Abstract
Mitochondrial structural and functional integrity defines the health of a cell by regulating cellular metabolism. Thus, mitochondria play an important role in both cell proliferation and cell death. Cancer cells are metabolically altered compared to normal cells for their ability to survive better and proliferate faster. Resistance to apoptosis is an important characteristic of cancer cells and given the contribution of mitochondria to apoptosis, it is imperative that mitochondria could behave differently in a tumor situation. The other feature associated with cancer cells is the Warburg effect, which engages a shift in metabolism. Although the Warburg effect often occurs in conjunction with dysfunctional mitochondria, the relationship between mitochondria, the Warburg effect, and cancer cell metabolism is not clearly decoded. Other than these changes, several mitochondrial gene mutations occur in cancer cells, mitochondrial biogenesis is affected and mitochondria see structural and functional variations. In cancer pharmacology, targeting mitochondria and mitochondria associated signaling pathways to reduce tumor proliferation is a growing field of interest. This chapter summarizes various changes in mitochondria in relevance to cancer, behavior of mitochondria during tumorigenesis, and the progress on using mitochondria as a therapeutic target for cancer.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abu-Amero KK, Alzahrani AS, Zou M, Shi Y (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
Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, Bellinger G, Sasaki AT, Locasale JW, Auld DS et al (2011) Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334:1278–1283
Appleyard MV, Murray KE, Coates PJ, Wullschleger S, Bray SE, Kernohan NM, Fleming S, Alessi DR, Thompson AM (2012) Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer 106:1117–1122
Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR et al (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 278:17190–17197
Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334:574–579
Balic A, Sorensen MD, Trabulo SM, Sainz B Jr, Cioffi M, Vieira CR, Miranda-Lorenzo I, Hidalgo M, Kleeff J, Erkan M et al (2014) Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling. Mol Cancer Ther 13:1758–1771
Belzacq AS, El Hamel C, Vieira HL, Cohen I, Haouzi D, Metivier D, Marchetti P, Brenner C, Kroemer G (2001) Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 20:7579–7587
Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C et al (2010) Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res 70:2465–2475
Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B, Wang T, Chen WW, Clish CB, Sabatini DM (2014) Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508:108–112
Bjelakovic G, Gluud C (2007) Surviving antioxidant supplements. J Natl Cancer Inst 99:742–743
Blanchard JL, Schmidt GW (1996) Mitochondrial DNA migration events in yeast and humans: integration by a common end-joining mechanism and alternative perspectives on nucleotide substitution patterns. Mol Biol Evol 13:537–548
Boland ML, Chourasia AH, Macleod KF (2013) Mitochondrial dysfunction in cancer. Front Oncol 3:292
Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472
Brooks C, Wei Q, Feng L, Dong G, Tao Y, Mei L, Xie ZJ, Dong Z (2007) Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc Natl Acad Sci U S A 104:11649–11654
Canter JA, Kallianpur AR, Parl FF, Millikan RC (2005) Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 65:8028–8033
Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657
Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H, Trapasso F, Drusco A, Shimizu M, Masciullo V et al (2003) Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci U S A 100:5956–5961
Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N (2009) Importing mitochondrial proteins: machineries and mechanisms. Cell 138:628–644
Chatterjee A, Mambo E, Sidransky D (2006) Mitochondrial DNA mutations in human cancer. Oncogene 25:4663–4674
Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031
Chen Z, Zhang H, Lu W, Huang P (2009) Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta 1787:553–560
Chinnery PF, Samuels DC, Elson J, Turnbull DM (2002) Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360:1323–1325
Chourasia AH, Macleod KF (2015) Tumor suppressor functions of BNIP3 and mitophagy. Autophagy 11:1937–1938
Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (2008) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:181–186
Cormio A, Milella F, Vecchiet J, Felzani G, Gadaleta MN, Cantatore P (2005) Mitochondrial DNA mutations in RRF of healthy subjects of different age. Neurobiol Aging 26:655–664
Dang CV (2010) Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res 70:859–862
Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8:870–879
Dominy JE Jr, Lee Y, Gerhart-Hines Z, Puigserver P (2010) Nutrient-dependent regulation of PGC-1alpha's acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5. Biochim Biophys Acta 1804:1676–1683
Don AS, Kisker O, Dilda P, Donoghue N, Zhao X, Decollogne S, Creighton B, Flynn E, Folkman J, Hogg PJ (2003) A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell 3:497–509
El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228
Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, Jen J, Sidransky D (2000) Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287:2017–2019
Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, Kataoka A, Nukina N, Takahashi R, Chiba T (2008) Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene 27:6002–6011
Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, Alberghina L, Stephanopoulos G, Chiaradonna F (2011) Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol 7:523
Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT et al (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458:762–765
Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899
Glasauer A, Sena LA, Diebold LP, Mazar AP, Chandel NS (2014) Targeting SOD1 reduces experimental non-small-cell lung cancer. J Clin Invest 124:117–128
Grivell LA (1983) Mitochondrial DNA. Sci Am 248:78–89
Habano W, Sugai T, Yoshida T, Nakamura S (1999) Mitochondrial gene mutation, but not large-scale deletion, is a feature of colorectal carcinomas with mitochondrial microsatellite instability. Int J Cancer 83:625–629
Hagen TM, Huang S, Curnutte J, Fowler P, Martinez V, Wehr CM, Ames BN, Chisari FV (1994) Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma. Proc Natl Acad Sci U S A 91:12808–12812
Hamanaka RB, Chandel NS (2010) Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci 35:505–513
Hanna RA, Quinsay MN, Orogo AM, Giang K, Rikka S, Gustafsson AB (2012) Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem 287:19094–19104
Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, Ding Z, Ying H, Boutin AT, Zhang H et al (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148:651–663
Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ (1997) Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 275:1649–1652
Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW et al (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397–409
Jeronimo C, Nomoto S, Caballero OL, Usadel H, Henrique R, Varzim G, Oliveira J, Lopes C, Fliss MS, Sidransky D (2001) Mitochondrial mutations in early stage prostate cancer and bodily fluids. Oncogene 20:5195–5198
Jones JB, Song JJ, Hempen PM, Parmigiani G, Hruban RH, Kern SE (2001) Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutations. Cancer Res 61:1299–1304
Jung SN, Yang WK, Kim J, Kim HS, Kim EJ, Yun H, Park H, Kim SS, Choe W, Kang I et al (2008) Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 29:713–721
Kang N, Zhang JH, Qiu F, Tashiro S, Onodera S, Ikejima T (2010) Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways. Cancer Lett 294:147–158
Karbowski M, Youle RJ (2003) Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ 10:870–880
Kelly PN, Strasser A (2011) The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ 18:1414–1424
Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185
Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 11:325–337
Larman TC, DePalma SR, Hadjipanayis AG, Cancer Genome Atlas Research Network, Protopopov A, Zhang J, Gabriel SB, Chin L, Seidman CE, Kucherlapati R et al (2012) Spectrum of somatic mitochondrial mutations in five cancers. Proc Natl Acad Sci U S A 109:14087–14091
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H et al (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15:110–121
Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG (2002) Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 277:20336–20342
Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP (2003) Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 22:5501–5510
Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O'Donnell KA, Kim JW, Yustein JT, Lee LA, Dang CV (2005) Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25:6225–6234
Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R, McNay EC, Yu T, Schwarzenbacher R, Bossy B et al (2008) Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A 105:2169–2174
Lightowlers RN, Chinnery PF, Turnbull DM, Howell N (1997) Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet 13:450–455
Liou GY, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44:479–496
Liu Z, Li D, Zheng X, Wang E, Wang J (2013) Selective induction of apoptosis: promising therapy in pancreatic cancer. Curr Pharm Des 19:2259–2268
Luciakova K, Kuzela S (1992) Increased steady-state levels of several mitochondrial and nuclear gene transcripts in rat hepatoma with a low content of mitochondria. Eur J Biochem 205:1187–1193
Margineantu DH, Gregory Cox W, Sundell L, Sherwood SW, Beechem JM, Capaldi RA (2002) Cell cycle dependent morphology changes and associated mitochondrial DNA redistribution in mitochondria of human cell lines. Mitochondrion 1:425–435
Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25:4777–4786
Maximo V, Soares P, Lima J, Cameselle-Teijeiro J, Sobrinho-Simoes M (2002) Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hurthle cell tumors. Am J Pathol 160:1857–1865
Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J (2009) A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A 106:11960–11965
Mitsuishi Y, Motohashi H, Yamamoto M (2012) The Keap1-Nrf2 system in cancers: stress response and anabolic metabolism. Front Oncol 2:200
Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R, Manstein DJ, Bossy-Wetzel E, Basanez G, Meda P et al (2010) Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142:889–901
Morrish F, Hockenbery D (2014) MYC and mitochondrial biogenesis. Cold Spring Harb Perspect Med 4
Nagaraj R, Gururaja-Rao S, Jones KT, Slattery M, Negre N, Braas D, Christofk H, White KP, Mann R, Banerjee U (2012) Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway. Genes Dev 26:2027–2037
Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803
Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ (2010) p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy 6:1090–1106
Neuzil J, Dyason JC, Freeman R, Dong LF, Prochazka L, Wang XF, Scheffler I, Ralph SJ (2007) Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II. J Bioenerg Biomembr 39:65–72
Okami J, Simeone DM, Logsdon CD (2004) Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Cancer Res 64:5338–5346
Ostman A, Frijhoff J, Sandin A, Bohmer FD (2011) Regulation of protein tyrosine phosphatases by reversible oxidation. J Biochem 150:345–356
Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348(Pt 3):607–614
Owusu-Ansah E, Banerjee U (2009) Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461:537–541
Parker DJ, Iyer A, Shah S, Moran A, Hjelmeland AB, Basu MK, Liu R, Mitra K (2015) A new mitochondrial pool of cyclin E, regulated by Drp1, is linked to cell-density-dependent cell proliferation. J Cell Sci 128:4171–4182
Parrella P, Xiao Y, Fliss M, Sanchez-Cespedes M, Mazzarelli P, Rinaldi M, Nicol T, Gabrielson E, Cuomo C, Cohen D et al (2001) Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. Cancer Res 61:7623–7626
Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S et al (2009) The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8:3984–4001
Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH et al (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci U S A 102:719–724
Pollak M (2014) Overcoming drug development bottlenecks with repurposing: repurposing biguanides to target energy metabolism for cancer treatment. Nat Med 20:591–593
Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B (1998) Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20:291–293
Qian W, Choi S, Gibson GA, Watkins SC, Bakkenist CJ, Van Houten B (2012) Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes ATM-dependent G2/M arrest and aneuploidy through DNA replication stress. J Cell Sci 125:5745–5757
Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330:1344–1348
Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF et al (2011) Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475:231–234
Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J (2011) Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A 108:10190–10195
Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z, Salgia R, Husain AN, Wietholt C, Archer SL (2012) Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J 26:2175–2186
Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA (2004) Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 64:985–993
Rumsey WL, Schlosser C, Nuutinen EM, Robiolio M, Wilson DF (1990) Cellular energetics and the oxygen dependence of respiration in cardiac myocytes isolated from adult rat. J Biol Chem 265:15392–15402
Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C et al (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:359–365
Salani B, Marini C, Rio AD, Ravera S, Massollo M, Orengo AM, Amaro A, Passalacqua M, Maffioli S, Pfeffer U et al (2013) Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. Sci Rep 3:2070
Sanchez-Cespedes M, Parrella P, Nomoto S, Cohen D, Xiao Y, Esteller M, Jeronimo C, Jordan RC, Nicol T, Koch WM et al (2001) Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors. Cancer Res 61:7015–7019
Sasaki R, Suzuki Y, Yonezawa Y, Ota Y, Okamoto Y, Demizu Y, Huang P, Yoshida H, Sugimura K, Mizushina Y (2008) DNA polymerase gamma inhibition by vitamin K3 induces mitochondria-mediated cytotoxicity in human cancer cells. Cancer Sci 99:1040–1048
Scarpulla RC, Vega RB, Kelly DP (2012) Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab 23:459–466
Schumacker PT (2006) Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell 10:175–176
Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167
Shaw AT, Winslow MM, Magendantz M, Ouyang C, Dowdle J, Subramanian A, Lewis TA, Maglathin RL, Tolliday N, Jacks T (2011) Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci U S A 108:8773–8778
Sherr CJ, McCormick F (2002) The RB and p53 pathways in cancer. Cancer Cell 2:103–112
Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, Kasai H (1994) Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res 54:3171–3172
Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, Hurren R, Jitkova Y, Gronda M, Maclean N et al (2011) Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20:674–688
Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942
Sowter HM, Ferguson M, Pym C, Watson P, Fox SB, Han C, Harris AL (2003) Expression of the cell death genes BNip3 and NIX in ductal carcinoma in situ of the breast; correlation of BNip3 levels with necrosis and grade. J Pathol 201:573–580
Tan EY, Campo L, Han C, Turley H, Pezzella F, Gatter KC, Harris AL, Fox SB (2007) BNIP3 as a progression marker in primary human breast cancer; opposing functions in in situ versus invasive cancer. Clin Cancer Res 13:467–474
Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P, Raschke I, Merkwirth C et al (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28:1589–1600
Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591
Tracy K, Dibling BC, Spike BT, Knabb JR, Schumacker P, Macleod KF (2007) BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol 27:6229–6242
Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446
Umeda S, Muta T, Ohsato T, Takamatsu C, Hamasaki N, Kang D (2000) The D-loop structure of human mtDNA is destabilized directly by 1-methyl-4-phenylpyridinium ion (MPP+), a parkinsonism-causing toxin. Eur J Biochem 267:200–206
Van den Bogert C, Muus P, Haanen C, Pennings A, Melis TE, Kroon AM (1988) Mitochondrial biogenesis and mitochondrial activity during the progression of the cell cycle of human leukemic cells. Exp Cell Res 178:143–153
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033
Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM et al (2013) PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23:287–301
Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431
Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12:685–698
Warburg O (1956) On respiratory impairment in cancer cells. Science 124:269–270
Wenz T (2013) Regulation of mitochondrial biogenesis and PGC-1alpha under cellular stress. Mitochondrion 13:134–142
Wong LJ, Lueth M, Li XN, Lau CC, Vogel H (2003) Detection of mitochondrial DNA mutations in the tumor and cerebrospinal fluid of medulloblastoma patients. Cancer Res 63:3866–3871
Yarosh W, Monserrate J, Tong JJ, Tse S, Le PK, Nguyen K, Brachmann CB, Wallace DC, Huang T (2008) The molecular mechanisms of OPA1-mediated optic atrophy in Drosophila model and prospects for antioxidant treatment. PLoS Genet 4, e6
Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12:9–14
Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59
Yuan P, Ito K, Perez-Lorenzo R, Del Guzzo C, Lee JH, Shen CH, Bosenberg MW, McMahon M, Cantley LC, Zheng B (2013) Phenformin enhances the therapeutic benefit of BRAF(V600E) inhibition in melanoma. Proc Natl Acad Sci U S A 110:18226–18231
Zhang J, Ney PA (2009) Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ 16:939–946
Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL (2007) HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11:407–420
Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, Hu W, Feng Z (2011) Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci U S A 108:16259–16264
Zhang X, Fryknas M, Hernlund E, Fayad W, De Milito A, Olofsson MH, Gogvadze V, Dang L, Pahlman S, Schughart LA et al (2014) Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun 5:3295
Zu XL, Guppy M (2004) Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun 313:459–465
Acknowledgments
I thank Drs. Harpreet Singh and James Barrett (Drexel University College of Medicine) for helpful discussions, and Dr. Frances Munoz and Kajol Shah for proof reading of the book chapter. The work was supported by a CURE grant.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Gururaja Rao, S. (2016). Mitochondrial Changes in Cancer. In: Singh, H., Sheu, SS. (eds) Pharmacology of Mitochondria. Handbook of Experimental Pharmacology, vol 240. Springer, Cham. https://doi.org/10.1007/164_2016_40
Download citation
DOI: https://doi.org/10.1007/164_2016_40
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-57311-3
Online ISBN: 978-3-319-57313-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)