Succinate dehydrogenase complex subunit C

Succinate dehydrogenase complex subunit C, also known as succinate dehydrogenase cytochrome b560 subunit, mitochondrial, is a is_associated_with::protein that in humans is encoded by the SDHC is_associated_with::gene. This gene encodes one of four nuclear-encoded subunits that comprise is_associated_with::succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the is_associated_with::tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral is_associated_with::membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the is_associated_with::inner mitochondrial membrane. There are several related is_associated_with::pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with is_associated_with::paragangliomas. Alternatively spliced transcript variants have been described.

Structure
The gene that codes for the SDHC protein is nuclear, even though the protein is located in the inner membrane of the is_associated_with::mitochondria. The location of the gene in humans is on the first chromosome at q21. The is_associated_with::gene is partitioned in 6 is_associated_with::exons. The SDHC gene produces an 18.6 kDa protein composed of 169 amino acids.

The SDHC protein is one of the two transmembrane subunits of the four-subunit is_associated_with::succinate dehydrogenase (Complex II) protein complex that resides in the inner is_associated_with::mitochondrial membrane. The other transmembrane subunit is is_associated_with::SDHD. The SDHC/is_associated_with::SDHD dimer is connected to the is_associated_with::SDHB electron transport subunit which, in turn, is connected to the is_associated_with::SDHA subunit.

Function
The SDHC protein is one of four nuclear-encoded subunits that comprise is_associated_with::succinate dehydrogenase, also known as Complex II of the is_associated_with::electron transport chain, a key enzyme complex of the is_associated_with::citric acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane.

SDHC forms part of the transmembrane is_associated_with::protein dimer with is_associated_with::SDHD that anchors is_associated_with::Complex II to the inner mitochondrial membrane. The SDHC/is_associated_with::SDHD dimer provides binding sites for is_associated_with::ubiquinone and water during electron transport at is_associated_with::Complex II. Initially, is_associated_with::SDHA oxidizes is_associated_with::succinate via is_associated_with::deprotonation at the is_associated_with::FAD binding site, forming FADH2 and leaving is_associated_with::fumarate, loosely bound to the active site, free to exit the protein. The electrons derived from succinate tunnel along the [Fe-S] relay in the is_associated_with::SDHB subunit until they reach the [3Fe-4S] is_associated_with::iron sulfur cluster. The electrons are then transferred to an awaiting is_associated_with::ubiquinone molecule at the Q pool active site in the SDHC/is_associated_with::SDHD dimer. The O1 is_associated_with::carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by is_associated_with::hydrogen bond interactions with Tyr83 of is_associated_with::SDHD. The presence of electrons in the [3Fe-4S] iron sulphur cluster induces the movement of ubiquinone into a second orientation. This facilitates a second hydrogen bond interaction between the O4 carbonyl group of ubiquinone and Ser27 of SDHC. Following the first single electron reduction step, a is_associated_with::semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to is_associated_with::ubiquinol.

Clinical significance
Mutations in this gene have been associated with paragangliomas. More than 30 mutations in the SDHC gene have been found to increase the risk of hereditary paraganglioma-pheochromocytoma type 3. People with this condition have paragangliomas, is_associated_with::pheochromocytomas, or both. An inherited SDHC gene mutation predisposes an individual to the condition, and a is_associated_with::somatic mutation that deletes the normal copy of the SDHC gene is needed to cause hereditary paraganglioma-pheochromocytoma type 3. Most of the inherited SDHC gene mutations change single amino acids in the SDHC protein sequence or result in a shortened protein. As a result, there is little or no SDH enzyme activity. Because the mutated SDH enzyme cannot convert is_associated_with::succinate to is_associated_with::fumarate, succinate accumulates in the cell. The excess succinate abnormally stabilizes is_associated_with::hypoxia-inducible factors (HIF), which also builds up in cells. Excess HIF stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development of tumors in people with hereditary paraganglioma-pheochromocytoma.