylation, anaplerosis, and biosynthetic metabolism. Because succinate can accumulate under conditions of hypoxia, SDH inhibition, or metabolic stress, it has emerged as a signaling molecule that influences immune cell function, inflammation, and tumor biology. For researchers, GO:0006105 is not merely a textbook metabolic step. Succinate levels are dynamically regulated by succinate dehydrogenase (SDH), by itaconate-mediated SDH inhibition, and by flux through the TCA cycle. These features make succinate metabolic process a tractable experimental system for studying immunometabolism, cancer metabolism, and liver disease. Genetic and pharmacological tools that alter succinate production or oxidation produce measurable changes in gene expression, cytokine secretion, and cellular differentiation, providing clear readouts for functional studies. This article integrates the QuickGO definition of GO:0006105 with verified PubMed literature to summarize the mechanism, key genes, disease relevance, and research methods for succinate metabolic process. It is intended for scientists designing CRISPR knockout, knock-in, or overexpression experiments, as well as for computational biologists interpreting metabolic and transcriptomic data in the context of this GO term.
succinate metabolic process At A Glance
| GO ID | GO:0006105 |
|---|---|
| GO term | succinate metabolic process |
| Ontology | biological_process |
| Synonym | succinate metabolism |
| Definition | The chemical reactions and pathways involving succinate, also known as butanedioate or ethane dicarboxylate, the dianion of succinic acid. Succinate is an important intermediate in metabolism and a component of the TCA cycle. |
| Major function | Production, oxidation, and interconversion of succinate as a TCA cycle intermediate and signaling metabolite |
| Key enzyme | Succinate dehydrogenase (SDH), which oxidizes succinate to fumarate in the TCA cycle and respiratory chain |
| Related metabolite | Itaconate, which inhibits SDH and links succinate metabolism to macrophage inflammation |
| Disease relevance | Inflammation, cancer, and liver diseases such as NAFLD and hepatocellular carcinoma |
What Is GO:0006105?
GO:0006105 succinate metabolic process is defined by QuickGO as the chemical reactions and pathways involving succinate, also known as butanedioate or ethane dicarboxylate, the dianion of succinic acid. Succinate is an important intermediate in metabolism and a component of the TCA cycle. In practice, this term covers enzymatic reactions that produce, consume, or interconvert succinate, including its oxidation to fumarate by succinate dehydrogenase and its formation from succinyl-CoA or other precursors.
Why Is succinate metabolic process Important in Cell Biology?
Succinate metabolic process is important because succinate is both a central TCA cycle intermediate and a signaling molecule that regulates immune responses, inflammation, and tumor progression. Dysregulation of succinate metabolism has been linked to macrophage activation, inflammatory diseases, and liver pathologies, making GO:0006105 a high-value target for mechanistic and translational research.
• Succinate is a key TCA cycle intermediate that connects oxidative phosphorylation to biosynthetic pathways.
• Succinate accumulation stabilizes HIF-1alpha and promotes a proinflammatory macrophage phenotype.
• Itaconate inhibits succinate dehydrogenase, directly linking succinate metabolism to anti-inflammatory responses.
• Succinate acts as a cytokine-like metabolite that can be sensed by immune cells.
• Succinate signaling is implicated in liver diseases, including NAFLD and hepatocellular carcinoma.
• Succinate dehydrogenase mutations and succinate accumulation are relevant to cancer metabolism and hereditary paraganglioma/pheochromocytoma.
• Metabolic engineering of succinate production in E. coli highlights its industrial and biotechnological importance.
• In vivo tracing of itaconate and succinate reveals degradation pathways and turnover kinetics relevant to metabolic modeling.
• Succinate metabolism is a tractable target for CRISPR-based functional genomics in immunometabolism.
What Happens During succinate metabolic process?
Succinate formation from succinyl-CoA and other precursors
In simple terms: Succinate is made when succinyl-CoA loses its CoA group.
In the TCA cycle, succinyl-CoA is converted to succinate by succinyl-CoA synthetase, generating GTP or ATP. Succinate can also be produced from other sources, including the glyoxylate cycle and amino acid catabolism. This step is a major entry point for succinate into the TCA cycle and is tightly coupled to cellular energy status.
Succinate oxidation by succinate dehydrogenase (SDH)
In simple terms: SDH converts succinate into fumarate while feeding electrons into the respiratory chain.
Succinate dehydrogenase (SDH), also known as complex II of the electron transport chain, oxidizes succinate to fumarate. This reaction is unique because it directly links the TCA cycle to oxidative phosphorylation. Inhibition of SDH by itaconate or other factors causes succinate accumulation, which can then act as a signaling molecule.
Succinate accumulation and signaling
In simple terms: When succinate builds up, it can send signals inside and outside the cell.
Succinate accumulation inhibits prolyl hydroxylases, stabilizing HIF-1alpha and driving expression of glycolytic and inflammatory genes. Succinate can also be secreted and act on neighboring cells via receptors such as SUCNR1, contributing to cytokine-like signaling. These signaling roles connect GO:0006105 to immune regulation and inflammation.
Itaconate-mediated regulation of succinate metabolism
In simple terms: Itaconate is a metabolite that puts the brakes on succinate oxidation.
Itaconate, produced from cis-aconitate in activated macrophages, inhibits succinate dehydrogenase. This inhibition leads to succinate accumulation and contributes to metabolic remodeling and anti-inflammatory effects. The interplay between itaconate and succinate is a paradigm for how metabolites regulate immune cell function.
Succinate turnover and degradation pathways
In simple terms: Succinate is not static; it is continuously made and broken down.
In vivo tracing studies have revealed that itaconate and succinate have distinct turnover kinetics and degradation pathways. Understanding these fluxes is essential for modeling succinate metabolic process in health and disease. Flux analysis in E. coli has also been used to optimize non-growth-associated succinate production, demonstrating the biotechnological relevance of this pathway.
Key Genes Involved in GO:0006105 succinate metabolic process
The following genes and proteins are central to succinate metabolic process, based on their roles in succinate production, oxidation, transport, and signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SDHA | Subunit A of succinate dehydrogenase, catalyzes succinate oxidation | Mutations cause SDH-deficient tumors; target for metabolic studies |
| SDHB | Subunit B of succinate dehydrogenase, iron-sulfur cluster | Mutations linked to paraganglioma and pheochromocytoma |
| SDHC | Subunit C of succinate dehydrogenase, membrane anchor | Component of complex II; relevant to mitochondrial respiration |
| SDHD | Subunit D of succinate dehydrogenase, membrane anchor | Mutations associated with hereditary paraganglioma |
| SUCLA2 | Succinyl-CoA synthetase, beta subunit, produces succinate | Mitochondrial DNA depletion syndromes; TCA cycle flux |
| SUCLG1 | Succinyl-CoA synthetase, alpha subunit | Encephalomyopathy; succinate production |
| SUCLG2 | Succinyl-CoA synthetase, GTP-specific beta subunit | TCA cycle anaplerosis |
| ACO2 | Aconitase, converts citrate to isocitrate in TCA cycle | Indirectly affects succinate levels |
| IDH2 | Isocitrate dehydrogenase 2, produces alpha-ketoglutarate | Links to succinate via TCA cycle |
| FH | Fumarate hydratase, converts fumarate to malate | Mutations cause fumarate accumulation and affect succinate |
| MDH2 | Malate dehydrogenase, converts malate to oxaloacetate | TCA cycle enzyme affecting succinate flux |
| IRG1 | Produces itaconate, which inhibits SDH | Key regulator of succinate accumulation in macrophages |
| HIF1A | Transcription factor stabilized by succinate | Mediates succinate signaling in inflammation and cancer |
| SUCNR1 | Succinate receptor | Mediates extracellular succinate signaling |
| PHD1/EGLN2 | Prolyl hydroxylase, inhibited by succinate | Links succinate to HIF stabilization |
| PHD2/EGLN1 | Prolyl hydroxylase, inhibited by succinate | Oxygen sensing and succinate signaling |
| PHD3/EGLN3 | Prolyl hydroxylase, inhibited by succinate | Regulates HIF and immune responses |
How Is succinate metabolic process Regulated?
Succinate metabolic process is regulated at multiple levels. Succinate dehydrogenase activity is inhibited by itaconate, leading to succinate accumulation and downstream signaling. Hypoxia and mitochondrial dysfunction can also alter succinate levels by affecting electron transport chain activity. In macrophages, succinate accumulation stabilizes HIF-1alpha, which transcriptionally regulates glycolytic and inflammatory genes, creating a feedback loop between metabolism and immune function. Additionally, in vivo tracing has shown that itaconate and succinate turnover are dynamically regulated, with distinct degradation pathways that influence their steady-state levels.
succinate metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SDHA | SDH-deficient paraganglioma/pheochromocytoma | SDHA knockout cell line; succinate measurement |
| SDHB | Hereditary paraganglioma and pheochromocytoma | SDHB knockout in chromaffin cells; HIF-1alpha reporter |
| IRG1 | Inflammation and macrophage polarization | IRG1 knockout macrophages; itaconate and succinate levels |
| HIF1A | Inflammation and cancer | HIF1A knockout; hypoxia response assays |
| SUCNR1 | Metabolic and inflammatory signaling | SUCNR1 knockout; succinate stimulation |
Succinate metabolism in inflammation and immunity
Succinate accumulation in activated macrophages promotes a proinflammatory state by stabilizing HIF-1alpha and inducing IL-1beta. Itaconate, produced by IRG1, inhibits SDH and limits succinate oxidation, acting as a negative feedback regulator. Dysregulation of this axis is implicated in inflammatory diseases such as sepsis and autoimmune conditions.
Succinate metabolism in cancer
Mutations in SDH subunits (SDHA, SDHB, SDHC, SDHD) lead to succinate accumulation, which inhibits prolyl hydroxylases and stabilizes HIF-1alpha, promoting tumorigenesis. Succinate is considered an oncometabolite in SDH-deficient tumors, including paragangliomas and pheochromocytomas. This links GO:0006105 directly to cancer metabolism and targeted therapies.
Succinate metabolism in liver diseases
Succinate has been increasingly recognized as a signaling molecule in liver diseases, including nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma. Succinate levels and signaling pathways are altered in these conditions, suggesting that targeting succinate metabolism could have therapeutic potential.
From succinate metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SDH subunit increase succinate levels? | SDHA/SDHB knockout cell lines |
| Does a point mutation in SDH affect enzyme activity? | SDHB point-mutation knock-in cells |
| Does tagging SDHA affect complex II assembly? | SDHA tagged knock-in |
| Does overexpression of IRG1 alter succinate metabolism? | IRG1 overexpression in macrophages |
| Does SUCNR1 mediate succinate signaling? | SUCNR1 knockout or overexpression |
| Can metabolic engineering increase succinate production? | E. coli flux solution space models |
How to Study the succinate metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Succinate and TCA cycle intermediate levels | Quantify succinate accumulation |
| Stable isotope tracing | Flux through succinate metabolic process | In vivo turnover kinetics |
| CRISPR knockout screening | Genes required for succinate regulation | Identify novel regulators |
| RNA-seq | Transcriptional response to succinate | HIF-1alpha target genes |
| Proteomics | Protein expression and modifications | SDH complex assembly |
| SDH activity assay | Enzyme activity of succinate dehydrogenase | Functional validation of mutations |
| HIF-1alpha reporter assay | HIF-1alpha stabilization | Succinate signaling |
| Seahorse respirometry | Mitochondrial respiration | Complex II function |
Metabolomics and flux analysis
Mass spectrometry-based metabolomics is used to quantify succinate and related TCA cycle intermediates. Stable isotope tracing can measure flux through succinate metabolic process, as demonstrated in in vivo itaconate tracing studies. These methods are essential for linking genotype to metabolic phenotype.
CRISPR screening and functional genomics
Genome-wide CRISPR knockout screens can identify genes that regulate succinate levels or succinate-dependent phenotypes. Such screens are particularly useful for discovering novel regulators of SDH activity or succinate signaling in immune cells.
Transcriptomics and proteomics
RNA-seq and proteomics can reveal how succinate accumulation affects gene expression, including HIF-1alpha target genes. These approaches help define the downstream consequences of altered succinate metabolic process.
Biochemical enzyme assays
Direct measurement of succinate dehydrogenase activity in cell lysates or isolated mitochondria provides a functional readout of succinate oxidation. Such assays are often combined with genetic manipulation of SDH subunits.
How CRISPR Can Be Used to Study GO:0006105 succinate metabolic process
Knockout
CRISPR knockout of SDH subunits (SDHA, SDHB, SDHC, SDHD) or IRG1 can be used to study loss-of-function effects on succinate levels and downstream signaling. These models are valuable for understanding SDH-deficient tumors and macrophage polarization.
Point Mutation
Point mutations in SDH genes, such as those found in hereditary paraganglioma, can be introduced using CRISPR base editing or HDR to study their impact on enzyme activity and succinate accumulation.
Knock-in
Knock-in of tagged SDHA or HIF1A reporters allows live-cell imaging and biochemical purification of succinate metabolism complexes. This approach helps dissect protein-protein interactions and subcellular localization.
Overexpression
Overexpression of IRG1 or SUCNR1 can be achieved by CRISPR-mediated knock-in of a strong promoter or by lentiviral delivery. These models are useful for studying the effects of increased itaconate production or succinate signaling.
How EDITGENE Supports succinate metabolic process Research
Researchers studying succinate metabolic process-related genes often need to determine whether a candidate gene is causally involved in succinate production, oxidation, or signaling. This requires precise genetic models that can isolate the contribution of individual genes to the pathway. EDITGENE provides a comprehensive suite of CRISPR-based services to support such studies, from knockout to knock-in and overexpression, along with library screening and bioinformatics.
Contact EDITGENE today to design your custom CRISPR model for succinate metabolic process research.
Frequently Asked Questions About succinate metabolic process
What is succinate metabolic process?
Succinate metabolic process (GO:0006105) is the set of chemical reactions and pathways involving succinate, a TCA cycle intermediate and signaling molecule.
What genes are involved in succinate metabolic process?
Key genes include SDHA, SDHB, SDHC, SDHD, SUCLA2, SUCLG1, SUCLG2, IRG1, HIF1A, and SUCNR1.
How is succinate produced in cells?
Succinate is produced from succinyl-CoA by succinyl-CoA synthetase and from other precursors in the TCA cycle.
What is the role of succinate dehydrogenase in succinate metabolism?
Succinate dehydrogenase (SDH) oxidizes succinate to fumarate, linking the TCA cycle to the electron transport chain.
How does itaconate affect succinate metabolism?
Itaconate inhibits succinate dehydrogenase, causing succinate accumulation and modulating macrophage inflammation.
Why is succinate considered a signaling molecule?
Succinate can stabilize HIF-1alpha and activate SUCNR1, acting as a cytokine-like metabolite.
What diseases are linked to succinate metabolism?
Succinate metabolism is linked to inflammation, cancer (e.g., SDH-deficient tumors), and liver diseases such as NAFLD.
How can I study succinate metabolic process in the lab?
Use metabolomics, stable isotope tracing, CRISPR knockout of SDH genes, and HIF-1alpha reporter assays.
What CRISPR models are available for succinate metabolism research?
Knockout, point mutation, knock-in, and overexpression models for genes like SDHA, SDHB, IRG1, and SUCNR1.
What is the GO ID for succinate metabolic process?
The GO ID is GO:0006105.
Conclusion
Succinate metabolic process (GO:0006105) is a fundamental biological process that bridges energy metabolism, immune signaling, and disease. The interplay between succinate, SDH, and itaconate has emerged as a paradigm for metabolite-driven regulation of inflammation and cancer. Understanding this pathway requires integrated approaches, from CRISPR-based genetic models to metabolomics and flux analysis. EDITGENE provides the tools and expertise to accelerate research on succinate metabolic process, from gene knockout to library screening and bioinformatics.
References
- 1. Lampropoulou V et al.. 2016. Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation.. Cell Metab 24(1):158-66 PMID: 27374498
- 2. Pålsson-McDermott EM et al.. 2025. Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.. Cell Metab 37(5):1049-1059 PMID: 40169002
- 3. Ryan DG et al.. 2019. Coupling Krebs cycle metabolites to signalling in immunity and cancer.. Nat Metab 1:16-33 PMID: 31032474
- 4. Willenbockel HF et al.. 2025. In vivo itaconate tracing reveals degradation pathway and turnover kinetics.. Nat Metab 7(9):1781-1790 PMID: 40931213
- 5. Nonnenmacher Y et al.. 2018. Biochemistry of proinflammatory macrophage activation.. Cell Mol Life Sci 75(12):2093-2109 PMID: 29502308
- 6. Zasłona Z et al.. 2020. Cytokine-like Roles for Metabolites in Immunity.. Mol Cell 78(5):814-823 PMID: 32333837
- 7. Chen H et al.. 2024. Succinate as a signaling molecule in the mediation of liver diseases.. Biochim Biophys Acta Mol Basis Dis 1870(2):166935 PMID: 37976628
- 8. Toya Y et al.. 2022. Metabolic pathway engineering for the non-growth-associated succinate production in Escherichia coli based on flux solution space.. J Biosci Bioeng 134(1):29-33 PMID: 35545466
