GO:1901290 succinyl-CoA biosynthetic process: Mitochondrial Energy Metabolism Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1901290 (succinyl-CoA biosynthetic process) describes the chemical reactions and pathways that form succinyl-CoA, a central mitochondrial acyl-CoA intermediate.
• Succinyl-CoA is produced mainly by the TCA cycle enzyme SUCLG1/SUCLA2/SUCLG2 and by ketone-body breakdown via OXCT1, and it feeds heme synthesis, ketolysis, and protein succinylation.
• Succinyl-CoA serves as a substrate for histone and non-histone protein succinylation, directly linking mitochondrial metabolism to chromatin regulation and gene expression.
• Dysregulated succinyl-CoA metabolism is implicated in chronic heart failure, leukemia progression, liver tumor growth, antibiotic resistance, and glioma.
• Key experimental models include SUCLG1, SUCLA2, SUCLG2, OXCT1, and KAT2A knockout, point-mutation, knock-in, and overexpression cell lines.
• CRISPR-based knockout, point-mutation, knock-in, overexpression, and library screening enable causal dissection of succinyl-CoA biosynthetic process in disease models.
Description
GO:1901290, succinyl-CoA biosynthetic process, is a biological_process term in the Gene Ontology that covers the chemical reactions and pathways resulting in the formation of succinyl-CoA. Succinyl-CoA is a four-carbon thioester of coenzyme A that sits at the intersection of the tricarboxylic acid (TCA) cycle, ketone-body catabolism, heme biosynthesis, and mitochondrial energy metabolism. Because succinyl-CoA is both an energy intermediate and a donor for protein succinylation, its biosynthesis is now recognized as a signaling node that connects mitochondrial flux to chromatin state and cell fate. Researchers study GO:1901290 because succinyl-CoA levels influence histone succinylation, mitochondrial biogenesis, ketolysis, and resource allocation during stress. In cancer, nuclear GTPSCS can act as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis, showing that succinyl-CoA pathway enzymes have moonlighting roles beyond the mitochondrion. In chronic heart failure, succinyl-CoA-based energy metabolism dysfunction has been documented, highlighting the pathway as a therapeutic target. This article summarizes the authoritative QuickGO definition, the core enzymatic steps, the genes and proteins involved, disease links, and the CRISPR and multi-omics methods used to interrogate succinyl-CoA biosynthetic process in publication-ready research.
succinyl-CoA biosynthetic process At A Glance
| GO ID | GO:1901290 |
|---|---|
| GO term | succinyl-CoA biosynthetic process |
| Ontology | biological_process |
| Synonym | succinyl-CoA anabolism; succinyl-CoA biosynthesis; succinyl-CoA formation; succinyl-CoA synthesis |
| Major function | Formation of succinyl-CoA, a TCA cycle intermediate and acyl-CoA donor for protein succinylation |
| Compartment | Mitochondrial matrix (canonical), with nuclear pools reported for GTPSCS |
| Key enzymes | SUCLG1, SUCLA2, SUCLG2, OXCT1, KAT2A-associated complexes |
| Related pathways | TCA cycle, ketone-body catabolism, heme biosynthesis, histone succinylation |
| Disease relevance | Chronic heart failure, leukemia, liver cancer, glioma, antibiotic resistance |
What Is GO:1901290?
According to QuickGO, GO:1901290 succinyl-CoA biosynthetic process is defined as the chemical reactions and pathways resulting in the formation of succinyl-CoA. In practical terms, it encompasses the enzymatic steps that generate succinyl-CoA from substrates such as succinate, succinyl-adenylate intermediates, or ketone bodies, and it is a child of acyl-CoA biosynthetic process and a component of mitochondrial energy metabolism.
Why Is succinyl-CoA biosynthetic process Important in Cell Biology?
Succinyl-CoA biosynthetic process is important because succinyl-CoA is not only a TCA cycle intermediate but also a substrate for lysine succinylation, a post-translational modification that regulates mitochondrial enzymes, chromatin, and metabolic flux. Perturbations in this pathway have been linked to chronic heart failure, leukemia progression, liver tumor growth, and antibiotic resistance, making it a high-value target for mechanistic and therapeutic studies.
• Supplies succinyl-CoA for the TCA cycle and mitochondrial ATP production.
• Provides the succinyl donor for histone H3 succinylation via KAT2A and the alpha-KGDH complex.
• Links mitochondrial metabolism to chromatin regulation and gene expression.
• Supports ketone-body catabolism through OXCT1 and SUCLA2 in liver and other tissues.
• Restricts POLRMT succinylation to modulate mitochondrial biogenesis in leukemia.
• Its dysfunction is observed in chronic heart failure energy metabolism.
• Contributes to antibiotic resistance through metabolism-dependent succinylation.
• Nuclear GTPSCS can promote histone lactylation and gliomagenesis.
• Serves as a target for small-molecule and genetic perturbation in cancer metabolism.
• Enables CRISPR screens to identify metabolic vulnerabilities in disease models.
What Happens During succinyl-CoA biosynthetic process?
Step 1: Substrate supply from the TCA cycle and ketone bodies
In simple terms: The cell first makes or imports the raw materials that will be turned into succinyl-CoA.
Succinyl-CoA biosynthesis draws on TCA cycle intermediates and ketone bodies. In the canonical mitochondrial route, succinyl-CoA is generated from succinate via succinyl-CoA synthetase (SUCLG1 with SUCLA2 or SUCLG2), while ketone-body catabolism via OXCT1 produces succinyl-CoA from acetoacetate-derived intermediates. Compartmentalized acyl-CoA metabolism ensures that these substrates are available for both energy production and post-translational modification.
Step 2: Enzymatic formation of succinyl-CoA
In simple terms: Specific enzymes assemble succinyl-CoA from its building blocks.
The succinyl-CoA synthetase complex, composed of SUCLG1 and either SUCLA2 or SUCLG2, catalyzes the reversible conversion of succinate to succinyl-CoA with concomitant nucleotide triphosphate formation. OXCT1 (SCOT) catalyzes the transfer of CoA from succinyl-CoA to acetoacetate during ketolysis, and SUCLA2 succinylation and activation promotes ketolysis and liver tumor growth. Tartryl-CoA has been shown to inhibit succinyl-CoA synthetase, providing a structural probe of the active site.
Step 3: Succinyl-CoA as a donor for protein succinylation
In simple terms: Succinyl-CoA can donate its succinyl group to proteins, changing their behavior.
Succinyl-CoA serves as the substrate for lysine succinylation of histones and mitochondrial proteins. KAT2A coupled with the alpha-KGDH complex acts as a histone H3 succinyltransferase, directly linking succinyl-CoA availability to chromatin state. Compartmentalized acyl-CoA metabolism therefore determines the local concentration of succinyl-CoA available for chromatin regulation.
Step 4: Downstream use in energy metabolism and mitochondrial biogenesis
In simple terms: The succinyl-CoA made is used to produce energy and to control mitochondrial renewal.
Succinyl-CoA feeds the TCA cycle and supports mitochondrial energy metabolism; its dysfunction has been documented in chronic heart failure. SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression, showing that succinyl-CoA pathway enzymes control mitochondrial gene expression. Metabolism-dependent succinylation also governs resource allocation for antibiotic resistance, linking succinyl-CoA flux to stress adaptation.
Step 5: Nuclear and moonlighting roles of succinyl-CoA pathway enzymes
In simple terms: Some succinyl-CoA enzymes also work in the nucleus and can influence cancer.
Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis, demonstrating that succinyl-CoA pathway enzymes can have nuclear, non-canonical functions. This expands the biological scope of GO:1901290 beyond the mitochondrion and connects it to epigenetic regulation in cancer.
Key Genes Involved in GO:1901290 succinyl-CoA biosynthetic process
The following genes and proteins are central to succinyl-CoA biosynthetic process, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SUCLG1 | Alpha subunit of succinyl-CoA synthetase; restricts POLRMT succinylation | Leukemia progression and mitochondrial biogenesis |
| SUCLA2 | Beta subunit of succinyl-CoA synthetase; succinylation and activation promotes ketolysis | Liver tumor growth and ketone metabolism |
| SUCLG2 | GTP-specific succinyl-CoA synthetase subunit | Mitochondrial acyl-CoA metabolism |
| OXCT1 | Ketone-body catabolism enzyme producing succinyl-CoA | Ketolysis and liver tumor growth |
| KAT2A | Histone H3 succinyltransferase coupled with alpha-KGDH | Chromatin regulation by succinyl-CoA |
| GTPSCS | Nuclear lactyl-CoA synthetase; succinyl-CoA pathway enzyme | Histone lactylation and gliomagenesis |
| POLRMT | Mitochondrial RNA polymerase regulated by succinylation | Mitochondrial biogenesis in leukemia |
| Alpha-KGDH complex | TCA cycle enzyme complex associated with KAT2A | Histone succinylation |
| SUCLA2/SUCLG2 | Nucleotide-specific succinyl-CoA synthetase isoforms | Compartmentalized acyl-CoA metabolism |
| ACAT1 | Mitochondrial acetoacetyl-CoA thiolase in ketone metabolism | Acyl-CoA metabolism |
| HMGCS2 | Ketogenesis enzyme upstream of succinyl-CoA use | Ketone-body metabolism |
| BDH1 | Ketone-body dehydrogenase | Ketolysis and succinyl-CoA production |
| SLC25A | Mitochondrial carrier family for acyl-CoA precursors | Compartmentalized metabolism |
| SDHA | TCA cycle enzyme upstream of succinate | Energy metabolism |
| SDHB | TCA cycle enzyme upstream of succinate | Energy metabolism |
| IDH2 | TCA cycle enzyme contributing to mitochondrial flux | Energy metabolism |
| GLS | Glutaminase supplying TCA cycle anaplerosis | Metabolic flux |
| ACLY | Acetyl-CoA producer influencing acyl-CoA pools | Acyl-CoA metabolism |
How Is succinyl-CoA biosynthetic process Regulated?
Succinyl-CoA biosynthetic process is regulated at multiple levels. Substrate availability from the TCA cycle and ketone bodies controls flux through SUCLG1/SUCLA2/SUCLG2 and OXCT1. Post-translational succinylation of SUCLA2 activates ketolysis and promotes liver tumor growth, creating a feedback loop between succinyl-CoA levels and enzyme activity. SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis, linking succinyl-CoA metabolism to mitochondrial gene expression. Compartmentalized acyl-CoA pools further regulate the availability of succinyl-CoA for chromatin modification. Metabolism-dependent succinylation governs resource allocation for antibiotic resistance, indicating stress-responsive regulation.
succinyl-CoA biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SUCLG1 | Leukemia progression and mitochondrial biogenesis | SUCLG1 knockout and rescue in leukemia cell lines |
| SUCLA2 | Liver tumor growth and ketolysis | SUCLA2 point-mutation and overexpression in liver cancer cells |
| OXCT1 | Ketolysis and liver tumor growth | OXCT1 knockout in hepatoma models |
| GTPSCS | Glioma and histone lactylation | GTPSCS knockout and knock-in in glioma cells |
| KAT2A | Chromatin regulation by succinylation | KAT2A knockout in cancer cell lines |
Succinyl-CoA biosynthetic process in chronic heart failure
Succinyl-CoA-based energy metabolism dysfunction has been reported in chronic heart failure, where impaired mitochondrial energy metabolism contributes to disease progression. This positions succinyl-CoA biosynthetic process as a potential target for metabolic intervention in heart failure.
Succinyl-CoA biosynthetic process in leukemia and mitochondrial biogenesis
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression, demonstrating that succinyl-CoA pathway enzymes can drive cancer cell mitochondrial renewal. This links GO:1901290 to leukemia biology and mitochondrial gene regulation.
Succinyl-CoA biosynthetic process in liver cancer and ketolysis
OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth, showing that succinyl-CoA metabolism supports liver cancer. Targeting this axis may offer therapeutic opportunities.
Succinyl-CoA biosynthetic process in glioma and histone lactylation
Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis, revealing a nuclear role for a succinyl-CoA pathway enzyme in brain tumors. This connects GO:1901290 to epigenetic regulation in glioma.
From succinyl-CoA biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does SUCLG1 loss alter mitochondrial biogenesis? | SUCLG1 knockout cell line |
| Does SUCLA2 succinylation affect ketolysis? | SUCLA2 point-mutation knock-in |
| Does OXCT1 drive liver tumor growth? | OXCT1 knockout mouse xenograft |
| Does GTPSCS promote histone lactylation? | GTPSCS knockout and overexpression in glioma cells |
| Does KAT2A mediate histone H3 succinylation? | KAT2A knockout with succinyl-CoA supplementation |
| Does succinyl-CoA flux affect antibiotic resistance? | Metabolic perturbation in bacterial models |
How to Study the succinyl-CoA biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS metabolomics | Succinyl-CoA and acyl-CoA levels | Flux analysis in knockout cells |
| Succinyl-proteomics | Lysine succinylation sites | Chromatin and mitochondrial regulation |
| RNA-seq | Transcriptional changes | Mitochondrial biogenesis and stress responses |
| Seahorse respirometry | Oxidative phosphorylation | Energy metabolism in heart failure models |
| CRISPR knockout screening | Gene essentiality and fitness | Identifying pathway vulnerabilities |
| Western blot | Protein succinylation and expression | Validation of SUCLG1/SUCLA2 regulation |
| Immunoprecipitation | Protein-protein interactions | KAT2A and alpha-KGDH complex assembly |
| Bioinformatics pathway analysis | Pathway enrichment and networks | Interpreting omics data for GO:1901290 |
Metabolomics and acyl-CoA profiling
Mass spectrometry-based metabolomics quantifies succinyl-CoA and related acyl-CoA species to measure flux through GO:1901290. Compartmentalized acyl-CoA metabolism can be resolved using subcellular fractionation.
Proteomics and succinylome analysis
Succinyl-proteomics identifies lysine succinylation sites on mitochondrial and nuclear proteins, linking succinyl-CoA levels to post-translational regulation. Antibodies against succinyl-lysine enable western blot and immunoprecipitation validation.
Transcriptomics and mitochondrial biogenesis assays
RNA-seq and mitochondrial DNA quantification assess mitochondrial biogenesis downstream of SUCLG1 and POLRMT regulation. Seahorse respirometry measures oxidative phosphorylation capacity.
CRISPR screening and functional genomics
Genome-wide CRISPR knockout and activation screens identify genes that modulate succinyl-CoA biosynthetic process and its disease phenotypes. Library screening with bioinformatics prioritizes metabolic vulnerabilities.
How CRISPR Can Be Used to Study GO:1901290 succinyl-CoA biosynthetic process
Knockout
CRISPR knockout of SUCLG1, SUCLA2, SUCLG2, OXCT1, or KAT2A ablates succinyl-CoA biosynthetic process enzymes and reveals loss-of-function phenotypes in cancer and metabolic models. Knockout cell lines are used to test mitochondrial biogenesis, ketolysis, and histone succinylation.
Point Mutation
Point-mutation knock-in of catalytic residues or succinylation sites in SUCLA2 and SUCLG1 tests whether specific residues are required for enzyme activity and downstream phenotypes. This approach distinguishes catalytic from scaffolding functions.
Knock-in
Knock-in of tagged or mutant alleles enables precise tracking of succinyl-CoA pathway enzymes and their interactions with POLRMT or chromatin complexes. Endogenous tagging supports localization and interaction studies.
Overexpression
Overexpression of SUCLG1, SUCLA2, OXCT1, or GTPSCS tests gain-of-function effects on mitochondrial biogenesis, ketolysis, and histone lactylation. Overexpression models are useful for validating oncogenic roles.
How EDITGENE Supports succinyl-CoA biosynthetic process Research
Researchers studying succinyl-CoA biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in mitochondrial metabolism, chromatin regulation, or disease progression. EDITGENE provides publication-ready CRISPR cell models and screening services to test these hypotheses rigorously.
Contact EDITGENE today to design your custom CRISPR model for succinyl-CoA biosynthetic process research.
Frequently Asked Questions About succinyl-CoA biosynthetic process
What is succinyl-CoA biosynthetic process?
It is the biological process defined by GO:1901290 that covers the chemical reactions and pathways resulting in the formation of succinyl-CoA.
What genes are involved in succinyl-CoA biosynthetic process?
Key genes include SUCLG1, SUCLA2, SUCLG2, OXCT1, and KAT2A, which catalyze succinyl-CoA formation and its use in succinylation.
What is the GO ID for succinyl-CoA biosynthetic process?
The Gene Ontology ID is GO:1901290.
Why is succinyl-CoA important in cancer?
Succinyl-CoA supports mitochondrial biogenesis in leukemia, ketolysis in liver tumors, and histone lactylation in glioma.
How is succinyl-CoA biosynthetic process regulated?
It is regulated by substrate availability, enzyme succinylation, and compartmentalized acyl-CoA pools.
What diseases are linked to succinyl-CoA metabolism?
Chronic heart failure, leukemia, liver cancer, glioma, and antibiotic resistance have been linked to succinyl-CoA pathway dysfunction.
What methods study succinyl-CoA biosynthetic process?
Metabolomics, succinyl-proteomics, RNA-seq, respirometry, and CRISPR screening are commonly used.
Can CRISPR knockout be used to study succinyl-CoA enzymes?
Yes, CRISPR knockout of SUCLG1, SUCLA2, OXCT1, and KAT2A is widely used to dissect pathway function.
What is the role of SUCLG1 in mitochondria?
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
How does succinyl-CoA affect chromatin?
Succinyl-CoA is the substrate for histone H3 succinylation by KAT2A coupled with the alpha-KGDH complex.
Conclusion
GO:1901290 succinyl-CoA biosynthetic process is a central metabolic pathway that produces succinyl-CoA for the TCA cycle, ketolysis, mitochondrial biogenesis, and protein succinylation. Its dysregulation is implicated in chronic heart failure, leukemia, liver cancer, glioma, and antibiotic resistance, making it a high-priority research area. CRISPR-based knockout, point-mutation, knock-in, overexpression, and library screening models, combined with metabolomics and succinyl-proteomics, provide a rigorous framework for causal studies of succinyl-CoA biosynthetic process in human disease.
References
- 1. Liu R et al.. 2025. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.. Cell Metab 37(2):377-394.e9 PMID: 39642882
- 2. Wang Y et al.. 2017. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.. Nature 552(7684):273-277 PMID: 29211711
- 3. Trefely S et al.. 2020. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.. Mol Metab 38:100941 PMID: 32199817
- 4. Takada S et al.. 2022. Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure.. Proc Natl Acad Sci U S A 119(41):e2203628119 PMID: 36201541
- 5. Yan W et al.. 2024. SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.. EMBO J 43(12):2337-2367 PMID: 38649537
- 6. Guo D et al.. 2025. OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth.. Mol Cell 85(4):843-856.e6 PMID: 39862868
- 7. Huang J et al.. 2020. Tartryl-CoA inhibits succinyl-CoA synthetase.. Acta Crystallogr F Struct Biol Commun 76(Pt 7):302-308 PMID: 32627745
- 8. Wu JH et al.. 2025. Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.. Sci Adv 11(34):eadu2856 PMID: 40845110
