SUCCINATE DEHYDROGENASE: STRUCTURE, FUNCTION, REGULATION, DISEASES - BIOLOGY - 2025

S uccinato dehydrogenase (SDH), also known as complex II of the electron transport chain, is a mitochondrial protein complex with enzymatic activity that works both Krebs cycle and the electron transport chain (cellular respiration).

It is an enzyme that is present in all aerobic cells. In eukaryotes it is a complex closely associated with the inner mitochondrial membrane, while in prokaryotes it is found in the plasma membrane.

General scheme of the mitochondrial succinate dehydrogenase complex (Source: Myself, based on Fvasconcellos vectorization. / Public domain, via Wikimedia Commons)

The succinate dehydrogenase complex, discovered around 1910 and first purified in 1954 by Singer and Kearney, has been extensively studied for several reasons:

- works both in the Krebs cycle (citric acid cycle or tricarboxylic acid cycle) and in the electron transport chain (catalyzes the oxidation of succinate to fumarate)

- its activity is regulated by different activators and inhibitors and

- is a complex associated with: iron not bound to a heme group, labile sulfur and flavin adenine dinucleotides (FAD)

It is encoded by the nuclear genome and it has been proven that mutations in the four genes that encode each of its subunits (A, B, C and D) result in various clinical pictures, that is, they can be quite negative from the point of view of the physical integrity of human beings.

Structure

The succinate dehydrogenase enzyme complex is made up of four subunits (heterotetramer) encoded by the nuclear genome, making it the only oxidative phosphorylation complex in the electron transport chain that does not have any subunits encoded by the mitochondrial genome.

Furthermore, this complex is the only one that does not pump protons through the inner mitochondrial membrane during its catalytic action.

According to studies carried out on the basis of the enzymatic complex of porcine heart cells, the succinate dehydrogenase complex consists of:

- a hydrophilic “ head ” that extends from the inner mitochondrial membrane into the mitochondrial matrix and

- a hydrophobic “ tail ” that is embedded in the inner mitochondrial membrane and that has a small segment that projects into the soluble intermembrane space of the mitochondrion

Structure of the succinate dehydrogenase complex (Source: Zephyris at the English language Wikipedia / CC BY-SA (http://creativecommons.org/licenses/by-sa/3.0/) via Wikimedia Commons)

Structure of the hydrophilic portion

The hydrophilic head is composed of the SdhA (70 kDa) and SdhB (27 kDa) subunits (Sdh1 and Sdh2 in yeast) and this comprises the catalytic center of the complex.

The SdhA and SdhB subunits contain redox cofactors that participate in the transfer of electrons towards ubiquinone (coenzyme Q10, a molecule that transports electrons between respiratory complexes I, II and III).

The SdhA subunit has a cofactor FAD (a coenzyme that participates in oxidation-reduction reactions) covalently attached to its structure, right at the binding site for succinate (the main substrate of the enzyme).

The SdhB subunit has 3 iron-sulfur (Fe-S) centers that mediate the transfer of electrons to ubiquinone. One of the centers, 2Fe-2S, is close to the FAD site of the SdhA subunit and the others (4Fe-4S and 3Fe-4S) are adjacent to the first.

Notably, structural studies indicate that the SdhB subunit forms the interface between the hydrophilic catalytic domain and the membrane “anchor” (hydrophobic) domain of the complex.

Structure of the hydrophobic portion

The membrane domain of the complex, as stated, consists of the SdhC (15 kDa) and SdhD (12-13 kDa) subunits (Sdh3 and Sdh4 in yeast), which are integral membrane proteins each formed by 3 transmembrane helices..

This domain contains a heme b portion attached at the interface between the SdhC and SdhD subunits, where each provides one of the two histidine ligands that hold them together.

Two binding sites for ubiquinone have been detected in this enzyme: one with high affinity and the other with low affinity.

The high affinity site, known as Qp (p for proximal) faces the mitochondrial matrix and is made up of specific amino acid residues located in the SdhB, SdhC and SdhD subunits.

The low affinity site, also called Qd (d for distal), is, in the portion of the inner mitochondrial membrane where the complex is inserted, closer to the intermembrane space, that is, further from the organelle matrix.

As a whole, the total complex has a molecular weight close to 200 kDa and has been determined to have a ratio of 4.2-5.0 nanomoles of flavin for each milligram of protein and 2-4 g of iron for each mole of flavin.

Function

The enzymatic complex succinate dehydrogenase plays an important role in the mitochondria, as it not only participates in the Krebs cycle (where it participates in the degradation of acetyl-CoA), but is also part of the respiratory chain, essential for energy production in the form of ATP.

In other words, it is a key enzyme for intermediate metabolism and aerobic ATP production.

- It is responsible for the oxidation of succinate to fumarate in the citric acid cycle

- Feeds complex III of the electron transport chain with electrons derived from the oxidation of succinate, which helps reduce oxygen and form water

- Electron transport generates an electrochemical gradient across the inner mitochondrial membrane, which favors ATP synthesis

Alternatively, electrons can be used to reduce molecules from a ubiquinone pool, producing the reducing equivalents needed to reduce superoxide anions that originate from the same respiratory chain or that come from exogenous sources.

Succinate Dehydrogenase Complex (Source: Johnhfst / Public domain, via Wikimedia Commons)

How does it work?

The A subunit of the complex (the one that is covalently bound to the coenzyme FAD) binds to the substrates, fumarate and succinate, as well as to their physiological regulators, oxaloacetate (competitive inhibitor) and ATP.

ATP displaces the bond between oxaloacetate and the SDH complex and, then, the electrons that are “passed” from succinate to the SdhA subunit are transferred to the iron and sulfur atom groups present in the SdhB subunit through the coenzyme FAD.

From the B subunit, these electrons reach the heme b sites of the SdhC and SdhD subunits, from where they are "delivered" to quinone coenzymes through their quinone binding sites.

The electron flow from succinate through these transporters and to the final acceptor, which is oxygen, is coupled to the synthesis of 1.5 ATP molecules for each electron pair through phosphorylation linked to the respiratory chain.

Enzyme defects

Mutations in the gene encoding the A subunit of the succinate dehydrogenase complex have been reported to cause encephalopathies during infancy, while mutations in the genes encoding the B, C, and D subunits have been associated with tumor formation.

Regulation

The activity of the succinate dehydrogenase complex can be regulated by post-translational modifications such as phosphorylation and acetylation, although inhibition of the active site can also occur.

The acetylation of some lysine residues can decrease the activity of this enzyme and this process is carried out by a deacetylase enzyme known as SIRT3; phosphorylation has the same effect on the enzyme.

In addition to these modifications, the SDH complex is also regulated by the intermediates of the Krebs cycle, specifically oxaloacetate and succinate. Oxaloacetate is a powerful inhibitor, while succinate favors the dissociation of oxaloacetate, functioning as an activator.

Succinate dehydrogenase deficiency

Succinate dehydrogenase deficiency is an abnormality or disorder of the mitochondrial respiratory chain. This deficiency is caused by mutations in the SDHA (or SDHAF1), SDHB, SDHC, and SDHD genes.

Different investigations have shown homozygous and heterozygous mutations in these genes, especially SDHA. Mutations in these genes cause amino acid substitutions in the protein (in any of the SDHA subunits, B, C, or D), or otherwise encode abnormally short proteins.

Consequently, amino acid substitutions and abnormally short protein encodings lead to disorders or alterations of the SDH enzyme, which cause a failure in the optimal capacity of the mitochondria to produce energy. This is what scientists call a mitochondrial respiratory chain disorder.

This disorder can be expressed phenotypically in humans in many ways. The best known are: deficiency or lack of language development, spastic quadriplegia, involuntary muscle contractions (dystonia), muscle weakness, and cardiomyopathies, among other related problems.

Some patients with succinate dehydrogenase deficiency may develop Leigh's disease or Kearns-saire syndrome.

How is dehydrogen succinate deficiency detected?

Certain studies suggest the use of qualitative histochemical tests and analyzes, as well as quantitative, enzymatic biochemical analyzes of the respiratory chain. Others, for their part, suggest the complete amplification by means of the polymerase chain reaction (PCR) of the exons of the subunits under study and then, the respective sequencing.

Tricarboxylic acid cycle (Krebs cycle). Taken and edited from: Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins (translated into Spanish by Alejandro Porto).

Related diseases

There is a large number of phenotypic expressions produced by disorders of the mitochondrial respiratory chain, due to the deficiency of succinate dehydrogenase. However, when it comes to syndromes or diseases, the following are discussed.

Leigh syndrome

It is a progressive neurological disease, associated with mutations in the nuclear genome (in this case of succinate dehydrogenase), which affect the pyruvate-dehydrogenase complex up to the oxidative phosphorylation pathway.

Symptoms appear before the individual's first year of age, but in rare cases, the first symptoms have been seen during adolescence.

Among the most commonly observed symptoms are: hypotonia with loss of cephalic control, involuntary movements, recurrent vomiting, respiratory problems, inability to move the eyeball, pyramidal and extrapyramidal signs among others. Seizures are not very common.

It is possible that the disease can be detected in prenatal diagnoses. There is no known cure or specific treatment, but some specialists suggest treatments with certain vitamins or cofactors.

Gastrointestinal stromal tumor (GIST)

Commonly called GIST, it is a type of tumor of the gastrointestinal tract, which usually develops in areas such as the stomach or small intestine. The cause of these is believed to be due to a certain group of highly specialized cells called ICC cells or interstitial cells of Cajal.

Other considerations about the cause of GISTs are mutations in certain types of genes, which according to some authors cause 90% of tumors. The genes involved are: KIT, PDGFRA, succinate dehydrogenase (SDH) genes - deficient.

Succinate dehydrogenase (SDH) - deficient, occurs mainly in young women, produces tumors in the stomach, and relatively frequently metastasizes to the lymph nodes. A small percentage occurs in children and in most cases, it is due to the lack of expression of the SDHB subunit.

Kearns-Sayre syndrome

It has been determined that some patients with succinate dehydrogenase deficiencies may manifest Kearns-Sayre syndrome. This disease is related to mitochondrial disorders, and is characterized by the absence of movement of the eyeballs.

Other features of this disease are retinitis pigmentosa, deafness, cardiomyopathy, and central nervous system disorders. These symptoms are usually seen before the patient reaches 20 years of age. There is no known prenatal diagnosis for this condition.

There is also no known cure for this disease. Treatment is palliative, that is, it only works to reduce the effects of the disease, not cure it. On the other hand, although it depends on the number of affected organs and the medical attention received, life expectancy is relatively normal.

References

1. Ackrell, BA, Kearney, EB, & Singer, TP (1978). Mammalian succinate dehydrogenase. In Methods in enzymology (Vol. 53, pp. 466-483). Academic Press.
2. Brière, JJ, Favier, J., Ghouzzi, VE, Djouadi, F., Benit, P., Gimenez, AP, & Rustin, P. (2005). Succinate dehydrogenase deficiency in human. Cellular and Molecular Life Sciences CMLS, 62 (19-20), 2317-2324.
3. Cecchini, G., Schröder, I., Gunsalus, RP, & Maklashina, E. (2002). Succinate dehydrogenase and fumarate reductase from Escherichia coli. Biochimica et Biophysica Acta (BBA) -Bioenergetics, 1553 (1-2), 140-157.
4. Hatefi, Y., & Davis, KA (1971). Succinate dehydrogenase. I. Purification, molecular properties, and substructure. Biochemistry, 10 (13), 2509-2516.
5. Hederstedt, LARS, & Rutberg, LARS (1981). Succinate dehydrogenase – a comparative review. Microbiological reviews, 45 (4), 542.
6. Nelson, DL, Lehninger, AL, & Cox, MM (2008). Lehninger principles of biochemistry. Macmillan.
7. Rutter, J., Winge, DR, & Schiffman, JD (2010). Succinate dehydrogenase – assembly, regulation and role in human disease. Mitochondrion, 10 (4), 393-401.