Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mitochondrial DNA mutations in human cancer

Abstract

Somatic mitochondrial DNA (mtDNA) mutations have been increasingly observed in primary human cancers. As each cell contains many mitochondria with multiple copies of mtDNA, it is possible that wild-type and mutant mtDNA can co-exist in a state called heteroplasmy. During cell division, mitochondria are randomly distributed to daughter cells. Over time, the proportion of the mutant mtDNA within the cell can vary and may drift toward predominantly mutant or wild type to achieve homoplasmy. Thus, the biological impact of a given mutation may vary, depending on the proportion of mutant mtDNAs carried by the cell. This effect contributes to the various phenotypes observed among family members carrying the same pathogenic mtDNA mutation. Most mutations occur in the coding sequences but few result in substantial amino acid changes raising questions as to their biological consequence. Studies reveal that mtDNA play a crucial role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. The origin of somatic mtDNA mutations in human cancer and their potential diagnostic and therapeutic implications in cancer are discussed. This review article provides a detailed summary of mtDNA mutations that have been reported in various types of cancer. Furthermore, this review offers some perspective as to the origin of these of mutations, their functional consequences in cancer development, and possible therapeutic implications.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1

References

  • Abnet CC, Huppi K, Carrera A, Armistead D, McKenney K, Hu N et al. (2004). BMC Cancer 4: 30.

  • Abu-Amero KK, Alzahrani AS, Zou M, Shi Y . (2005). Oncogene 24: 1455–1460.

  • Alonso A, Martin P, Albarran C, Aquilera B, Garcia O, Guzman A et al. (1997). Electrophoresis 18: 682–685.

  • Attardi G, Schatz G . (1988). Annu Rev Cell Biol 4: 289–333.

  • Bando H, Atsumi T, Nishio T, Niwa H, Mishima S, Shimizu C et al. (2005). Clin Cancer Res 11: 5784–5792.

  • Basso D, Millino C, Greco E, Romualdi C, Fogar P, Valerio A et al. (2004). Gut 53: 1159–1166.

  • Beck SA, Tisdale MJ . (2004). Lipids 39: 1187–1189.

  • Bianchi MS, Bianchi NO, Bailliet G . (1995). Cytogenet Cell Genet 71: 99–103.

  • Blanchard JL, Schmidt GW . (1996). Mol Biol Evol 13: 537–548.

  • Boitier E, Merad-Boudia M, Guguen-Guillouzo C, Defer N, Ceballos-Picot I, Leroux JP et al. (1995). Cancer Res 55: 3028–3035.

  • Boros LG, Brandes JL, Yusuf FI, Cascante M, Williams RD, Schirmer WJ . (1998). Med Hypotheses 50: 501–506.

  • Boros LG, Torday JS, Lim S, Bassilian S, Cascante M, Lee WN . (2000). Cancer Res 60: 1183–1185.

  • Burgart LJ, Zheng J, Shu Q, Strickler JG, Shibata D . (1995). Am J Pathol 147: 1105–1111.

  • Cantuti-Castelvetri I, Lin MT, Zheng K, Keller-McGandy CE, Betensky RA, Johns DR et al. (2005). Neurobiol Aging 26: 1343–1355.

  • Capuano F, Guerrieri F, Papa S . (1997). J Bioenerg Biomembr 29: 379–384.

  • Cavelier L, Jazin EE, Eriksson I, Prince J, Bave U, Oreland L et al. (1995). Genomics 29: 217–224.

  • Chinnery PF, Samuels DC, Elson J, Turnbull DM . (2002). Lancet 360: 1323–1325.

  • Chinnery PF, Taylor RW, Diekert K, Lill R, Turnbull DM, Lightowlers RN . (1999). Gene Therapy 6: 1919–1928.

  • Chowdhury SK, Gemin A, Singh G . (2005). Biochem Biophys Res Commun 333: 1139–1145.

  • Cooper R, Sarioglu S, Sokmen S, Fuzun M, Kupelioglu A, Valentine H et al. (2003). Br J Cancer 89: 870–876.

  • Cormio A, Milella F, Vecchiet J, Felzani G, Gadaleta MN, Cantatore P . (2005). Neurobiol Aging 26: 655–664.

  • Cuezva JM, Krajewska M, de Heredia ML, Krajewski S, Santamaria G, Kim H et al. (2002). Cancer Res 62: 6674–6681.

  • Del Bo R, Bordoni A, Martinelli Boneschi F, Crimi M, Sciacco M, Bresolin N et al. (2002). J Neurol Sci 202: 85–91.

  • Denda A, Kitayama W, Murata A, Kishida H, Sasaki Y, Kusuoka O et al. (2002). Carcinogenesis 23: 245–256.

  • Eigenbrodt E, Kallinowski F, Ott M, Mazurek S, Vaupel P . (1998). Anticancer Res 18: 3267–3274.

  • Espineda CE, Chang JH, Twiss J, Rajasekaran SA, Rajasekaran AK . (2004). Mol Biol Cell 15: 1364–1373.

  • Farrell LB, Gearing DP, Nagley P . (1988). Eur J Biochem 173: 131–137.

  • Ferretti A, Chen LL, Di Vito M, Barca S, Tombesi M, Cianfriglia M et al. (1993). Anticancer Res 13: 867–872.

  • Flierl A, Jackson C, Cottrell B, Murdock D, Seibel P, Wallace DC . (2003). Mol Ther 7: 550–557.

  • Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM et al. (2000). Science 287: 2017–2019.

  • Gearing DP, Nagley P . (1986). EMBO J 5: 3651–3655.

  • Giles RE, Blanc H, Cann HM, Wallace DC . (1980). Proc Natl Acad Sci USA 77: 6715–6719.

  • Griffiths JR . (2001). Bioessays 23: 295–296.

  • Grivell LA . (1983). Sci Am 248: 78–89.

  • Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V et al. (2002). Ann Neurol 52: 534–542.

  • Ha PK, Tong BC, Westra WH, Sanchez-Cespedes M, Parrella P, Zahurak M et al. (2002). Clin Cancer Res 8: 2260–2265.

  • Habano W, Nakamura S, Sugai T . (1998). Oncogene 17: 1931–1937.

  • Habano W, Sugai T, Yoshida T, Nakamura S . (1999). Int J Cancer 83: 625–629.

  • Han CB, Ma JM, Xin Y, Mao XY, Zhao YJ, Wu DY et al. (2005). World J Gastroenterol 11: 31–35.

  • Hardy S, El-Assaad W, Przybytkowski E, Joly E, Prentki M, Langelier Y . (2003). J Biol Chem 278: 31861–31870.

  • Heerdt BG, Halsey HK, Lipkin M, Augenlicht LH . (1990). Cancer Res 50: 1596–1600.

  • Hibi K, Nakayama H, Yamazaki T, Takase T, Taguchi M, Kasai Y et al. (2001). Int J Cancer 92: 319–321.

  • Hoberman HD . (1975). Cancer Res 35: 3332–3335.

  • Hockenbery DM, Giedt CD, O’Neill JW, Manion MK, Banker DE . (2002). Adv Cancer Res 85: 203–242.

  • Horton TM, Petros JA, Heddi A, Shoffner J, Kaufman AE, Graham Jr SD et al. (1996). Genes Chromosomes Cancer 15: 95–101.

  • Irwin CC, Malkin LI, Morris HP . (1978). Cancer Res 38: 1584–1588.

  • Isaacs C, Cavalli LR, Cohen Y, Pennanen M, Shankar LK, Freedman M et al. (2004). Breast Cancer Res Treat 84: 99–105.

  • Isidoro A, Martinez M, Fernandez PL, Ortega AD, Santamaria G, Chamorro M et al. (2004). Biochem J 378: 17–20.

  • Jeronimo C, Nomoto S, Caballero OL, Usadel H, Henrique R, Varzim G et al. (2001). Oncogene 20: 5195–5198.

  • Jessie BC, Sun CQ, Irons HR, Marshall FF, Wallace DC, Petros JA . (2001). Exp Gerontol 37: 169–174.

  • Jones JB, Song JJ, Hempen PM, Parmigiani G, Hruban RH, Kern SE . (2001). Cancer Res 61: 1299–1304.

  • Kolesnikova OA, Entelis NS, Jacquin-Becker C, Goltzene F, Chrzanowska-Lightowlers ZM, Lightowlers RN et al. (2004). Hum Mol Genet 13: 2519–2534.

  • Kolesnikova OA, Entelis NS, Mireau H, Fox TD, Martin RP, Tarassov IA . (2000). Science 289: 1931–1933.

  • Law RH, Devenish RJ, Nagley P . (1990). Eur J Biochem 188: 421–429.

  • Law RH, Farrell LB, Nero D, Devenish RJ, Nagley P . (1988). FEBS Lett 236: 501–505.

  • Leij-Halfwerk S, van den Berg JW, Sijens PE, Wilson JH, Oudkerk M, Dagnelie PC . (2000). Cancer Res 60: 618–623.

  • Liang BC, Hays L . (1996). Cancer Lett 105: 167–173.

  • Liang BC . (1996). Mutat Res 354: 27–33.

  • Lightowlers RN, Chinnery PF, Turnbull DM, Howell N . (1997). Trends Genet 13: 450–455.

  • Liu VW, Shi HH, Cheung AN, Chiu PM, Leung TW, Nagley P et al. (2001). Cancer Res 61: 5998–6001.

  • Lopez-Alarcon L, Eboli ML . (1986). Cancer Res 46: 5589–5591.

  • Luciakova K, Kuzela S . (1992). Eur J Biochem 205: 1187–1193.

  • Luft R . (1994). Proc Natl Acad Sci USA 91: 8731–8738.

  • Macheda ML, Rogers S, Best JD . (2005). J Cell Physiol 202: 654–662.

  • Maitra A, Cohen Y, Gillespie SE, Mambo E, Fukushima N, Hoque MO et al. (2004). Genome Res 14: 812–819.

  • Mambo E, Chatterjee A, Xing M, Tallini G, Haugen BR, Yeung SC et al. (2005). Int J Cancer 116: 920–924.

  • Mambo E, Gao X, Cohen Y, Guo Z, Talalay P, Sidransky D . (2003). Proc Natl Acad Sci USA 100: 1838–1843.

  • Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong JQ, Guy J et al. (2002). Nat Genet 30: 394–399.

  • Manfredi G, Gupta N, Vazquez-Memije ME, Sadlock JE, Spinazzola A, De Vivo DC et al. (1999). J Biol Chem 274: 9386–9391.

  • Maximo V, Soares P, Lima J, Cameselle-Teijeiro J, Sobrinho-Simoes M . (2002). Am J Pathol 160: 1857–1865.

  • Maxwell SA, Rivera A . (2003). J Biol Chem 278: 9784–9789.

  • Mazurek S, Boschek CB, Eigenbrodt E . (1997). J Bioenerg Biomembr 29: 315–330.

  • Meierhofer D, Mayr JA, Foetschl U, Berger A, Fink K, Schmeller N et al. (2004). Carcinogenesis 25: 1005–1010.

  • Miyazono F, Schneider PM, Metzger R, Warnecke-Eberz U, Baldus SE, Dienes HP et al. (2002). Oncogene 21: 3780–3783.

  • Modica-Napolitano JS, Aprille JR . (2001). Adv Drug Deliv Rev 49: 63–70.

  • Modica-Napolitano JS, Singh KK . (2004). Mitochondrion 4: 755–762.

  • Montanini L, Regna-Gladin C, Eoli M, Albarosa R, Carrara F, Zeviani M et al. (2005). J Neurooncol 74: 87–89.

  • Nagy A, Wilhelm M, Kovacs G . (2003). J Pathol 199: 237–242.

  • Nagy A, Wilhelm M, Sukosd F, Ljungberg B, Kovacs G . (2002). Genes Chromosomes Cancer 35: 256–260.

  • Nishikawa M, Nishiguchi S, Shiomi S, Tamori A, Koh N, Takeda T et al. (2001). Cancer Res 61: 1843–1845.

  • Nomoto S, Sanchez-Cespedes M, Sidransky D . (2002a). Methods Mol Biol 197: 107–117.

  • Nomoto S, Yamashita K, Koshikawa K, Nakao A, Sidransky D . (2002b). Clin Cancer Res 8: 481–487.

  • Ockner RK, Kaikaus RM, Bass NM . (1993). Hepatology 18: 669–676.

  • Parrella P, Seripa D, Matera MG, Rabitti C, Rinaldi M, Mazzarelli P et al. (2003). Cancer Lett 190: 73–77.

  • Parrella P, Xiao Y, Fliss M, Sanchez-Cespedes M, Mazzarelli P, Rinaldi M et al. (2001). Cancer Res 61: 7623–7626.

  • Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W et al. (2003). J Biol Chem 278: 37832–37839.

  • Peluso G, Nicolai R, Reda E, Benatti P, Barbarisi A, Calvani M . (2000). J Cell Physiol 182: 339–350.

  • Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J et al. (2005). Proc Natl Acad Sci USA 102: 719–724.

  • Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD et al. (1998). Nat Genet 20: 291–293.

  • Rogounovitch TI, Saenko VA, Shimizu-Yoshida Y, Abrosimov AY, Lushnikov EF, Roumiantsev PO et al. (2002). Cancer Res 62: 7031–7041.

  • Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA . (2004). Cancer Res 64: 985–993.

  • Rudlowski C, Moser M, Becker AJ, Rath W, Buttner R, Schroder W et al. (2004). Oncology 66: 404–410.

  • Sakai H, Suzuki T, Maeda M, Takahashi Y, Horikawa N, Minamimura T et al. (2004). FEBS Lett 563: 151–154.

  • Salas A, Yao YG, Macaulay V, Vega A, Carracedo A, Bandelt HJ . (2005). PLoS Med 2: e296.

  • Sanchez-Cespedes M, Parrella P, Nomoto S, Cohen D, Xiao Y, Esteller M et al. (2001). Cancer Res 61: 7015–7019.

  • Selvanayagam P, Rajaraman S . (1996). Lab Invest 74: 592–599.

  • Shaw JH, Wolfe RR . (1987). Ann Surg 205: 368–376.

  • Shin YK, Yoo BC, Chang HJ, Jeon E, Hong SH, Jung MS et al. (2005). Cancer Res 65: 3162–3170.

  • Sidransky D . (2002). Nat Rev Cancer 2: 210–219.

  • Simonnet H, Alazard N, Pfeiffer K, Gallou C, Beroud C, Demont J et al. (2002). Carcinogenesis 23: 759–768.

  • Simonnet H, Demont J, Pfeiffer K, Guenaneche L, Bouvier R, Brandt U et al. (2003). Carcinogenesis 24: 1461–1466.

  • Springer EL . (1980). Cancer Res 40: 803–817.

  • Sri-Pathmanathan RM, Plumb JA, Fearon KC . (1994). Int J Cancer 56: 900–905.

  • Srivastava S, Moraes CT . (2001). Hum Mol Genet 10: 3093–3099.

  • Stefaneanu L, Tasca C . (1979). Endocrinologie 17: 233–239.

  • Sun AS, Cederbaum AI . (1980). Cancer Res 40: 4677–4681.

  • Sun AS, Sepkowitz K, Geller SA . (1981). Lab Invest 44: 13–17.

  • Suzuki M, Toyooka S, Miyajima K, Iizasa T, Fujisawa T, Bekele NB et al. (2003). Clin Cancer Res 9: 5636–5641.

  • Tamori A, Nishiguchi S, Nishikawa M, Kubo S, Koh N, Hirohashi K et al. (2004). J Gastroenterol 39: 1063–1068.

  • Tan DJ, Bai RK, Wong LJ . (2002). Cancer Res 62: 972–976.

  • Tanaka M, Borgeld HJ, Zhang J, Muramatsu S, Gong JS, Yoneda M et al. (2002). J Biomed Sci 9: 534–541.

  • Tong BC, Ha PK, Dhir K, Xing M, Westra WH, Sidransky D et al. (2003). J Surg Oncol 82: 170–173.

  • Wang X . (2001). Genes Dev 15: 2922–2933.

  • Warburg O . (1956a). Science 124: 269–270.

  • Warburg O . (1956b). Science 123: 309–314.

  • Warburg O . (1956c). Oncologia 9: 75–83.

  • Weber K, Ridderskamp D, Alfert M, Hoyer S, Wiesner RJ . (2002). Biol Chem 383: 283–290.

  • Wenzel U, Schoberl K, Lohner K, Daniel H . (2005). J Cell Physiol 202: 379–390.

  • Wheelhouse NM, Lai PB, Wigmore SJ, Ross JA, Harrison DJ . (2005). Br J Cancer 92: 1268–1272.

  • Wong LJ, Lueth M, Li XN, Lau CC, Vogel H . (2003). Cancer Res 63: 3866–3871.

  • Wu CW, Yin PH, Hung WY, Li AF, Li SH, Chi CW et al. (2005). Genes Chromosomes Cancer 44: 19–28.

  • Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN et al. (2005). Cancer Res 65: 613–621.

  • Zhao YB, Yang HY, Zhang XW, Chen GY . (2005). World J Gastroenterol 11: 3304–3306.

Download references

Acknowledgements

This work was supported by NCI Grant CA-P01-77664.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D Sidransky.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chatterjee, A., Mambo, E. & Sidransky, D. Mitochondrial DNA mutations in human cancer. Oncogene 25, 4663–4674 (2006). https://doi.org/10.1038/sj.onc.1209604

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209604

Keywords

  • mitochondria
  • mutation
  • homoplasmy
  • reactive oxygen species (ROS)
  • molecular detection

Further reading

Search

Quick links