Clinical and Translational Oncology

, Volume 19, Issue 4, pp 409–418 | Cite as

Spotlight on the relevance of mtDNA in cancer

  • A. Cruz-Bermúdez
  • R. J. Vicente-Blanco
  • E. Gonzalez-Vioque
  • M. Provencio
  • M. Á. Fernández-Moreno
  • R. Garesse
Review Article

Abstract

The potential role of the mitochondrial genome has recently attracted interest because of its high mutation frequency in tumors. Different aspects of mtDNA make it relevant for cancer‘s biology, such as it encodes a limited but essential number of genes for OXPHOS biogenesis, it is particularly susceptible to mutations, and its copy number can vary. Moreover, most ROS in mitochondria are produced by the electron transport chain. These characteristics place the mtDNA in the center of multiple signaling pathways, known as mitochondrial retrograde signaling, which modifies numerous key processes in cancer. Cybrid studies support that mtDNA mutations are relevant and exert their effect through a modification of OXPHOS function and ROS production. However, there is still much controversy regarding the clinical relevance of mtDNA mutations. New studies should focus more on OXPHOS dysfunction associated with a specific mutational signature rather than the presence of mutations in the mtDNA.

Keywords

Cancer Warburg effect Mitochondria mtDNA OXPHOS ROS 

Abbreviations

OXPHOS

Oxidative phosphorylation

ROS

Reactive oxygen species

mtDNA

Mitochondrial DNA

Notes

Acknowledgements

Work in the authors’ laboratories is supported by “Instituto de Salud Carlos III” [PI13/01806 and PIE14/0064 to M.P., PI10/0703 and PI13/00556 to R.G. and PI04/1001 to M.A.F.M.]; “Comunidad Autónoma de Madrid” [S2010/BMD-2402 to R.G.]; “Fundación Mutua Madrileña” [10.04.02.0064 to M.A.F.M.]. We thank Dr. Bruno Sainz Jr. for helpful suggestions to the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. Elsevier Inc.; 2011;144:646–74.Google Scholar
  3. 3.
    Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012/03/20 ed. Elsevier Inc.; 2012;148:1145–59.Google Scholar
  4. 4.
    Larman TC, DePalma SR, Hadjipanayis AG, Protopopov A, Zhang J, Gabriel SB, et al. Spectrum of somatic mitochondrial mutations in five cancers. Proc Natl Acad Sci USA. 2012;109:14087–91.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife. 2014;3:1–28.CrossRefGoogle Scholar
  6. 6.
    Stewart JB, Alaei-Mahabadi B, Sabarinathan R, Samuelsson T, Gorodkin J, Gustafsson CM, et al. Simultaneous DNA and RNA mapping of somatic mitochondrial mutations across diverse human cancers. PLoS Genet. 2015;11:e1005333.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457–65.CrossRefPubMedGoogle Scholar
  8. 8.
    Greaves LC, Reeve AK, Taylor RW, Turnbull DM. Mitochondrial DNA and disease. J Pathol. 2012;226:274–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Itsara LS, Kennedy SR, Fox EJ, Yu S, Hewitt JJ, Sanchez-Contreras M, et al. Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations. PLoS Genet. 2014;10:e1003974.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Pinto M, Moraes CT. Mechanisms linking mtDNA damage and aging. Free Radic Biol Med Elsevier. 2015;85:250–8.CrossRefGoogle Scholar
  11. 11.
    Liou C-W, Lin T-K, Chen J-B, Tiao M-M, Weng S-W, Chen S-D, et al. Association between a common mitochondrial DNA D-loop polycytosine variant and alteration of mitochondrial copy number in human peripheral blood cells. J Med Genet. 2010;47:723–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Campbell CT, Kolesar JE, Kaufman B a. Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number. Biochim. Biophys. Acta. Elsevier B.V.; 2012;1819:921–9.Google Scholar
  13. 13.
    Guo J, Zheng L, Liu W, Wang X, Wang Z, Wang Z, et al. Frequent truncating mutation of TFAM induces mitochondrial DNA depletion and apoptotic resistance in microsatellite-unstable colorectal cancer. Cancer Res. 2011;71:2978–87.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    van Osch FHM, Voets AM, Schouten LJ, Gottschalk RWH, Simons CCJM, van Engeland M, et al. Mitochondrial DNA copy number in colorectal cancer: between tissue comparisons, clinicopathological characteristics and survival. Carcinogenesis. 2015;36:1502–10.PubMedGoogle Scholar
  15. 15.
    Mi J, Tian G, Liu S, Li X, Ni T, Zhang L, et al. The relationship between altered mitochondrial DNA copy number and cancer risk: a meta-analysis. Sci. Rep. Nature Publishing Group; 2015;5:10039.Google Scholar
  16. 16.
    Lin C-S, Wang L-S, Tsai C-M, Wei Y-H. Low copy number and low oxidative damage of mitochondrial DNA are associated with tumor progression in lung cancer tissues after neoadjuvant chemotherapy. Interact CardioVasc Thorac Surg. 2008;7:954–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Reznik E, Miller ML, Şenbabaoğlu Y, Riaz N, Sarungbam J, Tickoo SK, et al. Mitochondrial DNA copy number variation across human cancers. Elife. 2016;5:1–20.CrossRefGoogle Scholar
  18. 18.
    Pyle A, Hudson G, Wilson IJ, Coxhead J, Smertenko T, Herbert M, et al. Extreme-depth re-sequencing of mitochondrial DNA Finds no evidence of paternal transmission in humans. PLoS Genet. 2015;11:e1005040.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ruiz-Pesini E, Mishmar D, Brandon M. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science (80-.). 2004;303:223–7.Google Scholar
  20. 20.
    Coskun P, Wyrembak J, Schriner SE, Chen H-W, Marciniack C, Laferla F, et al. A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim. Biophys. Acta. Elsevier B.V.; 2012;1820:553–64.Google Scholar
  21. 21.
    Wang C, Wang Y, Wang H, Zhang R, Guo Z. Mitochondrial DNA haplogroup N is associated good outcome of gastric cancer. Tumour Biol. 2014;35:12555–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Kabekkodu SP, Bhat S, Mascarenhas R, Mallya S, Bhat M, Pandey D, et al. Mitochondrial DNA variation analysis in cervical cancer. Mitochondrion. © Elsevier B.V. and Mitochondria Research Society. All rights reserved.; 2014;16:73–82.Google Scholar
  23. 23.
    Wang Z, Choi S, Lee J, Huang Y-T, Chen F, Zhao Y, et al. Mitochondrial variations in non-small cell lung cancer (NSCLC) survival. Cancer Inf. 2015;14:1–9.Google Scholar
  24. 24.
    Weigl S, Paradiso A, Tommasi S. Mitochondria and familial predisposition to breast cancer. 2013;195–203.Google Scholar
  25. 25.
    Blein S, Bardel C, Danjean V, McGuffog L, Healey S, Barrowdale D, et al. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res. 2015;17:61.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bai R-K, Leal SM, Covarrubias D, Liu A, Wong L-JC. Mitochondrial genetic background modifies breast cancer risk. Cancer Res. 2007;67:4687–94.Google Scholar
  27. 27.
    Lam ET, Bracci PM, Holly E a, Chu C, Poon A, Wan E, et al. Mitochondrial DNA sequence variation and risk of pancreatic cancer. Cancer Res. 2012;72:686–95.Google Scholar
  28. 28.
    Fang H, Shen L, Chen T, He J, Ding Z, Wei J, et al. Cancer type-specific modulation of mitochondrial haplogroups in breast, colorectal and thyroid cancer. BMC Cancer. 2010;10:421.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Booker LM, Habermacher GM, Jessie BC, Sun QC, Baumann AK, Amin M, et al. North American White Mitochondrial Haplogroups in Prostate and Renal Cancer. J Urol. 2006;175:468–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Gómez-Durán A, Pacheu-Grau D, López-Gallardo E, Díez-Sánchez C, Montoya J, López-Pérez MJ, et al. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum Mol Genet. 2010;19:3343–53.CrossRefPubMedGoogle Scholar
  31. 31.
    D’Aquila P, Rose G, Panno ML, Passarino G, Bellizzi D. SIRT3 gene expression: a link between inherited mitochondrial DNA variants and oxidative stress. Gene Elsevier B.V.; 2012;497:323–9.Google Scholar
  32. 32.
    Pello, Martin MA, Carelli V, Nijtmans LG, Achilli A, Pala M, et al. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet. 2008;17:4001–11.Google Scholar
  33. 33.
    Kenney MC, Chwa M, Atilano SR, Falatoonzadeh P, Ramirez C, Malik D, et al. Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: implications for population susceptibility to diseases. Biochim. Biophys. Acta. Elsevier B.V.; 2014;1842:208–19.Google Scholar
  34. 34.
    Abbott J a, Francklyn CS, Robey-Bond SM. Transfer RNA and human disease. Front Genet. 2014;5:158.Google Scholar
  35. 35.
    Damas J, Samuels DC, Carneiro J, Amorim A, Pereira F. Mitochondrial DNA rearrangements in health and disease—a comprehensive study. Hum Mutat. 2014;35:1–14.CrossRefPubMedGoogle Scholar
  36. 36.
    Datta S, Ray A, Roy R, Roy B. Association of DNA sequence variation in mitochondrial DNA polymerase with mitochondrial DNA synthesis and risk of oral cancer. Gene. Elsevier B.V.; 2016;575:650–4.Google Scholar
  37. 37.
    Popanda O, Seibold P, Nikolov I, Oakes CC, Burwinkel B, Hausmann S, et al. Germline variants of base excision repair genes and breast cancer: a polymorphism in DNA polymerase gamma modifies gene expression and breast cancer risk. Int J Cancer. 2013;132:55–62.CrossRefPubMedGoogle Scholar
  38. 38.
    Ratanajaraya C, Nishiyama H, Takahashi M, Kawaguchi T, Saito R, Mikami Y, et al. A polymorphism of the POLG2 gene is genetically associated with the invasiveness of urinary bladder cancer in Japanese males. J Hum Genet. 2011;56:572–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Ding L, Liu Y. Borrowing Nuclear DNA Helicases to Protect Mitochondrial DNA. Int J Mol Sci. 2015;16:10870–87.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gandhi VV, Samuels DC. Correlated tissue expression of genes of cytoplasmic and mitochondrial nucleotide metabolisms in normal tissues is disrupted in transformed tissues. Nucleosides, Nucleotides Nucleic Acids. 2012;31:112–29.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Singh KK, Ayyasamy V, Owens KM, Koul MS, Vujcic M. Mutations in mitochondrial DNA polymerase-γ promote breast tumorigenesis. J. Hum. Genet. Nature Publishing Group. 2009;54:516–24.Google Scholar
  42. 42.
    Chen P-L, Chen C-F, Chen Y, Guo XE, Huang C-K, Shew J-Y, et al. Mitochondrial genome instability resulting from SUV3 haploinsufficiency leads to tumorigenesis and shortened lifespan. Oncogene. 2013;32:1193–201.CrossRefPubMedGoogle Scholar
  43. 43.
    Yadav N, Chandra D. Mitochondrial DNA mutations and breast tumorigenesis. Biochim. Biophys. Acta - Rev. Cancer. Elsevier B.V.; 2013;1836:336–44.Google Scholar
  44. 44.
    Yuan Y, Wang W, Li H, Yu Y, Tao J, Huang S, et al. Nonsense and Missense Mutation of Mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma. BMC Cancer. 2015;15:346.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Xu H, He W, Jiang H-G, Zhao H, Peng X-H, Wei Y-H, et al. Prognostic value of mitochondrial DNA content and G10398A polymorphism in non-small cell lung cancer. Oncol Rep. 2013;30:3006–12.PubMedGoogle Scholar
  46. 46.
    Hey-Mogensen M, Goncalves RLS, Orr AL, Brand MD. Production of superoxide/H2O2 by dihydroorotate dehydrogenase in rat skeletal muscle mitochondria. Free Radic Biol Med. 2014;72:149–55.CrossRefPubMedGoogle Scholar
  47. 47.
    Fisher-Wellman KH, Gilliam LAA, Lin C-T, Cathey BL, Lark DS, Neufer PD. Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload. Free Radic Biol Med. 2013;65:1201–8.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Mailloux RJ. Teaching the fundamentals of electron transfer reactions in mitochondria and the production and detection of reactive oxygen species. Redox Biol Elsevier. 2015;4C:381–98.CrossRefGoogle Scholar
  49. 49.
    Bleier L, Wittig I, Heide H, Steger M, Brandt U, Dröse S. Generator-specific targets of mitochondrial reactive oxygen species. Free Radic Biol Med Elsevier. 2015;78:1–10.CrossRefGoogle Scholar
  50. 50.
    Peralta D, Bronowska AK, Morgan B, Dóka É, Van Laer K, Nagy P, et al. A proton relay enhances H2O2 sensitivity of GAPDH to facilitate metabolic adaptation. Nat Chem Biol 2015;11.Google Scholar
  51. 51.
    Desouki MM, Kulawiec M, Bansal S, Das GC, Singh KK. Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors. Cancer Biol. Ther. Landes Bioscience Inc.; 2005;4:1367–73.Google Scholar
  52. 52.
    Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A. 2010/04/28 ed. 2010;107:8788–93.Google Scholar
  53. 53.
    Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2010/12/29 ed. 2011;21:103–15.Google Scholar
  54. 54.
    Sharma LK, Fang H, Liu J, Vartak R, Deng J, Bai Y. Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum Mol Genet. 2011/09/06 ed. 2011;20:4605–16.Google Scholar
  55. 55.
    Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. Elsevier Inc.; 2010;40:294–309.Google Scholar
  56. 56.
    Porporato PE, Payen VL, Pérez-Escuredo J, De Saedeleer CJ, Danhier P, Copetti T, et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 2014;8:754–66.CrossRefPubMedGoogle Scholar
  57. 57.
    Cruz-Bermúdez A, Vallejo C, Vicente-blanco RJ, Gallardo ME, Fernandez-Moreno MA, Quintanilla M, et al. Enhanced tumorigenicity by mitochondrial DNA mild mutations. Oncotarget. 2015;6:13628–43.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Formentini L, Sanchez-Arago M, Sanchez-Cenizo L, Cuezva JM. The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell. 2012;45:731–42.CrossRefPubMedGoogle Scholar
  59. 59.
    Maranzana E, Barbero G, Falasca AI, Lenaz G, Genova ML. Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid Redox Signal. 2013/04/16 ed. 2013;19:1469–80.Google Scholar
  60. 60.
    Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordóñez Á, et al. Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity. Cell Metab. 2011;14:768–79.CrossRefPubMedGoogle Scholar
  61. 61.
    Mailloux RJ, Harper M-E. Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic. Biol. Med. Elsevier Inc.; 2011;51:1106–15.Google Scholar
  62. 62.
    Dröse S, Brandt U, Wittig I. Mitochondrial respiratory chain complexes as sources and targets of thiol-based redox-regulation. Biochim. Biophys. Acta. Elsevier B.V.; 2014;1844:1344–54.Google Scholar
  63. 63.
    Tuppen H a L, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease. Biochim. Biophys. Acta. Elsevier B.V.; 2010;1797:113–28.Google Scholar
  64. 64.
    Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science. 2008;320:661–4.CrossRefPubMedGoogle Scholar
  65. 65.
    Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14:709–21.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science (80-.). 1989/10/27 ed. 1989;246:500–3.Google Scholar
  67. 67.
    Yarham JW, Al-Dosary M, Blakely EL, Alston CL, Taylor RW, Elson JL, et al. A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat. 2011;32:1319–25.CrossRefPubMedGoogle Scholar
  68. 68.
    Howell a N, Sager R. Tumorigenicity and its suppression in cybrids of mouse and Chinese hamster cell lines. Proc Natl Acad Sci USA. 1978;75:2358–62.Google Scholar
  69. 69.
    Hayashi J, Werbin H, Shay JW. Effects of normal human fibroblast mitochondrial DNA on segregation of HeLaTG Mitochondrial DNA and on tumorigenicity of HeLaTG cells. Cancer Res. 1986;46:4001–6.PubMedGoogle Scholar
  70. 70.
    Hayashi J, Takemitsu M, Nonaka I. Recovery of the missing tumorigenicity in mitochondrial DNA-less HeLa cells by introduction of mitochondrial DNA from normal human cells. Somat Cell Mol Genet. 1992;18:123–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Imanishi H, Hattori K, Wada R, Ishikawa K, Fukuda S, Takenaga K, et al. Mitochondrial DNA mutations regulate metastasis of human breast cancer cells. PLoS One. 2011;6:e23401.Google Scholar
  72. 72.
    Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, et al. mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA. 2005;102:719–24.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Shidara Y, Yamagata K, Kanamori T, Nakano K, Kwong JQ, Manfredi G, et al. Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res. 2005;65:1655–63.CrossRefPubMedGoogle Scholar
  74. 74.
    Park JS, Sharma LK, Li H, Xiang R, Holstein D, Wu J, et al. A heteroplasmic, not homoplasmic, mitochondrial DNA mutation promotes tumorigenesis via alteration in reactive oxygen species generation and apoptosis. Hum Mol Genet. 2009;18:1578–89.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Kaipparettu BA, Ma Y, Wong LJ. Functional effects of cancer mitochondria on energy metabolism and tumorigenesis: utility of transmitochondrial cybrids. Ann N Y Acad Sci. 2010;1201:137–46.CrossRefPubMedGoogle Scholar
  76. 76.
    Iommarini L, Kurelac I, Capristo M, Calvaruso MA, Giorgio V, Bergamini C, et al. Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment. Hum Mol Genet. 2014;23:1453–66.CrossRefPubMedGoogle Scholar
  77. 77.
    Calabrese C, Iommarini L, Kurelac I, Calvaruso MA, Capristo M, Lollini PL, et al. Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells. Cancer Metab. 2013;1:11.Google Scholar
  78. 78.
    Tan AS, Baty JW, Dong L-F, Bezawork-Geleta A, Endaya B, Goodwin J, et al. Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA. Cell Metab. Elsevier Inc.; 2015;21:81–94.Google Scholar
  79. 79.
    Berridge MV, Dong L, Neuzil J. Mitochondrial DNA in tumor initiation, progression, and metastasis: role of horizontal mtDNA transfer. Cancer Res. 2015;75:3203–8.CrossRefPubMedGoogle Scholar
  80. 80.
    Wallace DC. Mitochondria and cancer. Nat. Rev. Cancer. Nature Publishing Group; 2012;12:685–98.Google Scholar
  81. 81.
    Horan MP, Gemmell NJ, Wolff JN. From evolutionary bystander to master manipulator: the emerging roles for the mitochondrial genome as a modulator of nuclear gene expression. Eur J Hum Genet. 2013;21:1335–7.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Ward PS, Thompson CB. metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. Elsevier. 2012;21:297–308.CrossRefGoogle Scholar
  83. 83.
    Picard M, Zhang J, Hancock S, Derbeneva O, Golhar R, Golik P, et al. Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc Natl Acad Sci USA. 2014;111:E4033–42.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Amuthan G, Biswas G, Zhang SY, Klein-Szanto a, Vijayasarathy C, Avadhani NG. Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J. 2001;20:1910–20.Google Scholar
  85. 85.
    Tang W, Chowdhury AR, Guha M, Huang L, Van Winkle T, Rustgi AK, et al. Silencing of IkBβ mRNA causes disruption of mitochondrial retrograde signaling and suppression of tumor growth in vivo. Carcinogenesis. 2012;33:1762–8.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Mitsushita J, Lambeth JD, Kamata T. The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation. Cancer Res. 2004;64:3580–5.CrossRefPubMedGoogle Scholar
  87. 87.
    Veatch JR, McMurray M a, Nelson ZW, Gottschling DE. Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect. Cell. Elsevier Ltd; 2009;137:1247–58.Google Scholar
  88. 88.
    Pelicano H, Xu RH, Du M, Feng L, Sasaki R, Carew JS, et al. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J Cell Biol. 2006;175:913–23.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21:443–54.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Yen K, Lee C, Mehta H, Cohen P. The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J Mol Endocrinol. 2013;50:R11–9.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003/05/07 ed. 2003;423:456–61.Google Scholar
  92. 92.
    Mottaghi-Dastjerdi N, Soltany-Rezaee-Rad M, Sepehrizadeh Z, Roshandel G, Ebrahimifard F, Setayesh N. Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance. Daru. 2014/01/10 ed. 2014;22:14.Google Scholar
  93. 93.
    Monaghan RM, Whitmarsh AJ. mitochondrial proteins moonlighting in the nucleus. Trends Biochem. Sci. Elsevier Ltd; 2015;xx:1–8.Google Scholar
  94. 94.
    Ye X-Q, Li Q, Wang G-H, Sun F-F, Huang G-J, Bian X-W, et al. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer. 2011;129:820–31.CrossRefPubMedGoogle Scholar
  95. 95.
    Menendez JA, Alarcón T. Metabostemness: a new cancer hallmark. Front. Oncol. 2014;4:262.Google Scholar
  96. 96.
    Guha M, Srinivasan S, Ruthel G, Kashina AK, Carstens RP, Mendoza A, et al. Mitochondrial retrograde signaling induces epithelial-mesenchymal transition and generates breast cancer stem cells. Oncogene. Macmillan Publishers Limited; 2014;33:5238–50.Google Scholar
  97. 97.
    Yang M, Yan M, Zhang R, Li J, Luo Z. Side population cells isolated from human osteosarcoma are enriched with tumor-initiating cells. Cancer Sci. 2011;102:1774–81.CrossRefPubMedGoogle Scholar
  98. 98.
    Martins-Neves SR, Lopes ÁO, do Carmo A, Paiva A a, Simões PC, Abrunhosa AJ, et al. Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line. BMC Cancer. BioMed Central Ltd; 2012;12:139.Google Scholar
  99. 99.
    Heiden M Vander, Cantley L, Thompson C. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (80-.). 2009;324:1029–34.Google Scholar
  100. 100.
    Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004;429:417–23.CrossRefPubMedGoogle Scholar
  101. 101.
    Ahn CS, Metallo CM. Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab. 2015;3:1.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science (80-.). 2000;287:1997–9.Google Scholar
  103. 103.
    Takeuchi H, Fujimoto A, Hoon DSB. Detection of mitochondrial DNA alterations in plasma of malignant melanoma patients. Ann N Y Acad Sci. 2004;1022:50–4.CrossRefPubMedGoogle Scholar
  104. 104.
    Okochi O, Hibi K, Uemura T, Inoue S, Takeda S, Kanek T, et al. Detection of mitochondrial DNA alterations in the serum of hepatocellular carcinoma patients. Clin Cancer Res. 2002;8:2875–8.PubMedGoogle Scholar
  105. 105.
    Hibi K, Nakayama H, Yamazaki T, Takase T, Taguchi M, Kasai Y, et al. Detection of mitochondrial DNA alterations in primary tumors and corresponding serum of colorectal cancer patients. Int J Cancer. 2001;94:429–31.CrossRefPubMedGoogle Scholar
  106. 106.
    Yu M, Wan YF, Zou QH. Cell-free circulating mitochondrial DNA in the serum: a potential non-invasive biomarker for Ewing’s Sarcoma. Arch Med Res Elsevier Inc; 2012;43:389–94.Google Scholar
  107. 107.
    Duberow DP, Brait M, Hoque MO, Theodorescu D, Sidransky D, Dasgupta S, et al. High-performance detection of somatic D-loop mutation in urothelial cell carcinoma patients by polymorphism ratio sequencing. 2016;94:1015–1024.Google Scholar
  108. 108.
    Jerónimo C, Nomoto S, Caballero OL, Usadel H, Henrique R, Varzim G, et al. Mitochondrial mutations in early stage prostate cancer and bodily fluids. Oncogene. 2001;20:5195–8.CrossRefPubMedGoogle Scholar
  109. 109.
    Wong LJC, Lueth M, Li XN, Lau CC, Vogel H. Detection of mitochondrial DNA mutations in the tumor and cerebrospinal fluid of medulloblastoma patients. Cancer Res. 2003;63:3866–71.PubMedGoogle Scholar
  110. 110.
    Zhu W, Qin W, Bradley P, Wessel A, Puckett CL, Sauter ER. Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid. Carcinogenesis. 2005;26:145–52.CrossRefPubMedGoogle Scholar

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© Federación de Sociedades Españolas de Oncología (FESEO) 2016

Authors and Affiliations

  1. 1.Departamento de Bioquímica and Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER)Facultad de Medicina, UAMMadridSpain
  2. 2.Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC)Universidad Autónoma de Madrid (UAM)MadridSpain
  3. 3.Servicio de Oncología Médica, Instituto de Investigación Sanitaria Puerta de HierroHospital Universitario Puerta de Hierro-MajadahondaMadridSpain
  4. 4.Servicio de Bioquímica, Instituto de Investigación Sanitaria Puerta de HierroHospital Universitario Puerta de Hierro-MajadahondaMadridSpain
  5. 5.Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12)MadridSpain

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