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Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?

Nature Reviews Cancer volume 14, pages 709–721 (2014)Cite this article

Subjects

Key Points

  • Mitochondria contribute to the generation of ATP through oxidative phosphorylation, but they also participate in biosynthetic, metabolic and signalling functions in the cell. Some of the signalling functions are mediated by reactive oxygen species (ROS) that are generated by the electron transport chain. Alterations in mitochondrial ROS generation have been linked to a wide range of tumour cell types.

  • Mitochondria generate ROS when electrons residing on flavin groups, iron–sulphur centres or other electron transport 'way-stations' are diverted to O2, generating superoxide. Diverse 'antioxidant enzymes' scavenge ROS and/or reverse the effects of ROS on proteins, lipids and DNA, thereby limiting the scope of oxidative damage or redox signalling.

  • Mitochondrial ROS generation can be important in cancer because it activates cellular redox signalling that drives proliferative responses and triggers activation of transcription factors that promote tumorigenesis and survival, such as hypoxia-inducible factors (HIFs). Hypoxia triggers a paradoxical increase in the release of ROS from complex III to the mitochondrial intermembrane space, facilitating signalling, cell survival and proliferation.

  • Mitochondrial DNA can be damaged by ROS, and mutant mitochondrial proteins can augment ROS generation, creating a vicious cycle that contributes to cancer initiation or progression. Mitochondrial DNA mutations have been linked to a wide range of cancer types. In some cases, mitochondrial DNA mutations regulate the tumorigenic phenotype through their effect on ROS generation.

  • Mitochondrial ROS can contribute to genomic instability, and can contribute to the activation of mitochondria-dependent cell death pathways. However, a fuller understanding of the how altered mitochondrial ROS generation contributes to cancer progression is needed.

  • Oncogenes such as KRAS and MYC drive tumorigenesis in part by augmenting mitochondrial ROS generation.

  • As many tumour cells benefit from mitochondria-derived redox signalling, a useful therapeutic approach could revolve around the inhibition of tumour-promoting mitochondrial ROS signalling without interfering with ATP production. Such an approach could limit the ability of cells to activate protective responses, leaving them vulnerable to cytotoxic agents.

Abstract

Mitochondria cooperate with their host cells by contributing to bioenergetics, metabolism, biosynthesis, and cell death or survival functions. Reactive oxygen species (ROS) generated by mitochondria participate in stress signalling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behaviour. As mitochondria carry out important functions in normal cells, disabling their function is not a feasible therapy for cancer. However, ROS signalling contributes to proliferation and survival in many cancers, so the targeted disruption of mitochondria-to-cell redox communication represents a promising avenue for future therapy.

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Figure 1: Mitochondrial bioenergetic function.
Figure 2: Mitochondrial reactive oxygen species (ROS) generation.
Figure 3: Hypoxia and pseudohypoxia activate mitochondrial reactive oxygen species (ROS) generation and oxidant signalling that drives the tumour cell phenotype.
Figure 4: Mutations in tricarboxylic acid (TCA) cycle enzymes drive tumour cell progression through the generation of oxidant signalling.

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References

  1. Embley, T. M. & Martin, W. Eukaryotic evolution, changes and challenges. Nature 440, 623–630 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Martin, W., Hoffmeister, M., Rotte, C. & Henze, K. An overview of endosymbiotic models for the origins of eukaryotes, their ATP-producing organelles (mitochondria and hydrogenosomes), and their heterotrophic lifestyle. Biol. Chem. 382, 1521–1539 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Timmis, J. N., Ayliffe, M. A., Huang, C. Y. & Martin, W. Endosymbiotic gene transfer: organelle genomes forge eukaryotic chromosomes. Nature Rev. Genet. 5, 123–135 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Adams, K. L. & Palmer, J. D. Evolution of mitochondrial gene content: gene loss and transfer to the nucleus. Mol. Phylogenet. Evol. 29, 380–395 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Murphy, M. P. et al. Unraveling the biological roles of reactive oxygen species. Cell. Metab. 13, 361–366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chance, B., Sies, H. & Boveris, A. Hydroperoxide metabolism in mammalian organs. Physiol. Rev. 59, 527–605 (1979).

    Article  CAS  PubMed  Google Scholar 

  7. Quinlan, C. L. et al. The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I. J. Biol. Chem. 289, 8312–8325 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gardner, P. R. Superoxide-driven aconitase FE-S center cycling. Biosci. Rep. 17, 33–42 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Guzy, R. D. & Schumacker, P. T. Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp. Physiol. 91, 807–819 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Fabian, M. & Palmer, G. Hydrogen peroxide is not released following reaction of cyanide with several catalytically important derivatives of cytochrome c oxidase. FEBS Lett. 422, 1–4 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Han, D., Antunes, F., Canali, R., Rettori, D. & Cadenas, E. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J. Biol. Chem. 278, 5557–5563 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Bienert, G. P. et al. Specific aquaporins facilitate the diffusion of hydrogen peroxide across membranes. J. Biol. Chem. 282, 1183–1192 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Waypa, G. B. et al. Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells. Circ. Res. 106, 526–535 (2010). This study demonstrates how hypoxia-induced changes in mitochondrial ROS generation affect redox status in subcellular compartments differently.

    Article  CAS  PubMed  Google Scholar 

  14. Sabharwal, S. S., Waypa, G. B., Marks, J. D. & Schumacker, P. T. Peroxiredoxin-5 targeted to the mitochondrial intermembrane space attenuates hypoxia-induced reactive oxygen species signalling. Biochem. J. 456, 337–346 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Mills, G. C. Hemoglobin catabolism. I. Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown. J. Biol. Chem. 229, 189–197 (1957).

    CAS  PubMed  Google Scholar 

  16. Morgan, B. et al. Multiple glutathione disulfide removal pathways mediate cytosolic redox homeostasis. Nature Chem. Biol. 9, 119–125 (2013).

    Article  CAS  Google Scholar 

  17. Chae, H. Z. & Rhee, S. G. A thiol-specific antioxidant and sequence homology to various proteins of unknown function. Biofactors 4, 177–180 (1994).

    CAS  PubMed  Google Scholar 

  18. Kim, K., Kim, I. H., Lee, K. Y., Rhee, S. G. & Stadtman, E. R. The isolation and purification of a specific “protector” protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed-function oxidation system. J. Biol. Chem. 263, 4704–4711 (1988).

    CAS  PubMed  Google Scholar 

  19. Rhee, S. G., Chae, H. Z. & Kim, K. Peroxiredoxins: A historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic. Biol. Med. 38, 1543–1552 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Fan, J. et al. Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510, 298–302 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lewis, C. A. et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 55, 253–263 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Holmgren, A. Thioredoxin and glutaredoxin systems. J. Biol. Chem. 264, 13963–13966 (1989).

    CAS  PubMed  Google Scholar 

  23. Rhee, S. G., Jeong, W., Chang, T. S. & Woo, H. A. Sulfiredoxin, the cysteine sulfinic acid reductase specific to 2-Cys peroxiredoxin: its discovery, mechanism of action, and biological significance. Kidney Int. Suppl. S3–S8 (2007).

  24. Arner, E. S. & Holmgren, A. The thioredoxin system in cancer. Semin. Cancer Biol. 16, 420–426 (2006). This excellent review summarizes the role of thioredoxin and its contributions to the cellular phenotype of cancer cells.

    Article  CAS  PubMed  Google Scholar 

  25. Padmanabhan, B. et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol. Cell 21, 689–700 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Singh, A., Bodas, M., Wakabayashi, N., Bunz, F. & Biswal, S. Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance. Antioxid. Redox. Signal. 13, 1627–1637 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shibata, T. et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc. Natl Acad. Sci. USA 105, 13568–13573 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sullivan, L. B. et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol. Cell 51, 236–248 (2013). This study examines the mechanisms by which FH deficiency drives tumour cell behaviour in a redox-dependent manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009). This excellent review summarizes the role of the Warburg effect on cell proliferation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Le, A. et al. Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proc. Natl Acad. Sci. USA 111, 12486–12491 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Waypa, G. B. et al. Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation. Am. J. Respir. Crit. Care Med. 187, 424–432 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Farrow, K. N. et al. Brief hyperoxia increases mitochondrial oxidation and increases phosphodiesterase 5 activity in fetal pulmonary artery smooth muscle cells. Antioxid. Redox. Signal. 17, 460–470 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chandel, N. S. et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc. Natl Acad. Sci. USA 95, 11715–11720 (1998). This study was the first to demonstrate that mitochondria-derived ROS can regulate transcription through their control of HIF1α stability.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Waypa, G. B. et al. Increases in mitochondrial reactive oxygen species trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells. Circ. Res. 99, 970–978 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Chi, A. Y., Waypa, G. B., Mungai, P. T. & Schumacker, P. T. Prolonged hypoxia increases ROS signaling and RhoA activation in pulmonary artery smooth muscle and endothelial cells. Antioxid. Redox. Signal. 12, 603–610 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Guzy, R. D. et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell. Metab. 1, 401–408 (2005). This study demonstrated the importance of mitochondrial complex III in hypoxia-induced ROS generation that controls HIF1α stability.

    Article  CAS  PubMed  Google Scholar 

  37. Mansfield, K. D. et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-α activation. Cell. Metab. 1, 393–399 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bell, E. L., Emerling, B. M. & Chandel, N. S. Mitochondrial regulation of oxygen sensing. Mitochondrion. 5, 322–332 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010). This study examines the role of mitochondrial ROS signalling in the tumorigenic behaviour induced by KRAS activation.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sanjuan-Pla, A. et al. A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1α. FEBS Lett. 579, 2669–2674 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, ra8 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Woo, D. K. et al. Mitochondrial genome instability and ROS enhance intestinal tumorigenesis in APCMin/+ mice. Am. J. Pathol. 180, 24–31 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brandon, M., Baldi, P. & Wallace, D. C. Mitochondrial mutations in cancer. Oncogene 25, 4647–4662 (2006). This is an excellent review of the evidence linking mtDNA mutations and cancer.

    Article  CAS  PubMed  Google Scholar 

  44. Ishikawa, K. et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320, 661–664 (2008). This study demonstrates that mtDNA mutations can amplify tumour progression by increasing cellular ROS generation.

    Article  CAS  PubMed  Google Scholar 

  45. Alexeyev, M., Shokolenko, I., Wilson, G. & Ledoux, S. The maintenance of mitochondrial DNA integrity—critical analysis and update. Cold Spring Harb. Perspect. Biol. 5, a012641 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Larsen, N. B., Rasmussen, M. & Rasmussen, L. J. Nuclear and mitochondrial DNA repair: similar pathways? Mitochondrion 5, 89–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. He, Y. et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464, 610–614 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Clayton, D. A. & Vinograd, J. Circular dimer and catenate forms of mitochondrial DNA in human leukaemic leucocytes. Nature 216, 652–657 (1967).

    Article  CAS  PubMed  Google Scholar 

  49. Clayton, D. A. & Vinograd, J. Complex mitochondrial DNA in leukemic and normal human myeloid cells. Proc. Natl Acad. Sci. USA 62, 1077–1084 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Kulawiec, M., Salk, J. J., Ericson, N. G., Wanagat, J. & Bielas, J. H. Generation, function, and prognostic utility of somatic mitochondrial DNA mutations in cancer. Environ. Mol. Mutagen 51, 427–439 (2010).

    CAS  PubMed  Google Scholar 

  52. Chatterjee, A., Mambo, E. & Sidransky, D. Mitochondrial DNA mutations in human cancer. Oncogene 25, 4663–4674 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Coller, H. A. et al. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nature Genet. 28, 147–150 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Zhidkov, I., Livneh, E. A., Rubin, E. & Mishmar, D. MtDNA mutation pattern in tumors and human evolution are shaped by similar selective constraints. Genome Res. 19, 576–580 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Linnartz, B., Anglmayer, R. & Zanssen, S. Comprehensive scanning of somatic mitochondrial DNA alterations in acute leukemia developing from myelodysplastic syndromes. Cancer Res. 64, 1966–1971 (2004). This study tracked the association between the increase in mtDNA mutations over time and the progression from myelodysplastic syndrome to acute myeloid leukaemia in patients.

    Article  CAS  PubMed  Google Scholar 

  56. 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  PubMed  Google Scholar 

  57. Petros, J. A. et al. mtDNA mutations increase tumorigenicity in prostate cancer. Proc. Natl Acad. Sci. USA 102, 719–724 (2005). This study used cellular cybrids to examine the role of mtDNA mutations on ROS generation and tumorigenicity in prostate cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Trounce, I., Neill, S. & Wallace, D. C. Cytoplasmic transfer of the mtDNA nt 8993 T-->G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio. Proc. Natl Acad. Sci. USA 91, 8334–8338 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mattiazzi, M. et al. The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum. Mol. Genet. 13, 869–879 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Shidara, Y. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Vazquez, F. et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23, 287–301 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Namslauer, I. & Brzezinski, P. A mitochondrial DNA mutation linked to colon cancer results in proton leaks in cytochrome c oxidase. Proc. Natl Acad. Sci. USA 106, 3402–3407 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Samper, E., Nicholls, D. G. & Melov, S. Mitochondrial oxidative stress causes chromosomal instability of mouse embryonic fibroblasts. Aging Cell 2, 277–285 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. VanRemmen, H. et al. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol. Genom. 16, 29–37 (2003).

    Article  CAS  Google Scholar 

  65. Liu, L., Trimarchi, J. R., Smith, P. J. & Keefe, D. L. Mitochondrial dysfunction leads to telomere attrition and genomic instability. Aging Cell 1, 40–46 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Martinez-Outschoorn, U. E. et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 9, 3256–3276 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Degan, P. et al. In vivo accumulation of 8-hydroxy-2′-deoxyguanosine in DNA correlates with release of reactive oxygen species in Fanconi's anaemia families. Carcinogenesis 16, 735–741 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Ponte, F. et al. Improvement of genetic stability in lymphocytes from Fanconi anemia patients through the combined effect of α-lipoic acid and N-acetylcysteine. Orphanet. J. Rare. Dis. 7, 28 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Radisky, D. C. et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436, 123–127 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gerasimenko, J. V. et al. Menadione-induced apoptosis: roles of cytosolic Ca2+ elevations and the mitochondrial permeability transition pore. J. Cell Sci. 115, 485–497 (2002).

    CAS  PubMed  Google Scholar 

  71. Bernardi, P. Mitochondrial transport of cations: Channels, exchangers, and permeability transition. Physiol. Rev. 79, 1127–1155 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Giorgio, V. et al. Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc. Natl Acad. Sci. USA 110, 5887–5892 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Baines, C. P. et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658–662 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Loor, G. et al. Mitochondrial oxidant stress triggers cell death in simulated ischemia-reperfusion. Biochim. Biophys. Acta 1813, 1382–1394 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Schriewer, J. M., Peek, C. B., Bass, J. & Schumacker, P. T. ROS-mediated, PARP activity undermines mitochondrial function after permeability transition pore opening during myocardial ischemia-reperfusion. J. Am. Heart Assoc. 2, e000159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Dewhirst, M. W., Cao, Y. & Moeller, B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nature Rev. Cancer 8, 425–437 (2008).

    Article  CAS  Google Scholar 

  77. Trachootham, D. et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell 10, 241–252 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Lee, S. R. et al. Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 277, 20336–20342 (2002). This study demonstrated how H 2 O 2 generation can lead to the reversible inactivation of the lipid phosphatase PTEN, with important implications for cancer cell growth driven by excessive ROS signalling.

    Article  CAS  PubMed  Google Scholar 

  79. Kwon, J. et al. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc. Natl Acad. Sci. USA 101, 16419–16424 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gao, P. et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12, 230–238 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010). This is an excellent review of the role of HIF1 in cancer.

    Article  CAS  PubMed  Google Scholar 

  82. Keith, B. & Simon, M. C. Hypoxia-inducible factors, stem cells, and cancer. Cell 129, 465–472 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Semenza, G. L. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin. Cancer Biol. 19, 12–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Huang, L. E., Gu, J., Schau, M. & Bunn, H. F. Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl Acad. Sci. USA 95, 7987–7992 (1998). This is a classic paper describing the regions of the HIF1α protein that confer sensitivity to hypoxia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Epstein, A. C. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001). This study demonstrates the importance of SDH mutations in the formation of hereditary paragangliomas, thereby linking mitochondria to tumorigenic behaviour.

    Article  CAS  PubMed  Google Scholar 

  86. Ivan, M. et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464–468 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Chandel, N. S. et al. Reactive oxygen species generated at mitochondrial Complex III stabilize HIF-1-α during hypoxia: A mechanism of O2 sensing. J. Biol. Chem. 275, 25130–25138 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Brunelle, J. K. et al. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell. Metab. 1, 409–414 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Rustin, P. & Roetig, A. Inborn errors of complex II - Unusual human mitochondrial diseases. Biochim. Biophys. Acta 1553, 117–122 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Burnichon, N. et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 19, 3011–3020 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  94. Baysal, B. E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Gimenez-Roqueplo, A. P. et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am. J. Hum. Genet. 69, 1186–1197 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dekker, P. B. D. et al. SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology. J. Pathol. 201, 480–486 (2003).

    Article  CAS  Google Scholar 

  97. Astrom, K., Cohen, J. E., Willett-Brozick, J. E., Aston, C. E. & Baysal, B. E. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum. Genet. 113, 228–237 (2003).

    Article  PubMed  Google Scholar 

  98. Guzy, R. D., Sharma, B., Bell, E., Chandel, N. S. & Schumacker, P. T. Loss of SdhB, but not SdhA, subunit of Complex. II triggers ROS-dependent HIF activation and tumorigenesis. Mol. Cell. Biol. 28, 718–731 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Owens, K. M. et al. Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2-• and H2O2 . Free Radic. Biol. Med. 52, 160–166 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genet. 30, 406–410 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Pollard, P. J. et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum. Mol. Genet. 14, 2231–2239 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Isaacs, J. S. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Sudarshan, S. et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1α stabilization by glucose-dependent generation of reactive oxygen species. Mol. Cell. Biol. 29, 4080–4090 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2012).

    Article  CAS  Google Scholar 

  105. Semenza, G. L. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664–3671 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hu, Y. et al. K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res. 22, 399–412 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Dang, C. V. et al. Function of the c-Myc oncogenic transcription factor. Exp. Cell Res. 253, 63–77 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Li, F. et al. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol. Cell. Biol. 25, 6225–6234 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shim, H. et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA 94, 6658–6663 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chandel, N. S., Trzyna, W. C., McClintock, D. S. & Schumacker, P. T. Role of oxidants in NF-κB activation and TNF-α gene transcription induced by hypoxia and endotoxin. J. Immunol. 165, 1013–1021 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Schumacker, P. T. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 10, 175–176 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Hashemy, S. I., Ungerstedt, J. S., Avval, F. Z. & Holmgren, A. Motexafin gadolinium, a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase. J. Biol. Chem. 281, 10691–10697 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Goodman, M., Bostick, R. M., Kucuk, O. & Jones, D. P. Clinical trials of antioxidants as cancer prevention agents: past, present, and future. Free Radic. Biol. Med. 51, 1068–1084 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Creagan, E. T. et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N. Engl. J. Med. 301, 687–690 (1979).

    Article  CAS  PubMed  Google Scholar 

  116. Jung, H. J. et al. Terpestacin inhibits tumor angiogenesis by targeting UQCRB of mitochondrial complex III and suppressing hypoxia-induced reactive oxygen species production and cellular oxygen sensing. J. Biol. Chem. 285, 11584–11595 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors were supported by the US National Institutes of Health (NIH) Grants HL35440 and HL122062.

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Authors and Affiliations

  1. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA

    Simran S. Sabharwal & Paul T. Schumacker

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  1. Simran S. Sabharwal
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Correspondence to Paul T. Schumacker.

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PowerPoint slides

Glossary

Mitochondria

Organelles within eukaryotic cells that participate in energy production, biosynthetic processes, redox regulation, cell survival, signalling and cell death pathways.

ATP

(Adenosine triphosphate). A high-energy molecule that is hydrolysed by enzymes to provide the exergonic free energy required to carry out endergonic reactions.

Hypoxia

A condition in which the molecular oxygen concentration is decreased relative to normal physiological levels.

Reactive oxygen species

(ROS). Reactive molecules generated by the reduction of O2 with a single electron (superoxide), two electrons (hydrogen peroxide) or three electrons (hydroxyl radical).

ROS signalling

(Reactive oxygen species signalling). A cellular signal transduction mechanism involving oxidation–reduction reactions, usually resulting in a reversible alteration of protein structure and function that elicits a subsequent cellular response. ROS signalling frequently involves redox alterations of cysteine thiol (SH) groups in proteins.

Free radical

A molecule or atom containing an unpaired valence electron that renders it chemically reactive. Free radicals can potentially oxidize or reduce other molecules.

Tricarboxylic acid cycle

(TCA cycle). A system within mitochondria that participates in intermediary metabolism involved in energy production, inter-conversion of metabolites, and synthesis of small molecules needed for lipid or protein synthesis.

NADPH

A cofactor that is used by enzymes mediating electron transfer steps in energy production, lipid and nucleic acid synthesis, and the maintenance of intracellular oxidation–reduction status.

Superoxide dismutases

A family of enzymes that redistribute electrons between two superoxide anions to form a single molecule of hydrogen peroxide.

Hypoxia-inducible factors

(HIFs). A family of heterodimeric transcription factors that become activated during hypoxia or pseudohypoxia in a cell, and are responsible for potentially altering the expression of hundreds of genes involved in regulating cellular responses to hypoxia.

Mitochondrial DNA

(mtDNA). Circular loops of DNA containing ∼ 16.6 kilobases, located in the matrix of mitochondria. This DNA encodes 13 proteins, ribosomal RNAs and transfer RNAs that are required for a functional oxidative phosphorylation system.

Cybrids

Experimental cells that are formed by fusing a cell lacking mitochondrial DNA with an enucleated cytoplast containing mutant mitochondria.

Pseudohypoxic activators

Stimuli that trigger activation of cellular responses to hypoxia, even though the O2 level in the cell is normal.

AMP-activated protein kinase

(AMPK). A complex consisting of three proteins that has a central role in the regulation of cellular energy production and energy utilization.

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Sabharwal, S., Schumacker, P. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?. Nat Rev Cancer 14, 709–721 (2014). https://doi.org/10.1038/nrc3803

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