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A role for mitochondrial enzymes in inherited neoplasia and beyond

Key Points

  • Germline heterozygous mutations in the autosomally encoded mitochondrial enzyme subunits of succinate dehydrogenase (SDH), SDHB, SDHC and SDHD, are associated with hereditary predisposition to phaeochromocytoma and paraganglioma. By contrast, homozygous germline mutations in the catalytic active-site-bearing subunit SDHA causes Leigh syndrome, which is characterized by severe neurological dysfunction and seizures.

  • Germline heterozygous mutations in another autosomally encoded mitochondrial enzyme ? fumarate hydratase (fumarase, FH) ? are associated with hereditary predisposition to papillary renal-cell carcinoma and leiomyomatosis, whereas homozygous FH mutations cause neurodegeneration.

  • SDH and FH catalyse sequential steps in the Krebs tricarboxylic-acid cycle, which generates ATP ? the cell's currency of energy. SDH is a component of complex II of the respiratory electron-transport chain.

  • The hereditary neurological diseases might be explained by complete or near-complete lack of energy generation during development, leading to free-radical formation and mitochondrial-mediated apoptotic cell death.

  • Little data exist to explain the mechanism of predisposition to cancer. Hypotheses invoke free-radical formation, leading to activation of the HIF/angiogenesis pathway and mitochondrial-mediated anti-apoptotic activity.

  • The link between mitochondrial-associated inherited neurological disease and inherited cancer might be exploited for uncovering novel functions and mechanisms for mitochondrial enzymes beyond energy production, for novel gene discovery and for clinical utility.

Abstract

Mitochondrial defects have been associated with neurological disorders, as well as cancers. Two ubiquitously expressed mitochondrial enzymes ? succinate dehydrogenase (SDH) and fumarate hydratase (FH, fumarase) ? catalyse sequential steps in the Krebs tricarboxylic-acid cycle. Inherited heterozygous mutations in the genes encoding these enzymes cause predispositions to two types of inherited neoplasia syndromes that do not share any component tumours. Homozygous mutations in the same genes result in severe neurological impairment. Understanding this link between inherited cancer syndromes and neurological disease could provide further insights into the mechanisms by which mitochondrial deficiencies lead to tumour development.

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Figure 1: Schematic diagram of the SDHD and SDHB genes and germline heterozygous mutations found in the phaeochromocytoma?paraganglioma syndromes.
Figure 2: The FH gene and disease-associated mutations.

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References

  1. Latif, F. et al. Identification of the von Hippel?Lindau disease tumor suppressor gene. Science 260, 1317?1320 (1993).

    Article  CAS  Google Scholar 

  2. Mulligan, L. M. et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genet. 6, 70?74 (1994).

    Article  CAS  Google Scholar 

  3. Eng, C. et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET Mutation Consortium analysis. JAMA 276, 1575?1579 (1996).

    Article  CAS  Google Scholar 

  4. Kroll, A. J., Alexander, B., Cochios, F. & Pechet, L. Hereditary deficiencies of clotting factors VII and X associated with carotid-body tumors. N. Engl. J. Med. 270, 6?13 (1964).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Heutink, P. et al. A gene subject to genomic imprinting and responsible for hereditary paragangliomas maps to 11q23-qter. Hum. Mol. Genet. 1, 7?10 (1992).

    Article  CAS  Google Scholar 

  7. Heutink, P., van Schothorst, E. M. & van der Mey, A. G. L. Further localization of the gene for hereditary paragangliomas and evidence for linkage in unrelated families. Eur. J. Hum. Genet. 2, 148?158 (1994).

    Article  CAS  Google Scholar 

  8. Baysal, B. E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848?851 (2000). Identification of SDHD as the susceptiblity gene for 11q-linked hereditary paraganglioma families. SDHD is the first nuclear gene that encodes a mitochondrial component and that has been shown to be involved in a cancer-susceptiblity syndrome.

    Article  CAS  Google Scholar 

  9. Gimm, O., Armanios, M., Dziema, H., Neumann, H. P. H. & Eng, C. Somatic and occult germline mutations in SDHD, a mitochondrial complex II gene, in non-familial pheochromocytomas. Cancer Res. 60, 6822?6825 (2000).

    CAS  Google Scholar 

  10. Neumann, H. P. H. et al. Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346, 1459?1466 (2002). Population-based study showing that 25% of unrelated non-syndromic, non-familial phaeochromocytoma cases are due to germline mutations in one of four genes, including SDHD and SDHB.

    Article  CAS  Google Scholar 

  11. Baysal, B. E. et al. Prevalence of SDHB, SDHC and SDHD in clinic patients with head and neck paragangliomas. J. Med. Genet. 39, 178?183 (2002).

    Article  CAS  Google Scholar 

  12. Niemann, S. & Muller, U. Mutations in SDHC cause autosomal dominant paraganglioma. Nature Genet. 26, 141?150 (2000).

    Article  Google Scholar 

  13. Astuti, D. et al. Mutations in the mitochondrial complex II subunit SDHB cause susceptibility to familial paraganglioma and pheochromocytoma. Am. J. Hum. Genet. 69, 49?54 (2001). Identification of SDHB as the susceptibility gene for familial paraganglioma and/or phaeochromocytoma.

    Article  CAS  Google Scholar 

  14. Baysal, B. E. Hereditary paraganglioma targets diverse paranglia. J. Med. Genet. 39, 617?622 (2002).

    Article  CAS  Google Scholar 

  15. Kiuru, M. et al. Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am. J. Pathol. 159, 825?829 (2001).

    Article  CAS  Google Scholar 

  16. Launonen, V. et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc. Natl Acad. Sci. USA 98, 3387?3392 (2001).

    Article  CAS  Google Scholar 

  17. Delahunt, B. & Eble, J. N. Renal cell neoplasia. Pathology 34, 13?20 (2002).

    Article  Google Scholar 

  18. Kiuru, M. et al. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res. 62, 4554?4557 (2002).

    CAS  Google Scholar 

  19. Tomlinson, I. P. M. T. et al. Germline mutations in the fumarate hydratase gene predispose to dominantly inherited uterine fibroids, skin leiomyomata and renal cell cancer. Nature Genet. 30, 406?410 (2002). Identification of germline heterozygous mutations in FH that cause susceptibility to HLRCC.

    Article  CAS  Google Scholar 

  20. Alam, N. A. et al. Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q42. Am. J. Hum. Genet. 68, 1264?1269 (2001).

    Article  CAS  Google Scholar 

  21. Gimenez-Roqueplo, A. -P. et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes enzymatic activity of the complex II mitochondrial respiratory chain and activates the hypoxia pathway. Am. J. Hum. Genet. 69, 1186?1197 (2001). First demonstration of loss of enzymatic activity as a consequence of SDHD mutation and consequent alterations in molecules in the HIF pathway.

    Article  CAS  Google Scholar 

  22. Gimenez-Roqueplo, A. P. et al. Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J. Clin. Endocrinol. Metab. 87, 4771?4774 (2002).

    Article  CAS  Google Scholar 

  23. Maher, E. R. & Eng, C. The pressure rises: update on the genetics of phaeochromocytoma. Hum. Mol. Genet. 11, 2347?2354 (2002).

    Article  CAS  Google Scholar 

  24. Schapira, A. H. Mitochondrial dysfunction in neurodegenerative disorders. Biochim. Biophys. Acta 1366, 225?233 (1998).

    Article  CAS  Google Scholar 

  25. Leigh, D. Subacute necrotizing encephalomyelopathy in an infant. J. Neurol. Neurosurg. Psychiatr. 14, 216?221 (1951).

    Article  CAS  Google Scholar 

  26. Bourgeron, T. et al. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J. Clin. Invest. 93, 2514?2518 (1994).

    Article  CAS  Google Scholar 

  27. Parfait, B. et al. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum. Genet. 106, 236?243 (2000).

    Article  CAS  Google Scholar 

  28. Ackrell, B. A. C. Progress in understanding structure-function relationships in respiratory chain complex II. FEBS Lett. 466, 1?5 (2000).

    Article  CAS  Google Scholar 

  29. Oyedotun, K. S. & Lemire, B. D. The quinone-binding sites of the Saccharomyces cerevisiae succinate-ubiquinone oxidoreductase. J. Biol. Chem. 276, 16936?16943 (2001).

    Article  CAS  Google Scholar 

  30. Iverson, T. M., Luna-Chavez, C., Cecchini, G. & Rees, D. C. Structure of the Escherichia coli fumarate reductase complex. Science 284, 1961?1966 (1999).

    Article  CAS  Google Scholar 

  31. Vinogradov, A. D., Ackrell, B. A. C. & Singer, T. P. On the possible interrelations of the reactivity of soluble succinate dehydrogenase with ferricyanide, reconstitution activity and the Hipip iron-sulfur center. Biochem. Biophys. Res. Comm. 67, 803?809 (1975).

    Article  CAS  Google Scholar 

  32. Schmidt, D. M., Saghbini, M. & Scheffler, I. E. The C-terminus of the succinate dehydrogenase IP peptide of the Saccharomyces cerevisiae is signficiant for assembly of complex II. Biochemistry 31, 8442?8448 (1992).

    Article  CAS  Google Scholar 

  33. Arias-Sella, J. & Valcarcel, J. Chief cell hyperplasia in the human carotid body at high altitudes; physiologic and pathologic significance. Hum. Pathol. 7, 361?373 (1976).

    Article  Google Scholar 

  34. Chandel, N. S. et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. Natl Acad. Sci. USA 95, 11715?11720 (1998).

    Article  CAS  Google Scholar 

  35. Clifford, S. C. et al. Contrasting effects on HIF-1α regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel?Lindau disease. Hum. Mol. Genet. 10, 1029?1038 (2001).

    Article  CAS  Google Scholar 

  36. Hoffman, M. A. et al. von Hippel?Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. Hum. Mol. Genet. 10, 1019?1027 (2001).

    Article  CAS  Google Scholar 

  37. Teipel, J. W. & Hunt, R. L. The subunit interactions of fumarase. J. Biol. Chem. 246, 4859?4865 (1971).

    CAS  Google Scholar 

  38. van den Heuvel, L. et al. Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18kD (AQDQ) subunit. Am. J. Hum. Genet. 62, 262?268 (1998).

    Article  CAS  Google Scholar 

  39. Loeffen, J. et al. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am. J. Hum. Genet. 63, 1598?1608 (1998).

    Article  CAS  Google Scholar 

  40. Triepels, R. H., van den Heuvel, L. & Loeffen, J. Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I. Ann. Neurol. 45, 787?790 (1999).

    Article  CAS  Google Scholar 

  41. Tiranti, V. et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am. J. Hum. Genet. 63, 1609?1621 (1998).

    Article  CAS  Google Scholar 

  42. Valnot, I., von Kleist-Retzow, J. C. & Barrientos, A. A mutation in the human heme A:farnesyltransferrase gene (COX 10) causes cytochrome c oxidase deficiency. Hum. Mol. Genet. 9, 1245?1249 (2000).

    Article  CAS  Google Scholar 

  43. van Loo, G. et al. The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet. Cell Death Differ. 9, 1031?1042 (2002).

    Article  CAS  Google Scholar 

  44. Ravagnan, L., Roumier, T. & Kroemer, G. Mitochondria, the killer organelles and their weapons. J. Cell. Physiol. 192, 131?137 (2002).

    Article  CAS  Google Scholar 

  45. López-Barneo, J., Pardal, R. & Ortega-Sáez, P. Cellular mechanisms of oxygen sensing. Annu. Rev. Physiol. 63, 259?287 (2001).

    Article  Google Scholar 

  46. Miramar, M. D. et al. NADH-oxidase activity of mitochondrial apoptosis inducing factor (AIF). J. Biol. Chem. 276, 16391?16398 (2001).

    Article  CAS  Google Scholar 

  47. Scheulke, M., Smeitink, J. & Mariman, E. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nature Genet. 21, 260?261 (1999).

    Article  Google Scholar 

  48. Benit, P. et al. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am. J. Hum. Genet. 68, 1344?1352 (2001).

    Article  CAS  Google Scholar 

  49. Loeffen, J. et al. Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encphalomyopathy. Am. J. Hum. Genet. 49, 195?201 (2001).

    CAS  Google Scholar 

  50. de Lonlay, P. et al. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature Genet. 29, 57?60 (2001).

    Article  CAS  Google Scholar 

  51. Papadopoulou, L. C., Sue, C. M. & Davidson, M. Fatal infantile cardioencephalomyopathy with cytochrome c oxidase (COX) deficiency due to mutations in SCO2, a human COX assembly gene. Nature Genet. 23, 333?337 (1999).

    Article  CAS  Google Scholar 

  52. Valnot, I., Ormond, S. & Gigarel, N. Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase (COX) deficiency with neonatal-onset hepatic failure and encephalopathy. Am. J. Hum. Genet. 67, 1104?1109 (2000).

    CAS  PubMed Central  Google Scholar 

  53. Servidei, S. Mitochondrial encephalomyopathies: gene mutation. Neuromuscul. Disord. 12, 224?229 (2001).

    Google Scholar 

  54. Green, D. R. & Reed, J. C. Mitochondria and apoptosis. Science 281, 1309?1312 (1998).

    Article  CAS  Google Scholar 

  55. Yeh, J. J. et al. Two-dimensional gene scanning of the mitochondrial genome reveals somatic mutations in papillary thyroid carcinomas and multiple sequence variants in cases with sporadic thyroid tumors. Oncogene 19, 2060?2066 (2000).

    Article  CAS  Google Scholar 

  56. Polyak, K. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nature Genet. 20, 291?293 (1998).

    Article  CAS  Google Scholar 

  57. Jeronimo, C. et al. Mitochondrial mutations in early state prostate cancer and bodily fluids. Oncogene 20, 5195?5198 (2001).

    Article  CAS  Google Scholar 

  58. Kirches, E. et al. High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples. Int. J. Cancer 93, 534?538 (2001).

    Article  CAS  Google Scholar 

  59. Liu, V. W. et al. High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res. 61, 5998?6001 (2001).

    CAS  Google Scholar 

  60. Maximo, V. et al. Microsatellite instability, mitochondrial DNA large deletions, and mitochondrial DNA mutations in gastric carcinoma. Gene Chromosom. Cancer 32, 136?143 (2001).

    Article  CAS  Google Scholar 

  61. Parrella, P. et al. Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. Cancer Res. 61, 7623?7626 (2001).

    CAS  Google Scholar 

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Acknowledgements

C. E. is a recipient of the Doris Duke Distinguished Clinical Scientist Award and is supported by grants from the National Institutes of Health, National Cancer Institute, American Cancer Society, US Department of Defense Breast and Prostate Cancer Research Programs, Susan G. Komen Breast Cancer Research Foundation and Jimmy V Golf Classic Translational Cancer Research Award from the V Foundation. M. K. is supported by the Finnish Cancer Society, Duodecim, Kidney Foundation, Paulo Foundation, Maud Kuistila Foundation, Ida Montin Foundation, Finnish Oncology Foundation, Research and Science Foundation of Pharmos, and AstraZeneca. L. A. A. is supported by the Finnish Cancer Society, Sigrid Juselius Foundation, Helsinki Central Hospital and the Academy of Finland's Center of Excellence Award.

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Correspondence to Charis Eng.

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DATABASES

Cancer.gov

head and neck tumours

kidney cancer

LocusLink

AIF

BCS1

COX10

FH

HIF-1α

HIF-1β

NDUFS4

NDUFS7

NDUFS8

NDUFV1

PGL1

PGL2

SCO1

SCO2

SDHA

SDHB

SDHC

SDHD

SURF1

VHL

OMIM

Friedrich ataxia

HLRCC

Huntingdon's disease

Leigh syndrome

MCL

paraganglioma

Parkinson's disease

phaeochromocytoma

FURTHER INFORMATION

Medical Genetics Information Resource

Glossary

MATERNALLY IMPRINTED

Genes come in pairs (alleles) ? one inherited from the father and one from the mother. Maternal imprinting occurs when the maternal allele is transcriptionally silenced, usually because of promoter hypermethylation. In this situation, only the paternal allele is expressed.

FOUNDER EFFECT

When a germline mutation occurs in a community that has been isolated from the outside, or where little emigration or immigration has occurred for many decades or centuries, this 'founding' germline mutation is established and perpetrated for generations.

HYPERBARIC OXYGEN

Oxygen that is delivered at high tension/pressure, which is well above atmospheric oxygen tension at sea level (defined as 1 atm).

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Eng, C., Kiuru, M., Fernandez, M. et al. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3, 193–202 (2003). https://doi.org/10.1038/nrc1013

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