Abstract
Mitochondrial DNA (mtDNA) somatic mutations or mutations in nuclear genes encoding mitochondrial proteins important for the assembly, activity, or maintenance of the individual oxidative phosphorylation (OXPHOS) complexes have been observed in tumors. Although the functional consequence of such mutations is unclear at the moment, retrograde signaling in response to OXPHOS defects can activate various nuclear genes and signaling pathways that alter mitochondrial function, tumor invasion, metastasis, redox-sensitive pathways, programmed cell death pathways, calcium signaling pathways, and cellular pathways leading to global changes in cellular morphology and architecture. In addition, we have found that some cancer cell lines harboring deleterious mtDNA mutations upregulate the expression of members of the peroxisome-proliferator activated γ coactivator 1 family of coactivators, probably to sustain the necessary ATP production for cell proliferation. In this chapter, we describe such cellular adaptations and changes in response to OXPHOS defects that are associated with a variety of cancer cell types.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Warburg O. On the origin of cancer cells. Science 1956; 123(3191):309–314.
Pedersen PL, Greenawalt JW, Chan TL, Morris HP. A comparison of some ultrastructural and biochemical properties of mitochondria from Morris hepatomas 9618A, 7800, and 3924A. Cancer Res 1970; 30(11):2620–2626.
Polyak K, Li Y, Zhu H, et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 1998; 20(3):291–293.
Fliss MS, Usadel H, Caballero OL, et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 2000; 287(5460):2017–2019.
Liu VW, Shi HH, Cheung AN, et al. High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res 2001; 61(16):5998–6001.
Nagy A, Wilhelm M, Sukosd F, Ljungberg B, Kovacs G. Somatic mitochondrial DNA mutations in human chromophobe renal cell carcinomas. Genes Chromosomes Cancer 2002; 35(3):256–260.
Gupta A, Rosenberger SF, Bowden GT. Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed mouse keratinocyte cell lines. Carcinogenesis 1999; 20(11):2063–2073.
Irani K, Xia Y, Zweier JL, et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 1997; 275(5306):1649–1652.
Coller HA, Khrapko K, Bodyak ND, Nekhaeva E, Herrero-Jimenez P, Thilly WG. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat Genet 2001; 28(2):147–150.
Petros JA, Baumann AK, Ruiz-Pesini E, et al. mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 2005; 102(3):719–724.
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 2005; 65(5):1655–1663.
Amuthan G, Biswas G, Ananadatheerthavarada HK, Vijayasarathy C, Shephard HM, Avadhani NG. Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene 2002; 21(51):7839–7849.
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(8):1910–1920.
Simonnet H, Alazard N, Pfeiffer K, et al. Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma. Carcinogenesis 2002; 23(5): 759–768.
Simonnet H, Demont J, Pfeiffer K, et al. Mitochondrial complex I is deficient in renal oncocytomas. Carcinogenesis 2003; 24(9):1461–1466.
Savagner F, Franc B, Guyetant S, Rodien P, Reynier P, Malthiery Y. Defective mitochondrial ATP synthesis in oxyphilic thyroid tumors. J Clin Endocrinol Metab 2001; 86(10):4920–4925.
Akimoto M, Niikura M, Ichikawa M, et al. Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells. Biochem Biophys Res Commun 2005; 327(4):1028–1035.
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 2002; 30(4):406–410.
Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001; 69(1):49–54.
Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000; 26(3):268–270.
Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287(5454):848–851.
Srivastava S, Barrett JN, Moraes CT. PGC-1alpha/beta upregulation is associated with improved oxidative phosphorylation in cells harboring nonsense mtDNA mutations. Hum Mol Genet 2007; 16(8):993–1005.
Savagner F, Mirebeau D, Jacques C, et al. PGC-1-related coactivator and targets are upregulated in thyroid oncocytoma. Biochem Biophys Res Commun 2003; 310(3):779–784.
Villani G, Greco M, Papa S, Attardi G. Low reserve of cytochrome c oxidase capacity in vivo in the respiratory chain of a variety of human cell types. J Biol Chem 1998; 273(48): 31829–31836.
Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999; 98(1):115–124.
Jiang WG, Douglas-Jones A, Mansel RE. Expression of peroxisome-proliferator activated receptor-gamma (PPARgamma) and the PPARgamma co-activator, PGC-1, in human breast cancer correlates with clinical outcomes. Int J Cancer 2003; 106(5):752–757.
Ohta K, Endo T, Haraguchi K, Hershman JM, Onaya T. Ligands for peroxisome proliferator-activated receptor gamma inhibit growth and induce apoptosis of human papillary thyroid carcinoma cells. J Clin Endocrinol Metab 2001; 86(5):2170–2177.
van Waveren C, Sun Y, Cheung HS, Moraes CT. Oxidative phosphorylation dysfunction modulates expression of extracellular matrix--remodeling genes and invasion. Carcinogenesis 2006; 27(3):409–418.
Delsite R, Kachhap S, Anbazhagan R, Gabrielson E, Singh KK. Nuclear genes involved in mitochondria-to-nucleus communication in breast cancer cells. Mol Cancer 2002; 1(1):6.
Monteith GR, McAndrew D, Faddy HM, Roberts-Thomson SJ. Calcium and cancer: targeting Ca2+ transport. Nat Rev Cancer 2007; 7(7):519–530.
Giacomello M, Drago I, Pizzo P, Pozzan T. Mitochondrial Ca2+ as a key regulator of cell life and death. Cell Death Differ 2007; 14(7):1267–1274.
Biswas G, Adebanjo OA, Freedman BD, et al. Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk. EMBO J 1999; 18(3):522–533.
Biswas G, Anandatheerthavarada HK, Zaidi M, Avadhani NG. Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta. J Cell Biol 2003; 161(3):507–519.
Luo Y, Bond JD, Ingram VM. Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. Proc Natl Acad Sci USA 1997; 94(18): 9705–9710.
Cerutti PA. Prooxidant states and tumor promotion. Science 1985; 227(4685):375–381.
Burdon RH, Rice-Evans C. Free radicals and the regulation of mammalian cell proliferation. Free Radic Res Commun 1989; 6(6):345–358.
Burdon RH, Gill V, Rice-Evans C. Oxidative stress and tumour cell proliferation. Free Radic Res Commun 1990; 11(1–3):65–76.
Arora-Kuruganti P, Lucchesi PA, Wurster RD. Proliferation of cultured human astrocytoma cells in response to an oxidant and antioxidant. J Neurooncol 1999; 44(3):213–221.
Murrell GA, Francis MJ, Bromley L. Modulation of fibroblast proliferation by oxygen free radicals. Biochem J 1990; 265(3):659–665.
Mattiazzi M, Vijayvergiya C, Gajewski CD, et al. The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum Mol Genet 2004; 13(8):869–879.
Amstad P, Crawford D, Muehlematter D, Zbinden I, Larsson R, Cerutti P. Oxidants stress induces the proto-oncogenes, C-fos and C-myc in mouse epidermal cells. Bull Cancer 1990; 77(5):501–502.
Abate C, Patel L, Rauscher FJ 3rd, Curran T. Redox regulation of fos and jun DNA-binding activity in vitro. Science 1990; 249(4973):1157–1161.
Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L. Redox regulation of NF-kappa B activation. Free Radic Biol Med 1997; 22(6):1115–1126.
Baeuerle PA. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta 1991; 1072(1):63–80.
Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol 1997; 9(2): 240–246.
Shi X, Dong Z, Huang C, et al. The role of hydroxyl radical as a messenger in the activation of nuclear transcription factor NF-kappaB. Mol Cell Biochem 1999; 194(1–2):63–70.
Domann FE Jr, Levy JP, Finch JS, Bowden GT. Constitutive AP-1 DNA binding and transactivating ability of malignant but not benign mouse epidermal cells. Mol Carcinog 1994; 9(2):61–66.
Domann FE, Levy JP, Birrer MJ, Bowden GT. Stable expression of a c-JUN deletion mutant in two malignant mouse epidermal cell lines blocks tumor formation in nude mice. Cell Growth Differ 1994a; 5(1):9–16.
Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr, Sledge GW Jr. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 1997; 17(7):3629–3639.
Lee FS, Hagler J, Chen ZJ, Maniatis T. Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. Cell 1997; 88(2):213–222.
Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 1995; 270(28):16483–16486.
Gupta A, Butts B, Kwei KA, et al. Attenuation of catalase activity in the malignant phenotype plays a functional role in an in vitro model for tumor progression. Cancer Lett 2001; 173(2):115–125.
Oberley LW, Oberley TD. Role of antioxidant enzymes in cell immortalization and transformation. Mol Cell Biochem 1988; 84(2):147–153.
St Clair DK, Wan XS, Oberley TD, Muse KE, St. Clair WH. Suppression of radiation-induced neoplastic transformation by overexpression of mitochondrial superoxide dismutase. Mol Carcinog 1992; 6(4):238–242.
Zhao Y, Xue Y, Oberley TD, et al. Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Res 2001; 61(16):6082–6088.
Li JJ, Oberley LW, St. Clair DK, Ridnour LA, Oberley TD. Phenotypic changes induced in human breast cancer cells by overexpression of manganese-containing superoxide dismutase. Oncogene 1995; 10(10):1989–2000.
Li JJ, Oberley LW, Fan M, Colburn NH. Inhibition of AP-1 and NF-kappaB by manganese-containing superoxide dismutase in human breast cancer cells. FASEB J 1998; 12(15): 1713–1723.
Pich S, Bach D, Briones P, et al. The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet 2005; 14(11):1405–1415.
Chen H, Chomyn A, Chan DC. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 2005; 280(28):26185–26192.
Hruban Z, Swift H, Rechcigl M Jr. Fine structure of transplantable hepatomas of the rat. J Natl Cancer Inst 1965; 35(3):459–495.
Evans IH, Diala ES, Earl A, Wilkie D. Mitochondrial control of cell surface characteristics in Saccharomyces cerevisiae. Biochim Biophys Acta 1980; 602(1):201–206.
Soslau G, Fuhrer JP, Nass MM, Warren L. The effect of ethidium bromide on the membrane glycopeptides in control and virus-transformed cells. J Biol Chem 1974; 249(10):3014–3020.
Dey R, Moraes CT. Lack of oxidative phosphorylation and low mitochondrial membrane potential decrease susceptibility to apoptosis and do not modulate the protective effect of Bcl-x(L) in osteosarcoma cells. J Biol Chem 2000; 275(10):7087–7094.
Manfredi G, Kwong JQ, Oca-Cossio JA, et al. BCL-2 improves oxidative phosphorylation and modulates adenine nucleotide translocation in mitochondria of cells harboring mutant mtDNA. J Biol Chem 2003; 278(8):5639–5645.
Sekito T, Thornton J, Butow RA. Mitochondria-to-nuclear signaling is regulated by the subcellular localization of the transcription factors Rtg1p and Rtg3p. Mol Biol Cell 2000; 11(6):2103–2115.
Miceli MV, Jazwinski SM. Common and cell type-specific responses of human cells to mitochondrial dysfunction. Exp Cell Res 2005; 302(2):270–280.
Epstein CB, Waddle JA, Hale WT, et al. Genome-wide responses to mitochondrial dysfunction. Mol Biol Cell 2001; 12(2):297–308.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Humana Press, a part of Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Srivastava, S., Moraes, C.T. (2009). Cellular Adaptations to Oxidative Phosphorylation Defects in Cancer. In: Sarangarajan, R., Apte, S. (eds) Cellular Respiration and Carcinogenesis. Humana Press. https://doi.org/10.1007/978-1-59745-435-3_5
Download citation
DOI: https://doi.org/10.1007/978-1-59745-435-3_5
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-934115-07-7
Online ISBN: 978-1-59745-435-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)