Tipping the Balance in the Powerhouse of the Cell to “Protect” Colorectal Cancer

article has not abstract

Published in the journal: . PLoS Genet 8(6): e32767. doi:10.1371/journal.pgen.1002758
Category: Perspective
doi: 10.1371/journal.pgen.1002758


article has not abstract

Mitochondria are the bioenergetic centers of eukaryotic cells that produce ATP through oxidative phosphorylation. A byproduct of oxidative phosphorylation is the generation of reactive oxygen species (ROS). Cancer cells exhibit high basal levels of oxidative stress due to activation of oncogenes, loss of tumor suppressors, and the effects of the tumor microenvironment [1]. A large body of evidence suggests important roles for oxygen free radicals in the mutagenesis that drives carcinogenesis [2], the expansion of tumor clones, and the acquisition of malignant properties [3].

Several studies have reported that a high frequency of clonal and, therefore, selected mitochondrial mutations are present in a variety of human tumors [4][15]. Mitochondrial DNA (mtDNA) mutations in cancer cells include intragenic deletions, missense and chain-termination point mutations, and alterations of homopolymeric sequences that result in frameshift mutations [16], [17]. The biological impact of a given mutation may vary, depending on the proportion of mutant mtDNAs carried by the cell. The assumption from these studies is that this high frequency of clonal mutations arises from the ROS produced in mitochondria by the escape of oxygen free radicals during oxidative phosphorylation, and that these mutations play a role in driving cancer (Figure 1). Therefore, genomic instability of mitochondria was thought to be a hallmark of cancer.

Network modeling of the interconnections among the crucial factors involved in metabolic flow and signaling pathways of the Warburg effect to “protect” the cancer cells.
Fig. 1. Network modeling of the interconnections among the crucial factors involved in metabolic flow and signaling pathways of the Warburg effect to “protect” the cancer cells.
(A) Cancer cells make use of their nutrient-rich environment by taking in glucose and converting it into molecular precursors by aerobic glycolysis (shown in yellow). This is mediated by activation of proto-oncogenes such as AKT and MYC and other genes in important growth factor signaling pathways. Moreover, RAS-mediated activation of HIF1 induces adaptation to hypoxic environments and promotes “niches” that are conducive to cancer cells. In addition, the use of antioxidants and recycling of NADPH as defense mechanisms to sequester ROS favor the survival of cancer cells. (B) Oxidative phosphorylation (OXPHOS) impairment leads to crippled mitochondrial respiration. The dysfunctional TCA cycle generates fewer reactive oxygen species that may or may not induce DNA damage, and this subsequently leads to fewer mitochondrial DNA mutations. (C) Efficient repair of mtDNA leads to fewer mutations and less mitochondrial dysfunction. (D) In contrast, normal, low proliferative cells utilize OXPHOS and generate ROS that induce mtDNA damage and increase mutation frequency (shown in green).

Cancer arises from a mutator phenotype and it has been established that the random mutation rate of the nuclear DNA of tumors is quite high [18]. However, little is known about the random mutation rates of mitochondria derived from tumors. In this issue of PLoS Genetics, Ericson and colleagues [19] report their striking finding that the random mutation frequency of colorectal tumor mtDNA is significantly lower than that of nuclear DNA or of mtDNA in the surrounding normal tissue. These results were obtained using the random mutation capture assay that was developed to measure random, and not clonal, mutations [19]. This group also shows that the mitochondria from the colon tumors use aerobic glycolysis rather than oxidative phosphorylation to generate energy for the cells. Importantly, this metabolic shift from oxidative phosphorylation to aerobic glycolysis is likely to produce fewer ROS that damage mtDNA and lead to mutagenesis, mitochondrial dysfunction, and cell death.

Seven decades ago, Warburg discovered that mitochondria in cancer cells metabolize glucose by aerobic glycolysis and suggested that this was a result of impaired mitochondrial function that contributes to tumorigenesis [20], [21]. Recently, Thompson and colleagues suggested that mitochondrial function itself is not impaired in cancer cells that metabolize glucose by aerobic glycolysis, and that this type of anabolic metabolism is critical for the production of essential cellular building blocks including dNTPs, amino acids, and lipids [22] (Figure 1). Growth factor signaling by activated AKT, Myc, and other proto-oncogenes results in altered mitochondrial metabolism [22]. For example, a majority of human tumors harbor mutations in the AKT gene, and activated AKT enhances glucose uptake, allowing cells to maintain a higher than adequate level of ATP [23]. What is unknown is whether the colon tumors that were characterized by the Bielas group [19] harbor activated proto-oncogenes. Nevertheless, the picture that now emerges is that aerobic glycolysis enhances growth of cancer cells by anabolic metabolism without producing high levels of ROS that could inactivate the power supply of the cell.

Other explanations for the low frequency of random mitochondrial mutations in colon tumors include highly efficient DNA repair (for excellent review see [24]) and the coupling of antioxidant proteins to the NADPH/NADP balance (Figure 1). Recent studies have demonstrated that mtDNA is repaired by a variety of mechanisms, including short- and long-patch base excision repair, mismatch repair, and homologous recombination [24][27]. The sanitation of dNTPs is also likely to result in fewer mutations. Antioxidant proteins may also play a role in the low random mutation rate observed in mitochondria. Proteins such as reduced glutathione (GSH) or thioredoxin that are closely coupled to the NADPH/NADP balance can inactivate ROS [28], [29]. The presence of NADPH and other free radical scavengers may be more pronounced in the colorectal tumor environment to neutralize the impact of oxidative stress (Figure 1).

What are the implications of the findings of Ericson et al. [19] for future cancer therapy strategy or biomarker discovery? Cancer cells exhibit increased uptake of glucose, which increases the bioenergetic competence required of malignant cells. This metabolic feature has led to the hypothesis that inhibition of glycolysis may abolish ATP and important precursor generation in cancer cells and thus may preferentially kill the malignant cells [30], [31]. Nuclear genetic and epigenetic changes have been the cornerstone of such studies. In addition to these strategies, it is likely that mutated genes that function to alter mitochondrial metabolic competence in tumors, including HIF-1 and MYC, will emerge as new drug targets and molecular markers of prognosis and responses to therapy. In addition, targeting mtDNA repair proteins could serve as a potential alternative approach to kill cancer cells. The work of the Ericson et al. [19] adds significantly to our understanding of the roles of mitochondria in supporting the growth of tumors. In combination with recent findings regarding mitochondrial metabolism in cancer cells, this groundbreaking finding suggests that novel drugs that target the powerhouse of cancer cells are likely to make a significant impact on cancer treatment.


1. CairnsRAHarrisIMcCrackenSMakTW 2011 Cancer cell metabolism. Cold Spring Harb Symp Quant Biol E-pub ahead of print 12 December 2011

2. LoebLASpringgateCFBattulaN 1974 Errors in DNA replication as a basis of malignant changes. Cancer Res 34 2311 2321

3. MoolgavkarSHLuebeckEG 2003 Multistage carcinogenesis and the incidence of human cancer. Genes Chromosomes Cancer 38 302 306

4. Abu-AmeroKKAlzahraniASZouMShiY 2005 High frequency of somatic mitochondrial DNA mutations in human thyroid carcinomas and complex I respiratory defect in thyroid cancer cell lines. Oncogene 24 1455 1460

5. AlonsoAMartinPAlbarranCAquileraBGarciaO 1997 Detection of somatic mutations in the mitochondrial DNA control region of colorectal and gastric tumors by heteroduplex and single-strand conformation analysis. Electrophoresis 18 682 685

6. LiuVWShiHHCheungANChiuPMLeungTW 2001 High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res 61 5998 6001

7. MontaniniLRegna-GladinCEoliMAlbarosaRCarraraF 2005 Instability of mitochondrial DNA and MRI and clinical correlations in malignant gliomas. J Neurooncol 74 87 89

8. NagyAWilhelmMKovacsG 2003 Mutations of mtDNA in renal cell tumours arising in end-stage renal disease. J Pathol 199 237 242

9. NomotoSYamashitaKKoshikawaKNakaoASidranskyD 2002 Mitochondrial D-loop mutations as clonal markers in multicentric hepatocellular carcinoma and plasma. Clin Cancer Res 8 481 487

10. PetrosJABaumannAKRuiz-PesiniEAminMBSunCQ 2005 mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci U S A 102 719 724

11. Sanchez-CespedesMAhrendtSAPiantadosiSRosellRMonzoM 2001 Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers. Cancer Res 61 1309 1313

12. TanDJBaiRKWongLJ 2002 Comprehensive scanning of somatic mitochondrial DNA mutations in breast cancer. Cancer Res 62 972 976

13. WuCWYinPHHungWYLiAFLiSH 2005 Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer. Genes Chromosomes Cancer 44 19 28

14. Modica-NapolitanoJSSinghKK 2004 Mitochondrial dysfunction in cancer. Mitochondrion 4 755 762

15. SinghKKKulawiecMStillIDesoukiMMGeradtsJ 2005 Inter-genomic cross talk between mitochondria and the nucleus plays an important role in tumorigenesis. Gene 354 140 146

16. CopelandWCWachsmanJTJohnsonFMPentaJS 2002 Mitochondrial DNA alterations in cancer. Cancer Invest 20 557 569

17. CarewJSHuangP 2002 Mitochondrial defects in cancer. Mol Cancer 1 9

18. BielasJHLoebLA 2005 Quantification of random genomic mutations. Nat Methods 2 285 290

19. EricsonNGKulawiecMVermulstMSheahanKO'SullivanJ 2012 Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet 8 e1002689 doi:10.1371/journal.pgen.1002689

20. WarburgO 1956 On the origin of cancer cells. Science 123 309 314

21. WarburgO 1956 On respiratory impairment in cancer cells. Science 124 269 270

22. WardPSThompsonCB 2012 Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21 297 308

23. ElstromRLBauerDEBuzzaiMKarnauskasRHarrisMH 2004 Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64 3892 3899

24. LiuPDempleB 2010 DNA repair in mammalian mitochondria: Much more than we thought? Environ Mol Mutagen 51 417 426

25. AkbariMVisnesTKrokanHEOtterleiM 2008 Mitochondrial base excision repair of uracil and AP sites takes place by single-nucleotide insertion and long-patch DNA synthesis. DNA Repair (Amst) 7 605 616

26. FukuiHMoraesCT 2009 Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum Mol Genet 18 1028 1036

27. KraytsbergYSchwartzMBrownTAEbralidseKKunzWS 2004 Recombination of human mitochondrial DNA. Science 304 981

28. HamanakaRBChandelNS 2011 Cell biology. Warburg effect and redox balance. Science 334 1219 1220

29. SattlerUGMueller-KlieserW 2009 The anti-oxidant capacity of tumour glycolysis. Int J Radiat Biol 85 963 971

30. IzyumovDSAvetisyanAVPletjushkinaOYSakharovDVWirtzKW 2004 “Wages of fear”: transient threefold decrease in intracellular ATP level imposes apoptosis. Biochim Biophys Acta 1658 141 147

31. Munoz-PinedoCRuiz-RuizCRuiz de AlmodovarCPalaciosCLopez-RivasA 2003 Inhibition of glucose metabolism sensitizes tumor cells to death receptor-triggered apoptosis through enhancement of death-inducing signaling complex formation and apical procaspase-8 processing. J Biol Chem 278 12759 12768

Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics

2012 Číslo 6

Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Deprese u dětí a adolescentů
nový kurz
Autoři: MUDr. Vlastimil Nesnídal

Konsenzuální postupy v léčbě močových infekcí

COVID-19 up to date
Autoři: doc. MUDr. Vladimír Koblížek, Ph.D., MUDr. Mikuláš Skála, prof. MUDr. František Kopřiva, Ph.D., prof. MUDr. Roman Prymula, CSc., Ph.D.

Betablokátory a Ca antagonisté z jiného úhlu
Autoři: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Chronické žilní onemocnění a možnosti konzervativní léčby

Všechny kurzy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se