Skip to main content

Mitochondrial Tumor Suppressors

  • Chapter
  • First Online:
Mitochondria and Cancer
  • 1244 Accesses

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Alam, N. A., Barclay, E., Rowan, A. J., Tyrer, J. P., Calonje, E., Manek, S., Kelsell, D., Leigh, I., Olpin, S., and Tomlinson, I. P. 2005. Clinical features of multiple cutaneous and uterine leiomyomatosis: An underdiagnosed tumor syndrome. Arch. Dermatol. 141: 199–206.

    Article  PubMed  Google Scholar 

  • Amar, L., Bertherat, J., Baudin, E., Ajzenberg, C., Bressac-de Paillerets, B., Chabre, O., Chamontin, B., Delemer, B., Giraud, S., Murat, A., Niccoli-Sire, P., Richard, S., Rohmer, V., Sadoul, J. L., Strompf, L., Schlumberger, M., Bertagna, X., Plouin, P. F., Jeunemaitre, X., and Gimenez-Roqueplo, A. P. 2005. Genetic testing in pheochromocytoma or functional paraganglioma. J. Clin. Oncol. 23: 8812–8818.

    Article  CAS  PubMed  Google Scholar 

  • Arias-Stella, J. and Valcarcel, J. 1976. Chief cell hyperplasia in the human carotid body at high altitudes; physiologic and pathologic significance. Hum. Pathol. 7: 361–373.

    Article  CAS  PubMed  Google Scholar 

  • Astrom, K., Cohen, J. E., Willett-Brozick, J. E., Aston, C. E., and Baysal, B. E. 2003. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: Evidence for an oxygen-sensing defect. Hum. Genet. 113: 228–237.

    Article  PubMed  Google Scholar 

  • Astuti, D., Latif, F., Dallol, A., Dahia, P. L., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C., and Maher, E. R. 2001. Gene mutations in the succinate dehydrogenase subunitSDHB. cause susceptibility to familial pheochromocytoma and to familial paraganglioma Am. J. Hum. Genet. 69: 49–54.

    Article  CAS  PubMed  Google Scholar 

  • Barker, K. T., Bevan, S., Wang, R., Lu, Y. J., Flanagan, A. M., Bridge, J. A., Fisher, C., Finlayson, C. J., Shipley, J., and Houlston, R. S. 2002. Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas. Br. J. Cancer 87: 446–448.

    Article  CAS  PubMed  Google Scholar 

  • Bayley, J. P., Devilee, P., and Taschner, P. E. 2005. The SDH mutation database: An online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency. BMC Med. Genet. 6: 39.

    Article  PubMed  Google Scholar 

  • Baysal, B. E. 2002. Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet. 39: 617–622.

    Article  CAS  PubMed  Google Scholar 

  • Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der, M. A., Taschner, P. E., Rubinstein, W. S., Myers, E. N., Richard, C. W., III, Cornelisse, C. J., Devilee, P., and Devlin, B. 2000. Mutations inSDHD., a mitochondrial complex II gene, in hereditary paraganglioma Science 287: 848–851.

    Article  CAS  PubMed  Google Scholar 

  • Baysal, B. E., Willett-Brozick, J. E., Lawrence, E. C., Drovdlic, C. M., Savul, S. A., McLeod, D. R., Yee, H. A., Brackmann, D. E., Slattery, W. H., III, Myers, E. N., Ferrell, R. E., and Rubinstein, W. S. 2002. Prevalence ofSDHB.,SDHC, andSDHD germline mutations in clinic patients with head and neck paragangliomas J. Med. Genet. 39: 178–183.

    Article  CAS  PubMed  Google Scholar 

  • Bourgeron, T., Chretien, D., Poggi-Bach, J., Doonan, S., Rabier, D., Letouze, P., Munnich, A., Rotig, A., Landrieu, P., and Rustin, P. 1994. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J. Clin. Invest. 93: 2514–2518.

    Article  CAS  PubMed  Google Scholar 

  • Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., and Rotig, A. 1995. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat. Genet. 11: 144–149.

    Article  CAS  PubMed  Google Scholar 

  • Brandon, M., Baldi, P., and Wallace, D. C. 2006. Mitochondrial mutations in cancer. Oncogene 25: 4647–4662.

    Article  CAS  PubMed  Google Scholar 

  • Brouwers, F. M., Eisenhofer, G., Tao, J. J., Kant, J. A., Adams, K. T., Linehan, W. M., and Pacak, K. 2006. High frequency ofSDHB. germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing J. Clin. Endocrinol. Metab. 91: 4505–4509.

    Article  CAS  PubMed  Google Scholar 

  • Cecchini, G., Maklashina, E., Yankovskaya, V., Iverson, T. M., and Iwata, S. 2003. Variation in proton donor/acceptor pathways in succinate:quinone oxidoreductases. FEBS Lett. 545: 31–38.

    Article  CAS  PubMed  Google Scholar 

  • Coller, H. A., Khrapko, K., Bodyak, N. D., Nekhaeva, E., Herrero-Jimenez, P., and Thilly, W. G. 2001. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat. Genet. 28: 147–150.

    Article  CAS  PubMed  Google Scholar 

  • Dahia, P. L., Ross, K. N., Wright, M. E., Hayashida, C. Y., Santagata, S., Barontini, M., Kung, A. L., Sanso, G., Powers, J. F., Tischler, A. S., Hodin, R., Heitritter, S., Moore, F., Dluhy, R., Sosa, J. A., Ocal, I. T., Benn, D. E., Marsh, D. J., Robinson, B. G., Schneider, K., Garber, J., Arum, S. M., Korbonits, M., Grossman, A., Pigny, P., Toledo, S. P., Nose, V., Li, C., and Stiles, C. D. 2005. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 1: 72–80.

    Article  CAS  PubMed  Google Scholar 

  • Gallardo, M. E., Moreno-Loshuertos, R., Lopez, C., Casqueiro, M., Silva, J., Bonilla, F., Rodriguez, D. C., and Enriquez, J. A. 2006. m.6267G > A: A recurrent mutation in the human mitochondrial DNA that reduces cytochrome c oxidase activity and is associated with tumors. Hum. Mutat. 27: 575–582.

    Article  CAS  PubMed  Google Scholar 

  • Gatenby, R. A. and Gillies, R. J. 2004. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer4: 891–899.

    Article  CAS  PubMed  Google Scholar 

  • Gottlieb, E. and Tomlinson, I. P. 2005. Mitochondrial tumour suppressors: A genetic and biochemical update. Nat. Rev. Cancer 5: 857–866.

    Article  CAS  PubMed  Google Scholar 

  • Ishii, N., Fujii, M., Hartman, P. S., Tsuda, M., Yasuda, K., Senoo-Matsuda, N., Yanase, S., Ayusawa, D., and Suzuki, K. 1998. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394: 694–697.

    Article  CAS  PubMed  Google Scholar 

  • Kaelin, W. G. 2005. Proline hydroxylation and gene expression. Annu. Rev. Biochem. 74: 115–128.

    Article  CAS  PubMed  Google Scholar 

  • Kiuru, M. and Launonen, V. 2004. Hereditary leiomyomatosis and renal cell cancer (HLRCC). Curr. Mol. Med. 4: 869–875.

    Article  CAS  PubMed  Google Scholar 

  • Kiuru, M., Lehtonen, R., Arola, J., Salovaara, R., Jarvinen, H., Aittomaki, K., Sjoberg, J., Visakorpi, T., Knuutila, S., Isola, J., Delahunt, B., Herva, R., Launonen, V., Karhu, A., and Aaltonen, L. A. 2002. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res. 62: 4554–4557.

    CAS  PubMed  Google Scholar 

  • Lee, S., Nakamura, E., Yang, H., Wei, W., Linggi, M. S., Sajan, M. P., Farese, R. V., Freeman, R. S., Carter, B. D., Kaelin, W. G., Jr., and Schlisio, S. 2005. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8: 155–167.

    Article  PubMed  Google Scholar 

  • Neumann, H. P., Bausch, B., McWhinney, S. R., Bender, B. U., Gimm, O., Franke, G., Schipper, J., Klisch, J., Altehoefer, C., Zerres, K., Januszewicz, A., Eng, C., Smith, W. M., Munk, R., Manz, T., Glaesker, S., Apel, T. W., Treier, M., Reineke, M., Walz, M. K., Hoang-Vu, C., Brauckhoff, M., Klein-Franke, A., Klose, P., Schmidt, H., Maier-Woelfle, M., Peczkowska, M., Szmigielski, C., and Eng, C. 2002. Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346: 1459–1466.

    Article  CAS  PubMed  Google Scholar 

  • Neumann, H. P., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., and Eng, C. 2004. Distinct clinical features of paraganglioma syndromes associated withSDHB. andSDHD gene mutations JAMA 292: 943–951.

    Article  CAS  PubMed  Google Scholar 

  • Niemann, S. and Muller, U. 2000. Mutations inSDHC. cause autosomal dominant paraganglioma, type 3 Nat. Genet. 26: 268–270.

    Article  CAS  PubMed  Google Scholar 

  • Oyedotun, K. S., Sit, C. S., and Lemire, B. D. 2007. The Saccharomyces cerevisiae succinate dehydrogenase does not require heme for ubiquinone reduction. Biochim. Biophys. Acta 1767: 1436–1445.

    Article  CAS  PubMed  Google Scholar 

  • Parker, W. H. 2007. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil. Steril. 87: 725–736.

    Article  PubMed  Google Scholar 

  • Piruat, J. I., Pintado, C. O., Ortega-Saenz, P., Roche, M., and Lopez-Barneo, J. 2004. The mitochondrialSDHD. gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia Mol. Cell Biol. 24: 10933–10940.

    Article  CAS  PubMed  Google Scholar 

  • Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., Hargreaves, I. P., Heales, S. J., Chung, Y. L., Griffiths, J. R., Dalgleish, A., McGrath, J. A., Gleeson, M. J., Hodgson, S. V., Poulsom, R., Rustin, P., and Tomlinson, I. P. 2005. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum. Mol. Genet. 14: 2231–2239.

    Article  CAS  PubMed  Google Scholar 

  • Pollard, P. J., Spencer-Dene, B., Shukla, D., Howarth, K., Nye, E., El Bahrawy, M., Deheragoda, M., Joannou, M., McDonald, S., Martin, A., Igarashi, P., Varsani-Brown, S., Rosewell, I., Poulsom, R., Maxwell, P., Stamp, G. W., and Tomlinson, I. P. 2007. Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 11: 311–319.

    Article  CAS  PubMed  Google Scholar 

  • Salas, A., Yao, Y. G., Macaulay, V., Vega, A., Carracedo, A., and Bandelt, H. J. 2005. A critical reassessment of the role of mitochondria in tumorigenesis. PLoS Med. 2: e296.

    Article  PubMed  Google Scholar 

  • Saraste, M. 1999. Oxidative phosphorylation at the fin de siecle. Science 283: 1488–1493.

    Article  CAS  PubMed  Google Scholar 

  • Schiavi, F., Boedeker, C. C., Bausch, B., Peczkowska, M., Gomez, C. F., Strassburg, T., Pawlu, C., Buchta, M., Salzmann, M., Hoffmann, M. M., Berlis, A., Brink, I., Cybulla, M., Muresan, M., Walter, M. A., Forrer, F., Valimaki, M., Kawecki, A., Szutkowski, Z., Schipper, J., Walz, M. K., Pigny, P., Bauters, C., Willet-Brozick, J. E., Baysal, B. E., Januszewicz, A., Eng, C., Opocher, G., and Neumann, H. P. 2005. Predictors and prevalence of paraganglioma syndrome associated with mutations of theSDHC. gene JAMA 294: 2057–2063.

    Article  CAS  PubMed  Google Scholar 

  • Schofield, C. J. and Ratcliffe, P. J. 2004. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 5: 343–354.

    Article  CAS  PubMed  Google Scholar 

  • Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., and Gottlieb, E. 2005. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7: 77–85.

    Article  CAS  PubMed  Google Scholar 

  • Shambaugh, G. E., III. 1977. Urea biosynthesis I. The urea cycle and relationships to the citric acid cycle. Am. J. Clin. Nutr. 30: 2083–2087.

    CAS  PubMed  Google Scholar 

  • Smith, E. H., Janknecht, R., and Maher, L. J., III. 2007. Succinate inhibition of {alpha}-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum. Mol. Genet. 16: 3136–3148.

    Article  CAS  PubMed  Google Scholar 

  • Sun, F., Huo, X., Zhai, Y., Wang, A., Xu, J., Su, D., Bartlam, M., and Rao, Z. 2005. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell 121: 1043–1057.

    Article  CAS  PubMed  Google Scholar 

  • Suzuki, T., Sato, M., Yoshida, T., and Tuboi, S. 1989. Rat liver mitochondrial and cytosolic fumarases with identical amino acid sequences are encoded from a single gene. J. Biol. Chem. 264: 2581–2586.

    CAS  PubMed  Google Scholar 

  • Szeto, S. S., Reinke, S. N., Sykes, B. D., and Lemire, B. D. 2007. Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. J. Biol. Chem. 282: 27518–27526.

    Article  CAS  PubMed  Google Scholar 

  • Timmers, H. J., Kozupa, A., Eisenhofer, G., Raygada, M., Adams, K. T., Solis, D., Lenders, J. W., and Pacak, K. 2007. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. J. Clin. Endocrinol. Metab. 92: 779–786.

    Article  CAS  PubMed  Google Scholar 

  • Tomlinson, I. P., Alam, N. A., Rowan, A. J., Barclay, E., Jaeger, E. E., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., Roylance, R. R., Olpin, S., Bevan, S., Barker, K., Hearle, N., Houlston, R. S., Kiuru, M., Lehtonen, R., Karhu, A., Vilkki, S., Laiho, P., Eklund, C., Vierimaa, O., Aittomaki, K., Hia, M., Sistonen, P., Paetau, A., Salovaara, R., Herva, R., Launonen, V., and Aaltonen, L. A.. 2002Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat. Genet. 30: 406–410.

    Article  CAS  PubMed  Google Scholar 

  • Tran, Q. M., Rothery, R. A., Maklashina, E., Cecchini, G., and Weiner, J. H. 2007. Escherichia coli succinate dehydrogenase variant lacking the heme b. Proc. Natl. Acad. Sci. USA 104: 18007–18012.

    Article  CAS  PubMed  Google Scholar 

  • Vanharanta, S., Pollard, P. J., Lehtonen, H. J., Laiho, P., Sjoberg, J., Leminen, A., Aittomaki, K., Arola, J., Kruhoffer, M., Orntoft, T. F., Tomlinson, I. P., Kiuru, M., Arango, D., and Aaltonen, L. A. 2006. Distinct expression profile in fumarate-hydratase-deficient uterine fibroids. Hum. Mol. Genet. 15: 97–103.

    Article  CAS  PubMed  Google Scholar 

  • Yankovskaya, V., Horsefield, R., Tornroth, S., Luna-Chavez, C., Miyoshi, H., Leger, C., Byrne, B., Cecchini, G., and Iwata, S. 2003. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299: 700–704.

    Article  CAS  PubMed  Google Scholar 

  • Van der Mey, A. G., Maaswinkel-Mooy, P. D., Cornelisse, C. J., Schmidt, P. H., and van de Kamp, J. J. 1989. Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet 2: 1291–1294.

    Article  CAS  PubMed  Google Scholar 

  • Wallace, D. C. 2005. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39: 359–407.

    Article  CAS  PubMed  Google Scholar 

  • Warburg, O. 1956. On the origin of cancer cells. Science 123: 309–314.

    Article  CAS  PubMed  Google Scholar 

  • Wei, M. H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., Walther, M. M., Merino, M. J., Zbar, B., Linehan, W. M., and Toro, J. R. 2006. Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J. Med. Genet. 43: 18–27.

    Article  CAS  PubMed  Google Scholar 

  • Zanssen, S., and Schon, E. A. 2005. Mitochondrial DNA mutations in cancer. PLoS Medicine, 2: e401.

    Article  Google Scholar 

Download references

Acknowledgments

Author’s work is supported by an NIH grant R01CA112364.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bora E. Baysal .

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Baysal, B.E. (2009). Mitochondrial Tumor Suppressors. In: Mitochondria and Cancer. Springer, New York, NY. https://doi.org/10.1007/978-0-387-84835-8_9

Download citation

Publish with us

Policies and ethics