SDHB

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.{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–1053 | date = Oct 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}{{cite web | title = SDHB - Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial | url = https://amino.heartproteome.org/web/protein/P21912 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | access-date = 2018-07-18 | archive-date = 2018-07-19 | archive-url = https://web.archive.org/web/20180719024425/https://amino.heartproteome.org/web/protein/P21912 | url-status = dead }} 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.{{cite journal | vauthors = Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z | title = Crystal structure of mitochondrial respiratory membrane protein complex II. | journal = Cell | volume = 121 | issue = 7 | pages = 1043–1057 | date = 1 July 2005 | pmid = 15989954 | doi = 10.1016/j.cell.2005.05.025 | s2cid = 16697879 | doi-access = free }}

Image:SDHBfunction.svg

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:

1. SDHA converts succinate to fumarate as part of the Citric Acid Cycle. This reaction also converts FAD to FADH₂.
2. Electrons from the FADH₂ are transferred to the SDHB subunit iron clusters [2Fe-2S],[4Fe-4S],[3Fe-4S].
3. 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.{{cite journal | vauthors = Horsefield R, Yankovskaya V, Sexton G, Whittingham W, Shiomi K, Omura S, Byrne B, Cecchini G, Iwata S | title = Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction. | journal = The Journal of Biological Chemistry | volume = 281 | issue = 11 | pages = 7309–7316 | date = 17 March 2006 | pmid = 16407191 | doi = 10.1074/jbc.m508173200 | doi-access = free }}

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.

Paragangliomas caused by SDHB mutations have several distinguishing characteristics:

1. Malignancy is common, ranging from 38%-83%{{cite journal | vauthors = Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C | title = Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations | journal = JAMA | volume = 292 | issue = 8 | pages = 943–951 | date = August 2004 | pmid = 15328326 | doi = 10.1001/jama.292.8.943 | s2cid = 21673619 }}{{cite journal | vauthors = Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K | title = High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 11 | pages = 4505–4509 | date = November 2006 | pmid = 16912137 | doi = 10.1210/jc.2006-0423 | doi-access = free }} 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.
2. Malignant paragangliomas caused by SDHB are usually (perhaps 92%) extra-adrenal. Sporadic pheochromocytomas/paragangliomas are extra-adrenal in less than 10% of cases.
3. 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 screenedConference: National Institute of Health (U.S.A.), "SDHB-related Pheochromocytoma: Recent Discoveries & Current Diagnostic and Therapeutic Approaches", September 29, 2006 to determine the frequency of silent carriers.
4. 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.

The precise pathway leading from SDHB mutation to tumorigenesis is not determined; there are several proposed mechanisms.{{cite journal | vauthors = Gottlieb E, Tomlinson IP | title = Mitochondrial tumour suppressors: a genetic and biochemical update | journal = Nature Reviews. Cancer | volume = 5 | issue = 11 | pages = 857–866 | date = November 2005 | pmid = 16327764 | doi = 10.1038/nrc1737 | s2cid = 20851047 }}

Image:SDHBpathways.svg

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.

SDH inactivation can block the oxidation of succinate, starting a cascade of reactions:

1. The succinate accumulated in the mitochondrial matrix diffuses through the inner and outer mitochondrial membranes to the cytosol (purple dashed arrows in Figure 2).
2. Under normal cellular function, HIF1-α in the cytosol is quickly hydroxylated by prolyl hydroxylase (PHD), shown with the light blue arrow. This process is blocked by the accumulated succinate.
3. HIF1-α stabilizes and passes to the cell nucleus (orange arrow) where it combines with HIF1-β to form an active HIF complex that induces the expression of tumor causing genes.{{cite journal | vauthors = Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E | title = Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase | journal = Cancer Cell | volume = 7 | issue = 1 | pages = 77–85 | date = January 2005 | pmid = 15652751 | doi = 10.1016/j.ccr.2004.11.022 | doi-access = free }}

This pathway raises the possibility of a therapeutic treatment. The build-up of succinate inhibits PHD activity. PHD action normally requires oxygen and alpha-ketoglutarate as cosubstrates and ferrous iron and ascorbate as cofactors. Succinate competes with α-ketoglutarate in binding to the PHD enzyme. Therefore, increasing α-ketoglutarate levels can offset the effect of succinate accumulation.

Normal α-ketoglutarate does not permeate cell walls efficiently, and it is necessary to create a cell permeating derivative (e.g. α-ketoglutarate esters). In-vitro trials show this supplementation approach can reduce HIF1-α levels, and may result in a therapeutic approach to tumours resulting from SDH deficiency.{{cite journal | vauthors = MacKenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM, Watson DG, Gottlieb E | title = Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells | journal = Molecular and Cellular Biology | volume = 27 | issue = 9 | pages = 3282–3289 | date = May 2007 | pmid = 17325041 | pmc = 1899954 | doi = 10.1128/MCB.01927-06 }}

Paraganglionic tissue is derived from the neural crest cells present in an embryo. Abdominal extra-adrenal paraganglionic cells secrete catecholamines that play an important role in fetal development. After birth these cells usually die, a process that is triggered by a decline in nerve growth factor (NGF)which initiates apoptosis (cell death).

This cell death process is mediated by an enzyme called prolyl hydroxylase EglN3. Succinate accumulation caused by SDH inactivation inhibits the prolyl hydroxylase EglN3.{{cite journal | vauthors = Lee S, Nakamura E, Yang H, Wei W, Linggi MS, Sajan MP, Farese RV, Freeman RS, Carter BD, Kaelin WG, Schlisio S | title = Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer | journal = Cancer Cell | volume = 8 | issue = 2 | pages = 155–167 | date = August 2005 | pmid = 16098468 | doi = 10.1016/j.ccr.2005.06.015 | doi-access = free }} The net result is that paranglionic tissue that would normally die after birth remains, and this tissue may be able to trigger paraganglioma/pheochromocytoma later.

Inhibition of the Citric Acid Cycle forces the cell to create ATP glycolytically in order to generate its required energy. The induced glycolytic enzymes could potentially block cell apoptosis.

The mRNA transcripts of the SDHB gene in human are edited through an unknown mechanism at ORF nucleotide position 136 causing the conversion of C to U and thus generating a stop codon resulting in the translation of the edited transcripts to a truncated SDHB protein with an R46X amino acid change. This editing has been shown in monocytes and some human lymphoid cell-lines,{{cite journal | vauthors = Baysal BE | title = A recurrent stop-codon mutation in succinate dehydrogenase subunit B gene in normal peripheral blood and childhood T-cell acute leukemia | journal = PLOS ONE | volume = 2 | issue = 5 | pages = e436 | date = May 2007 | pmid = 17487275 | pmc = 1855983 | doi = 10.1371/journal.pone.0000436 | bibcode = 2007PLoSO...2..436B | doi-access = free }} {{open access}} and is enhanced by hypoxia.{{cite journal | vauthors = Baysal BE, De Jong K, Liu B, Wang J, Patnaik SK, Wallace PK, Taggart RT | title = Hypoxia-inducible C-to-U coding RNA editing downregulates SDHB in monocytes | journal = PeerJ | volume = 1 | pages = e152 | year = 2013 | pmid = 24058882 | pmc = 3775634 | doi = 10.7717/peerj.152 | doi-access = free }}

{{TCACycle_WP78|highlight=SDHB}}

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• [http://chromium.liacs.nl/lovd_sdh/index.php?select_db=SDHB Database of identified SDHB mutations.] {{Webarchive|url=https://web.archive.org/web/20060421214649/http://chromium.liacs.nl/lovd_sdh/index.php?select_db=SDHB |date=2006-04-21 }}

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