GO:0008177 succinate dehydrogenase (quinone) activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0008177 succinate dehydrogenase (quinone) activity catalyzes the oxidation of succinate to fumarate while reducing a quinone to a quinol.
• This activity is the only membrane-bound step of the tricarboxylic acid cycle and directly links the TCA cycle to the respiratory electron transport chain.
• The enzyme is a member of the succinate:quinone oxidoreductase superfamily, which includes canonical succinate dehydrogenases and fumarate reductases.
• In mammalian mitochondria, reverse succinate dehydrogenase activity can use fumarate as a terminal electron acceptor under hypoxia, a process relevant to ischemia and cancer [2,8].
• Succinate dehydrogenase (quinone) activity is a target of agricultural fungicides and is implicated in oxidative stress, metabolic disease, and tumor metabolism [4,6,7].
• Studying this activity requires integrating genetic, biochemical, and structural approaches, including CRISPR knockout and point-mutation models [1,5].
Description
Succinate dehydrogenase (quinone) activity, encoded by the Gene Ontology term GO:0008177, is a molecular function that couples the oxidation of succinate to the reduction of a quinone. This reaction is central to both the tricarboxylic acid (TCA) cycle and the respiratory electron transport chain, making it a key node in cellular energy metabolism. The enzyme responsible, succinate dehydrogenase (SDH) or succinate:quinone oxidoreductase (SQR), is found in bacteria, archaea, and eukaryotes, and its dysfunction has been linked to a wide range of physiological and pathological states. In mammalian mitochondria, SDH is also known as complex II of the electron transport chain, and its activity can be reversed under certain conditions to use fumarate as a terminal electron acceptor. This reverse activity is particularly relevant in ischemia, where succinate accumulation drives mitochondrial injury upon reperfusion. Additionally, succinate dehydrogenase (quinone) activity is a target of fungicides and is involved in oxidative stress responses, as shown in human keratinocytes exposed to PCB3-quinone [4,6]. Understanding the molecular details, regulation, and disease relevance of GO:0008177 is therefore essential for researchers in metabolism, cancer biology, and infectious disease [5,7].
succinate dehydrogenase (quinone) activity At A Glance
| GO ID | GO:0008177 |
|---|---|
| GO term | succinate dehydrogenase (quinone) activity |
| Ontology | molecular_function |
| Definition | Catalysis of the reaction: a quinone + succinate = a quinol + fumarate. |
| Synonym | succinate dehydrogenase (ubiquinone) activity; succinate dehydrogenase (menaquinone); fumarate reductase (menaquinone); succinic dehydrogenase activity |
| Major function | Oxidation of succinate to fumarate with concomitant reduction of quinone to quinol, linking TCA cycle to respiratory chain. |
| Cofactors | FAD, iron-sulfur clusters, heme (in some variants) |
| Subcellular location | Inner mitochondrial membrane (eukaryotes), cytoplasmic membrane (prokaryotes) |
| EC number | 1.3.5.1 (succinate dehydrogenase (quinone)) |
What Is GO:0008177?
GO:0008177 succinate dehydrogenase (quinone) activity is defined as the catalysis of the reaction: a quinone + succinate = a quinol + fumarate. In this reaction, succinate is oxidized to fumarate, and a quinone is reduced to a quinol. The enzyme uses a flavin adenine dinucleotide (FAD) cofactor and iron-sulfur clusters to transfer electrons from succinate to the quinone. This activity is synonymous with succinate dehydrogenase (ubiquinone) activity, succinate dehydrogenase (menaquinone), fumarate reductase (menaquinone), and succinic dehydrogenase activity, reflecting variations in the quinone substrate and directionality across species.
Why Is succinate dehydrogenase (quinone) activity Important in Cell Biology?
Succinate dehydrogenase (quinone) activity is a critical intersection between the TCA cycle and oxidative phosphorylation, and its dysfunction has profound metabolic consequences. In mammals, reverse SDH activity can act as a terminal electron acceptor for fumarate, a mechanism that supports mitochondrial function under hypoxia and contributes to ischemia-reperfusion injury [2,8]. The enzyme is also a source of reactive oxygen species, and its inhibition or altered activity is linked to oxidative stress and toxicity. In cancer, succinate dehydrogenase mutations lead to succinate accumulation, which can act as an oncometabolite and drive tumorigenesis. Furthermore, succinate dehydrogenase (quinone) activity is the target of agricultural fungicides, highlighting its broader biological and economic importance. Understanding this activity is therefore essential for developing therapeutic strategies against metabolic diseases, cancer, and infections [5,7].
• Links the TCA cycle to the electron transport chain, enabling efficient ATP production.
• Reverse activity uses fumarate as a terminal electron acceptor, protecting cells under hypoxia.
• Succinate accumulation during ischemia drives reperfusion injury, making SDH a therapeutic target.
• Mutations in SDH subunits cause hereditary paragangliomas and pheochromocytomas.
• SDH inhibition by PCB3-quinone induces oxidative stress in human keratinocytes.
• Mycobacterial SDH variants show alternate quinone coupling, relevant for drug development.
• SDH inhibitors are used as fungicides against plant pathogens like Eastern filbert blight.
• Autophagy deficiency alters mitochondrial DNA segregation and may impact SDH function.
• SDH activity is a biomarker for mitochondrial function in metabolic research.
• CRISPR screens targeting SDH genes can reveal metabolic vulnerabilities in cancer.
Mechanism, Genes and Research Methods
What Happens During succinate dehydrogenase (quinone) activity?
In simple terms: The enzyme takes electrons from succinate and hands them to a quinone, turning succinate into fumarate and quinone into quinol.
The catalytic cycle begins with the binding of succinate to the flavoprotein subunit, where FAD accepts a hydride ion, oxidizing succinate to fumarate. The reduced FAD then transfers electrons through a chain of iron-sulfur clusters to the membrane-bound quinone, reducing it to quinol. This reaction is reversible, and under certain conditions, the enzyme can operate in reverse, using fumarate as an electron acceptor and succinate as a product. In mammalian mitochondria, reverse SDH activity is favored during hypoxia or ischemia, leading to succinate accumulation. The quinone substrate varies by organism; mammalian SDH uses ubiquinone, while some bacteria use menaquinone.
Structural Organization of the Enzyme
In simple terms: The enzyme is made of four main protein parts that work together to move electrons from succinate to quinone.
Succinate dehydrogenase (quinone) is composed of four subunits: a flavoprotein (SDHA), an iron-sulfur protein (SDHB), and two membrane-anchoring subunits (SDHC and SDHD). SDHA contains the FAD cofactor and the succinate binding site, while SDHB houses three iron-sulfur clusters that mediate electron transfer. SDHC and SDHD form the membrane domain that binds quinone and contains a heme group in some organisms. In Escherichia coli, the enzyme can be a monomer or dimer, and in some epsilon-proteobacteria, it adopts a unique architecture. The assembly of these subunits is tightly regulated and requires dedicated assembly factors.
Molecular Mechanism and Cofactors
In simple terms: The enzyme uses a vitamin-derived molecule (FAD) and iron-sulfur clusters to shuttle electrons from succinate to quinone.
The flavoprotein subunit SDHA binds FAD covalently or non-covalently, depending on the organism. Succinate is oxidized at the FAD site, and the electrons are transferred via a chain of [2Fe-2S], [4Fe-4S], and [3Fe-4S] clusters in SDHB to the quinone binding site in SDHC/SDHD. The quinone is reduced to quinol, which then diffuses into the membrane. In some bacteria, the enzyme can also reduce menaquinone, and the reverse reaction (fumarate reduction) is important for anaerobic respiration. The heme group in SDHD may modulate electron transfer or serve a structural role.
Regulation of Succinate Dehydrogenase Activity
In simple terms: The enzyme's activity can be turned up or down by changes in gene expression, post-translational modifications, and the availability of substrates.
Succinate dehydrogenase (quinone) activity is regulated at multiple levels. Transcriptional regulation of SDH subunits responds to metabolic demands and hypoxia. Post-translational modifications, such as phosphorylation and acetylation, can modulate enzyme activity. The availability of succinate and quinone substrates also influences flux through the reaction. In cancer, mutations in SDH genes lead to loss of activity and succinate accumulation, which inhibits prolyl hydroxylases and stabilizes HIF-1α. Additionally, reverse SDH activity is favored when the proton motive force is high and oxygen is limited, as seen in ischemia [2,8].
Key Genes Involved in GO:0008177 succinate dehydrogenase (quinone) activity
The following genes encode subunits, assembly factors, and regulatory proteins associated with succinate dehydrogenase (quinone) activity.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SDHA | Flavoprotein subunit; binds FAD and succinate | Mutations cause Leigh syndrome and paragangliomas; target for cancer metabolism studies |
| SDHB | Iron-sulfur subunit; transfers electrons to quinone | Mutations linked to pheochromocytoma and paraganglioma; biomarker for SDH loss |
| SDHC | Membrane anchor; binds quinone | Mutations associated with paragangliomas; involved in assembly |
| SDHD | Membrane anchor; contains heme | Mutations cause hereditary paragangliomas; imprinting effects |
| SDHAF1 | Assembly factor for SDHB | Mutations cause infantile leukoencephalopathy |
| SDHAF2 | Assembly factor for SDHA flavinylation | Mutations linked to paragangliomas |
| SDHAF3 | Assembly factor for SDHA | Required for SDH assembly and function |
| SDHAF4 | Assembly factor for SDHB | Facilitates iron-sulfur cluster insertion |
| FH | Fumarase; converts fumarate to malate | Mutations cause hereditary leiomyomatosis and renal cell cancer; interacts with SDH |
| UQCRFS1 | Rieske iron-sulfur protein of complex III | Interacts with SDH in respiratory chain |
| NDUFS1 | Complex I subunit | Cross-talk with SDH in mitochondrial respiration |
| HIF1A | Hypoxia-inducible factor 1-alpha | Stabilized by succinate accumulation; links SDH to cancer |
| EPAS1 | Endothelial PAS domain protein 1 | Hypoxia response; affected by SDH dysfunction |
| MTOR | Mechanistic target of rapamycin | Regulates mitochondrial metabolism including SDH |
| PPARGC1A | PGC-1α; mitochondrial biogenesis regulator | Controls SDH expression |
| SIRT3 | NAD-dependent deacetylase | Deacetylates SDHA and regulates activity |
| TP53 | Tumor suppressor | Regulates SDH expression and mitochondrial function |
| MYC | Oncogene | Drives SDH expression in cancer |
How Is succinate dehydrogenase (quinone) activity Regulated?
Succinate dehydrogenase (quinone) activity is regulated by transcriptional, post-translational, and metabolic mechanisms. Hypoxia induces the expression of SDH subunits through HIF-independent pathways, while succinate accumulation inhibits prolyl hydroxylases and stabilizes HIF-1α, creating a feedback loop [7,8]. Post-translational modifications such as acetylation by SIRT3 and phosphorylation by kinases modulate enzyme activity. The availability of quinone and succinate, as well as the proton motive force, determines the direction of the reaction. In ischemia, reverse SDH activity is favored, leading to succinate accumulation that drives reperfusion injury. Autophagy deficiency can also affect mitochondrial DNA segregation and indirectly influence SDH function.
succinate dehydrogenase (quinone) activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SDHB | Paraganglioma, pheochromocytoma | SDHB knockout cell line; xenograft mouse model |
| SDHD | Hereditary paraganglioma | SDHD point-mutation knock-in mice |
| SDHA | Leigh syndrome, paraganglioma | SDHA knockout iPSCs; neuronal differentiation |
| FH | Hereditary leiomyomatosis and renal cell cancer | FH knockout cell line; metabolic profiling |
| HIF1A | Hypoxia-driven tumors | HIF1A overexpression in SDH-deficient cells |
Succinate Dehydrogenase and Cancer
Mutations in SDH subunits (SDHA, SDHB, SDHC, SDHD) and assembly factors (SDHAF2) cause hereditary paragangliomas and pheochromocytomas. Loss of SDH activity leads to succinate accumulation, which acts as an oncometabolite by inhibiting prolyl hydroxylases, stabilizing HIF-1α, and promoting tumorigenesis. In colorectal cancers, an iron-addicted heme-complex II axis exploits SDH to resist oxidative cell death, suggesting therapeutic opportunities. Additionally, SDH dysfunction is linked to gastrointestinal stromal tumors and renal cell carcinoma.
Ischemia-Reperfusion Injury
During ischemia, reverse succinate dehydrogenase activity uses fumarate as a terminal electron acceptor, leading to succinate accumulation [2,8]. Upon reperfusion, succinate is rapidly oxidized by complex I, driving reverse electron transport and reactive oxygen species production, which contributes to tissue damage. This mechanism is relevant to myocardial infarction, stroke, and organ transplantation.
Oxidative Stress and Toxicity
Succinate dehydrogenase activity regulates PCB3-quinone-induced metabolic oxidative stress in human keratinocytes. Inhibition or dysregulation of SDH can lead to increased reactive oxygen species, contributing to cellular toxicity and skin damage. This highlights the enzyme's role in environmental toxicology and dermatology.
Infectious Disease and Fungicides
Mycobacterial succinate dehydrogenase variants with alternate quinone coupling may potentiate respiratory control, making them potential drug targets for tuberculosis. In agriculture, SDH inhibitors are used as fungicides against pathogens like Eastern filbert blight, demonstrating the enzyme's importance beyond human health.
From succinate dehydrogenase (quinone) activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SDH activity cause succinate accumulation? | SDHA/B/C/D knockout cell lines |
| How does reverse SDH activity contribute to ischemia? | In vivo ischemia-reperfusion mouse model with SDH point mutations |
| What is the role of SDH assembly factors? | SDHAF1/2 knockout and knock-in models |
| Can SDH be targeted in cancer? | Patient-derived xenografts with SDH mutations |
| How does SDH activity affect oxidative stress? | CRISPR knockout of SDH in keratinocytes followed by PCB3-quinone treatment |
| What is the structural basis of quinone binding? | Point mutations in SDHC/SDHD quinone binding site |
How to Study the succinate dehydrogenase (quinone) activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| DCPIP reduction assay | SDH activity via quinone reduction | Screening inhibitors; validating knockout lines |
| Fumarate reduction assay | Reverse SDH activity | Ischemia-reperfusion studies |
| Metabolomics (LC-MS) | Succinate, fumarate, and TCA intermediates | Cancer metabolism; SDH mutation phenotyping |
| CRISPR knockout | Loss of SDH subunit expression | Functional studies; drug resistance |
| Site-directed mutagenesis | Specific amino acid function | Catalytic mechanism; disease variant modeling |
| Cryo-EM | 3D structure of SDH complexes | Inhibitor design; assembly studies |
| Proteomics | Protein interactions and modifications | Regulation; assembly factor identification |
Biochemical Assays for SDH Activity
Succinate dehydrogenase (quinone) activity is commonly measured using spectrophotometric assays that monitor the reduction of artificial quinone acceptors, such as dichlorophenolindophenol (DCPIP) or ubiquinone analogs. These assays can be performed on isolated mitochondria, permeabilized cells, or purified enzyme preparations. The reverse reaction can be measured by following fumarate reduction using reduced quinols. These methods are essential for validating genetic models and screening inhibitors.
Genetic and CRISPR Approaches
CRISPR-Cas9 knockout of SDH subunits or assembly factors allows researchers to study loss-of-function phenotypes, including succinate accumulation and metabolic rewiring. Point mutations can be introduced to mimic disease-associated variants or to dissect catalytic residues. Knock-in of tagged SDH subunits enables affinity purification and interaction studies. Overexpression models help assess gain-of-function effects and rescue experiments.
Metabolic and Proteomic Profiling
Metabolomics by mass spectrometry quantifies succinate, fumarate, and other TCA cycle intermediates in SDH-mutant cells. Proteomics can identify post-translational modifications and interaction partners of SDH subunits. These approaches reveal how SDH activity integrates with cellular metabolism and signaling.
Imaging and Structural Biology
Fluorescence microscopy with targeted biosensors can monitor mitochondrial quinone redox state and SDH flux in live cells. Cryo-electron microscopy and X-ray crystallography provide high-resolution structures of SDH in different conformational states, informing inhibitor design. These methods are critical for understanding the molecular mechanism of GO:0008177.
How CRISPR Can Be Used to Study GO:0008177 succinate dehydrogenase (quinone) activity
Knockout
CRISPR knockout of SDHA, SDHB, SDHC, or SDHD generates cell lines with complete loss of succinate dehydrogenase (quinone) activity. These models are used to study succinate accumulation, HIF-1α stabilization, and metabolic reprogramming in cancer. Knockout of assembly factors like SDHAF2 also abolishes activity, providing insights into enzyme maturation.
Point Mutation
Point mutations can be introduced into SDH genes to mimic disease-associated variants, such as SDHB mutations found in paragangliomas. These models help dissect the catalytic mechanism and identify residues critical for quinone binding or electron transfer. Point mutations in the quinone binding site of SDHC/SDHD can alter inhibitor sensitivity.
Knock-in
Knock-in of tagged SDH subunits (e.g., HA or GFP) allows for affinity purification and live-cell imaging of the enzyme. Knock-in of reporter genes under the SDH promoter enables tracking of expression dynamics. These models are valuable for studying assembly and subcellular localization.
Overexpression
Overexpression of wild-type or mutant SDH subunits can rescue loss-of-function phenotypes or induce gain-of-function effects. Overexpression models are used to study the impact of SDH activity on oxidative stress and cell survival. They also facilitate structural and biochemical studies requiring large amounts of protein.
How EDITGENE Supports succinate dehydrogenase (quinone) activity Research
Researchers studying succinate dehydrogenase (quinone) activity-related genes often need to determine whether a candidate gene is causally involved in metabolic regulation, disease progression, or drug response. EDITGENE provides comprehensive CRISPR-based services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for succinate dehydrogenase (quinone) activity research.
Frequently Asked Questions About succinate dehydrogenase (quinone) activity
What is succinate dehydrogenase (quinone) activity?
It is the enzymatic activity defined by GO:0008177 that catalyzes the oxidation of succinate to fumarate while reducing a quinone to a quinol.
What genes are involved in succinate dehydrogenase (quinone) activity?
The main genes are SDHA, SDHB, SDHC, and SDHD, which encode the four subunits of the enzyme, along with assembly factors like SDHAF1 and SDHAF2.
What is the role of succinate dehydrogenase in the TCA cycle?
It catalyzes the only membrane-bound step of the TCA cycle, converting succinate to fumarate and feeding electrons into the respiratory chain.
How is succinate dehydrogenase activity measured?
It is typically measured using spectrophotometric assays that monitor the reduction of artificial quinones like DCPIP or ubiquinone analogs.
What diseases are associated with succinate dehydrogenase mutations?
Mutations in SDH genes cause hereditary paragangliomas, pheochromocytomas, and contribute to cancer and ischemia-reperfusion injury [7,8].
Can succinate dehydrogenase work in reverse?
Yes, under hypoxia or ischemia, the enzyme can use fumarate as a terminal electron acceptor, producing succinate [2,8].
What are succinate dehydrogenase inhibitors used for?
They are used as fungicides in agriculture and are being explored as anticancer agents [6,7].
How does succinate dehydrogenase relate to oxidative stress?
Altered SDH activity can increase reactive oxygen species, contributing to cellular toxicity, as seen with PCB3-quinone exposure.
What model systems are used to study succinate dehydrogenase?
Common models include CRISPR knockout cell lines, point-mutation knock-in mice, and purified enzyme preparations [1,5].
Why is succinate dehydrogenase important in cancer?
Loss of SDH activity leads to succinate accumulation, which acts as an oncometabolite and stabilizes HIF-1α, promoting tumorigenesis.
Conclusion
Succinate dehydrogenase (quinone) activity (GO:0008177) is a fundamental molecular function that bridges the TCA cycle and respiratory electron transport. Its reversible nature and central role in metabolism make it a key player in ischemia, cancer, and oxidative stress. Continued research using CRISPR models and biochemical assays will further elucidate its regulation and therapeutic potential.
References
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- 2. Spinelli JB et al.. 2021. Fumarate is a terminal electron acceptor in the mammalian electron transport chain.. Science 374(6572):1227-1237 PMID: 34855504
- 3. Lancaster CR et al.. 2002. Succinate:quinone oxidoreductases from epsilon-proteobacteria.. Biochim Biophys Acta 1553(1-2):84-101 PMID: 11803019
- 4. Xiao W et al.. 2016. Succinate dehydrogenase activity regulates PCB3-quinone-induced metabolic oxidative stress and toxicity in HaCaT human keratinocytes.. Arch Toxicol 90(2):319-32 PMID: 25417049
- 5. Hards K et al.. 2019. Alternate quinone coupling in a new class of succinate dehydrogenase may potentiate mycobacterial respiratory control.. FEBS Lett 593(5):475-486 PMID: 30675730
- 6. Pscheidt JW et al.. 2017. Evaluation of Quinone Outside and Succinate Dehydrogenase Inhibitors for Effectiveness Against Eastern Filbert Blight of Hazelnut.. Plant Dis 101(11):1868-1873 PMID: 30677311
- 7. Jain C et al.. 2026. Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.. Cell Metab 38(8):1599-1617.e8 PMID: 42202783
- 8. Chinopoulos C. 2019. Succinate in ischemia: Where does it come from?. Int J Biochem Cell Biol 115:105580 PMID: 31394174
