Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene. The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone => fumarate + ubiquinol). SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD. The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein with three iron-sulfur clusters. It weighs 30 kDa.
Structure The gene that codes for the SDHB protein is nuclear, not mitochondrial DNA. However, the expressed protein is located in the inner membrane of the mitochondria. The location of the gene in humans is on the first chromosome at locus p36.1-p35. The gene is coded in 1,162 base pairs, partitioned in 8 exons. The expressed protein weighs 31.6 kDa and is composed of 280 amino acids. SDHB contains the iron-sulphur clusters necessary for tunneling electrons through the complex. It is located between SDHA and the two transmembrane subunits SDHC and SDHD.
Function
The SDH complex is located on the inner membrane of the mitochondria and participates in both the Citric Acid Cycle and Respiratory chain. SDHB acts as an intermediate in the basic SDH enzyme action shown in Figure 1:
SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH2. Electrons from the FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S]. Finally the electrons are transferred to the Ubiquinone (Q) pool via the SDHC/SDHD subunits. This function is part of the Respiratory chain. Initially, SDHA oxidizes succinate via deprotonation at the FAD binding site, forming FADH2 and leaving fumarate, loosely bound to the active site, free to exit the protein. Electrons from FADH2 are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S] and tunnel along the [Fe-S] relay until they reach the [3Fe-4S] iron sulfur cluster. The electrons are then transferred to an awaiting ubiquinone molecule at the Q pool active site in the SDHC/SDHD dimer. The O1 carbonyl oxygen of ubiquinone is oriented at the active site (image 4) by hydrogen bond interactions with Tyr83 of 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 semiquinone radical species is formed. The second electron arrives from the [3Fe-4S] cluster to provide full reduction of the ubiquinone to ubiquinol.
Clinical significance Germline mutations in the gene can cause familial paraganglioma (in old nomenclature, Paraganglioma Type PGL4). The same condition is often called familial pheochromocytoma. Less frequently, renal cell carcinoma can be caused by this mutation. Paragangliomas related to SDHB mutations have a high rate of malignancy. When malignant, treatment is currently the same as for any malignant paraganglioma/pheochromocytoma.
Cancer Paragangliomas caused by SDHB mutations have several distinguishing characteristics:
Malignancy is common, ranging from 38%-83% in carriers with disease. In contrast, tumors caused by SDHD mutations are almost always benign. Sporadic paragangliomas are malignant in less than 10% of cases. Malignant paragangliomas caused by SDHB are usually (perhaps 92%) extra-adrenal. Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases. The penetrance of the gene is often reported as 77% by age 50 (i.e. 77% of carriers will have at least one tumour by the age of 50). This is likely an overestimate. Currently (2011), families with silent SDHB mutations are being screened to determine the frequency of silent carriers. The average age of onset is approximately the same for SDHB vs non-SDHB related disease (approximately 36 years). Mutations causing disease have been seen in exons 1 through 7, but not 8. As with the SDHC and SDHD genes, SDHB is a tumor suppressor gene. Tumor formation generally follows the Knudson "two hit" hypothesis. The first copy of the gene is mutated in all cells, however the second copy functions normally. When the second copy mutates in a certain cell due to a random event, Loss of Heterozygosity (LOH) occurs and the SDHB protein is no longer produced. Tumor formation then becomes possible. Given the fundamental nature of the SDH protein in all cellular function, it is not currently understood why only paraganglionic cells are affected. However, the sensitivity of these cells to oxygen levels may play a role.
Disease pathways The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms.
Generation of reactive oxygen species
When succinate-ubiquinone activity is inhibited, electrons that would normally transfer through the SDHB subunit to the Ubiquinone pool are instead transferred to O2 to create Reactive Oxygen Species (ROS) such as superoxide. The dashed red arrow in Figure 2 shows this. ROS accumulate and stabilize the production of HIF1-α. HIF1-α combines with HIF1-β to form the stable HIF heterodimeric complex, in turn leading to the induction of antiapoptotic genes in the cell nucleus.
Succinate accumulation in the cytosol SDH inactivation can block the oxidation of succinate, starting a cascade of reactions:
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