Hereditary Paraganglioma/Pheochromocytoma and Inherited Succinate Dehydrogenase Deficiency

Favier, Judith; Brière, Jean-Jacques; Strompf, Laurence; Amar, Laurence; Filali, Mounir; Jeunemaı̂tre, Xavier; Rustin, Pierre; Gimenez-Roqueplo, Anne-Paule

doi:10.1159/000084685

Cited by 66 publications

(63 citation statements)

References 87 publications

(45 reference statements)

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“…As many of the genetic aspects of mitochondrial tumour suppressor genes have been discussed in several recent extensive reviews (Baysal, 2003;Eng et al, 2003;Favier et al, 2005;Gottlieb and Tomlinson, 2005), only a brief history of the field will be given and more current data will be covered in this review. In particular, attention will be given to recent findings concerning the potential mechanisms of tumorigenesis in SDH and FH-linked tumours.…”

Section: Mitochondrial Tumour Suppressor Genesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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Section: Mitochondrial Tumour Suppressor Genesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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“…Pheochromocytomas are derived from the chromaffin cells of the adrenal medulla. The only curative therapy is the early surgical resection of the tumors (22). Noticeably, paragangliomas of the carotid body can be caused by chronic hypoxia as well, as observed in patients living in high altitude or suffering from chronic obstructive pulmonary disease (30).…”

Section: Sdh B- C- and D-subunit-encoding Genes Act As Tumor Supprementioning

confidence: 99%

Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation

Brière¹,

Favier²,

Gimenez-Roqueplo³

et al. 2006

American Journal of Physiology-Cell Physiology

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A renewed interest in tricarboxylic acid cycle enzymopathies has resulted from the report that, in addition to devastating encephalopathies, these can result in various types of tumors in human. We first review the major features of the cycle that may underlie this surprising variety of clinical features. After discussing the rare cases of encephalopathies associated with specific deficiencies of some of the tricarboxylic acid cycle enzyme, we finally examine the mechanism possibly causing tumor/cancer formation in the cases of mutations affecting fumarase or succinate dehydrogenase genes.

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“…Yet substantial changes in mitochondrial respiration and in the activity of ETC are observed during exposure to hypoxia (9) as the side effects of drugs leading to hepatotoxicity (10) and cardiotoxicity (11) in the inherited succinate dehydrogenase deficiency associated with the development of paragangliomas and pheochromocytomas (12), etc. Activation of p53 in response to an obstruction of mitochondrial ETC may additionally contribute to tissue damage.…”

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confidence: 99%

Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway

Khutornenko

Roudko

Chernyak

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

140

122

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While many functions of the p53 tumor suppressor affect mitochondrial processes, the role of altered mitochondrial physiology in a modulation of p53 response remains unclear. As mitochondrial respiration is affected in many pathologic conditions such as hypoxia and intoxications, the impaired electron transport chain could emit additional p53-inducing signals and thereby contribute to tissue damage. Here we show that a shutdown of mitochondrial respiration per se does not trigger p53 response, because inhibitors acting in the proximal and distal segments of the respiratory chain do not activate p53. However, strong p53 response is induced specifically after an inhibition of the mitochondrial cytochrome bc1 (the electron transport chain complex III). The p53 response is triggered by the deficiency in pyrimidines that is developed due to a suppression of the functionally coupled mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). In epithelial carcinoma cells the activation of p53 in response to mitochondrial electron transport chain complex III inhibitors does not require phosphorylation of p53 at Serine 15 or up-regulation of p14 ARF . Instead, our data suggest a contribution of NQO1 and NQO2 in stabilization of p53 in the nuclei. The results establish the deficiency in pyrimidine biosynthesis as the cause of p53 response in the cells with impaired mitochondrial respiration.dihydroorotate dehydrogenase | mitochondrial electron transport chain | NQO1 and NQO2 | p53 tumor suppressor | apoptosis T he mitochondrion is the major power station of the cell that generates most of the cell's supply of ATP. In addition, mitochondria are involved in a range of intracellular processes, such as cell growth and division, differentiation, apoptosis, and intracellular signaling (1). The molecular mechanism of mitochondrial energy transformation involves the electron transport chain (ETC) that consists of electron transfer complexes I-IV embedded in the inner mitochondrial membrane. The ETC converts high energy potential of electrons from NADH and FADH 2 into the energy of electrochemical proton gradient across the inner membrane that drives the synthesis of ATP by the ATP-synthase (complex V). Besides, mitochondria participate in the synthesis of many metabolic intermediates, including the de novo biosynthesis of pyrimidines. The latter process is catalyzed by dihydroorotate dehydrogenase (DHODH), an FMN flavoprotein in the inner mitochondrial membrane, which transfers electrons from dihydroorotate to ubiquinone of the ETC for further oxidation (2).The p53 tumor suppressor mediates important quality control functions by limiting proliferation and survival of abnormal or damaged cells. Mitochondria are critically important for the p53-mediated cell death, because p53 controls transcription of several genes that affect the release of mitochondrial cytochrome c (3). In addition, p53 can induce a transcription-independent apoptosis through the direct interaction with Bcl-2 family proteins (4). On the ...

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Hereditary Paraganglioma/Pheochromocytoma and Inherited Succinate Dehydrogenase Deficiency

Cited by 66 publications

References 87 publications

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation

Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway

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