Endocrine Pathology

, Volume 17, Issue 3, pp 203–211 | Cite as

Role of mitochondrial mutations in cancer

  • Bora E. Baysal


A role for mitochondria in cancer causation has been implicated through identification of mutations in the mitochondrial DNA (mtDNA) and in nuclear-encoded mitochondrial genes. Although many mtDNA mutations were detected in common tumors, an unequivocal causal link between heritable mitochondrial abnormalities and cancer is provided only by the germ line mutations in the nuclear-encoded genes for succinate dehydrogenase (mitochondrial complex II) and fumarate hydratase (fumarase). The absence of evidence for highly penetrant tumors caused by inherited mtDNA mutations contrasts with the frequent occurrence of mtDNA mutations in many different tumor types. Thus, either the majority of diverse mtDNA mutations observed in tumors are not important for the process of carcinogenesis or that they play a common oncogenic role.

Key Words

Paraganglioma hereditary leiomyomatosis and renal cell cancer syndrome Krebs cycle oxidative phosphorylation pheochromocytoma electron transport chain 


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  1. 1.
    Smeitink, J, van den HL, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2:342–352, 2001.PubMedCrossRefGoogle Scholar
  2. 2.
    Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407, 2005.PubMedCrossRefGoogle Scholar
  3. 3.
    Saraste M. Oxidative phosphorylation at the fin de siecle. Science 283:1488–1493, 1999.PubMedCrossRefGoogle Scholar
  4. 4.
    Carew JS, Huang P. Mitochondrial defects in cancer. Mol Cancer 1:9, 2002.PubMedCrossRefGoogle Scholar
  5. 5.
    Czarnecka AM, Golik P, Bartnik E. Mitochondrial DNA mutations in human neoplasia. J Appl Genet 47:67–78, 2006.PubMedGoogle Scholar
  6. 6.
    Copeland WC, Wachsman JT, Johnson FM, Penta JS. Mitochondrial DNA alterations in cancer. Cancer Invest 20:557–569, 2002.PubMedCrossRefGoogle Scholar
  7. 7.
    Baysal BE, Ferrell RE, Wilett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851, 2000.PubMedCrossRefGoogle Scholar
  8. 8.
    Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 39:178–183, 2002.PubMedCrossRefGoogle Scholar
  9. 9.
    Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346: 1459–1466, 2002.PubMedCrossRefGoogle Scholar
  10. 10.
    Bayley JP, Devilee P, Taschner PE. 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, 2005.PubMedCrossRefGoogle Scholar
  11. 11.
    Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30:406–410, 2002.PubMedCrossRefGoogle Scholar
  12. 12.
    Cecchini G. Function and structure of complex II of the respiratory chain. Annu Rev Biochem 72:77–109, 2003.PubMedCrossRefGoogle Scholar
  13. 13.
    Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 113:228–237, 2003.PubMedCrossRefGoogle Scholar
  14. 14.
    Dahia PL, Ross KN, Wright ME, et al. A HIF1 alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1:72–80, 2005.PubMedCrossRefGoogle Scholar
  15. 15.
    Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85, 2005.PubMedCrossRefGoogle Scholar
  16. 16.
    Pugh CW, Ratcliffe PJ. The von Hippel-Lindau tumor suppressor, hypoxia-inducible factor-1 (HIF-1) degradation, and cancer pathogenesis. Semin Cancer Biol 13:83–89, 2003.PubMedCrossRefGoogle Scholar
  17. 17.
    Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8:143–153, 2005.PubMedCrossRefGoogle Scholar
  18. 18.
    Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 111:1037–1054, 2003.PubMedGoogle Scholar
  19. 19.
    Vanharanta S, Pollard PJ, Lehtonen HJ, et al. Distinct expression profile in fumarate-hydratase-deficient uterine fibroids. Hum Mol Genet 15:97–103, 2006.PubMedCrossRefGoogle Scholar
  20. 20.
    Pavlovich CP, Schmidt LS. Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer 4:381–393, 2004.PubMedCrossRefGoogle Scholar
  21. 21.
    Baysal BE. Krebs cycle enzymes as tumor suppressors. Drug Discovery Today: Disease Mechanisms 2:247–254, 2005.CrossRefGoogle Scholar
  22. 22.
    Ishii N, Fujii M, Hartman PS, et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394:694–697, 1998.PubMedCrossRefGoogle Scholar
  23. 23.
    Rodriguez-Cuevas S, Lopez-Garza J, Labastida-Almendaro S. Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level. Head Neck 20:374–378, 1998.PubMedCrossRefGoogle Scholar
  24. 24.
    Arias-Stella J, Valcarcel J. Chief cell hyperplasia in the human carotid body at high altitudes; physiologic and pathologic significance. Hum Pathol 7:361–373, 1976.PubMedCrossRefGoogle Scholar
  25. 25.
    Jech M, Alvarado-Cabrero I, Albores-Saavedra J, Dahia PL, Tischler AS. Genetic analysis of high altitude paragangliomas. Endocrine Pathol 17:201–202, 2006.CrossRefGoogle Scholar
  26. 26.
    Baysal BE. Genomic imprinting and environment in hereditary paraganglioma. Am J Med Genet C Semin Med Genet 129:85–90, 2004.PubMedCrossRefGoogle Scholar
  27. 27.
    Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med 353:2042–2055, 2005.PubMedCrossRefGoogle Scholar
  28. 28.
    Shoffner JM. Oxidative phosphorylation diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited disease. New York, NY: McGraw-Hill, 2001; 2367–2423.Google Scholar
  29. 29.
    Da Sylva TR, Connor A, Mburu Y, Keystone E, Wu GE. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res Ther 7:R844-R851, 2005.PubMedCrossRefGoogle Scholar
  30. 30.
    Salas A, Yao YG, Macaulay V, Vega A, Carracedo A, Bandelt HJ. A critical reassessment of the role of mitochondria in tumorigenesis. PLoS Med 2:e296, 2005.PubMedCrossRefGoogle Scholar
  31. 31.
    Gallardo ME, Moreno-Loshuertos R, Lopez C, et al. 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, 2006.PubMedCrossRefGoogle Scholar
  32. 32.
    Petros JA, Baumann AK, Ruiz-Pesini E, et al. mtDNA mutations increase tumorigenenicity in prostate cancer. Proc Natl Acad Sci USA 102:719–724, 2005.PubMedCrossRefGoogle Scholar
  33. 33.
    Shidara Y, Yamagata K, Kanamori T, et al. Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res 65:1655–1663, 2005.PubMedCrossRefGoogle Scholar
  34. 34.
    Futreal PA, Coin L, Marshall M, et al. A census of human cancer genes. Nat Rev Cancer 4:177–183, 2004.PubMedCrossRefGoogle Scholar
  35. 35.
    Weir B, Zhao X, Meyerson M. Somatic alterations in the human cancer genome. Cancer Cell 6:433–438, 2004.PubMedCrossRefGoogle Scholar
  36. 36.
    Rodriguez-Viciana P, Tetsu O, Tidyman WE, et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311:1287–1290, 2006.PubMedCrossRefGoogle Scholar
  37. 37.
    Coller HA, Khrapko K, Bodyak ND, Nekhaev, E, Herrero-Jimenez P, Thilly WG. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat Genet 28:147–150, 2001.PubMedCrossRefGoogle Scholar
  38. 38.
    Piruat JI, Pintado CO, Ortega-Saenz P, Roche M, Lopez-Barneo J. The mitochondrial SDHD 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, 2004.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  • Bora E. Baysal
    • 1
  1. 1.Department of Obstetrics, Gynecology and Reproductive SciencesUniversity of Pittsburgh School of Medicine, Graduate School of Public Health-Department of Human Genetics, Magee-Womens Research Institute-Room 424Pittsburgh

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