scholarly journals Succinate dehydrogenase (SDHx) mutations in pituitary tumors: could this be a new role for mitochondrial complex II and/or Krebs cycle defects?

2012 ◽  
Vol 19 (6) ◽  
pp. C33-C40 ◽  
Author(s):  
Paraskevi Xekouki ◽  
Constantine A Stratakis

Succinate dehydrogenase (SDH) or mitochondrial complex II is a multimeric enzyme that is bound to the inner membrane of mitochondria and has a dual role as it serves both as a critical step of the tricarboxylic acid or Krebs cycle and as a member of the respiratory chain that transfers electrons directly to the ubiquinone pool. Mutations in SDH subunits have been implicated in the formation of familial paragangliomas (PGLs) and/or pheochromocytomas (PHEOs) and in Carney–Stratakis syndrome. More recently, SDH defects were associated with predisposition to a Cowden disease phenotype, renal, and thyroid cancer. We recently described a kindred with the coexistence of familial PGLs and an aggressive GH-secreting pituitary adenoma, harboring anSDHDmutation. The pituitary tumor showed loss of heterozygosity at theSDHDlocus, indicating the possibility thatSDHD's loss was causatively linked to the development of the neoplasm. In total, 29 cases of pituitary adenomas presenting in association with PHEOs and/or extra-adrenal PGLs have been reported in the literature since 1952. Although a number of other genetic defects are possible in these cases, we speculate that the association of PHEOs and/or PGLs with pituitary tumors is a new syndromic association and a novel phenotype for SDH defects.

Plant Science ◽  
2020 ◽  
Vol 294 ◽  
pp. 110458 ◽  
Author(s):  
Jin Seok Shin ◽  
Won Mi So ◽  
Soo Youn Kim ◽  
Minsoo Noh ◽  
Sujin Hyoung ◽  
...  

2021 ◽  
Vol 118 (15) ◽  
pp. e2022308118
Author(s):  
Xiaoting Zhou ◽  
Yan Gao ◽  
Weiwei Wang ◽  
Xiaolin Yang ◽  
Xiuna Yang ◽  
...  

Complex II, also known as succinate dehydrogenase (SQR) or fumarate reductase (QFR), is an enzyme involved in both the Krebs cycle and oxidative phosphorylation. Mycobacterial Sdh1 has recently been identified as a new class of respiratory complex II (type F) but with an unknown electron transfer mechanism. Here, using cryoelectron microscopy, we have determined the structure of Mycobacterium smegmatis Sdh1 in the presence and absence of the substrate, ubiquinone-1, at 2.53-Å and 2.88-Å resolution, respectively. Sdh1 comprises three subunits, two that are water soluble, SdhA and SdhB, and one that is membrane spanning, SdhC. Within these subunits we identified a quinone-binding site and a rarely observed Rieske-type [2Fe-2S] cluster, the latter being embedded in the transmembrane region. A mutant, where two His ligands of the Rieske-type [2Fe-2S] were changed to alanine, abolished the quinone reduction activity of the Sdh1. Our structures allow the proposal of an electron transfer pathway that connects the substrate-binding and quinone-binding sites. Given the unique features of Sdh1 and its essential role in Mycobacteria, these structures will facilitate antituberculosis drug discovery efforts that specifically target this complex.


2012 ◽  
Vol 73 (3) ◽  
pp. 429-441 ◽  
Author(s):  
Shaobai Huang ◽  
Nicolas L. Taylor ◽  
Elke Ströher ◽  
Ricarda Fenske ◽  
A. Harvey Millar

2015 ◽  
Vol 208 (3) ◽  
pp. 776-789 ◽  
Author(s):  
Douglas Jardim-Messeder ◽  
Andréia Caverzan ◽  
Rafael Rauber ◽  
Eduardo de Souza Ferreira ◽  
Márcia Margis-Pinheiro ◽  
...  

ChemMedChem ◽  
2017 ◽  
Vol 12 (13) ◽  
pp. 1033-1044 ◽  
Author(s):  
Hezhen Wang ◽  
Bader Huwaimel ◽  
Kshitij Verma ◽  
James Miller ◽  
Todd M. Germain ◽  
...  

2015 ◽  
Vol 22 (4) ◽  
pp. T71-T82 ◽  
Author(s):  
Bora E Baysal ◽  
Eamonn R Maher

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of α-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.


2013 ◽  
Vol 2 (1) ◽  
pp. 73-80 ◽  
Author(s):  
Sali M. K. Farhan ◽  
Jian Wang ◽  
John F. Robinson ◽  
Piya Lahiry ◽  
Victoria M. Siu ◽  
...  

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Aloka B. Bandara ◽  
Joshua C. Drake ◽  
David A. Brown

Abstract Background Succinate dehydrogenase (Complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the mitochondrial Krebs cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Mutations in Complex II are associated with a number of pathologies. SDHD, one of the four subunits of Complex II, serves by anchoring the complex to the inner-membrane and transferring electrons from the complex to ubiquinone. Thus, modeling SDHD dysfunction could be a valuable tool for understanding its importance in metabolism and developing novel therapeutics, however no suitable models exist. Results Via CRISPR/Cas9, we mutated SDHD in HEK293 cells and investigated the in vitro role of SDHD in metabolism. Compared to the parent HEK293, the knockout mutant HEK293ΔSDHD produced significantly less number of cells in culture. The mutant cells predictably had suppressed Complex II-mediated mitochondrial respiration, but also Complex I-mediated respiration. SDHD mutation also adversely affected glycolytic capacity and ATP synthesis. Mutant cells were more apoptotic and susceptible to necrosis. Treatment with the mitochondrial therapeutic idebenone partially improved oxygen consumption and growth of mutant cells. Conclusions Overall, our results suggest that SDHD is vital for growth and metabolism of mammalian cells, and that respiratory and growth defects can be partially restored with treatment of a ubiquinone analog. This is the first report to use CRISPR/Cas9 approach to construct a knockout SDHD cell line and evaluate the efficacy of an established mitochondrial therapeutic candidate to improve bioenergetic capacity.


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