Skip to main content
SpringerLink
Log in

Voltage-Dependent Anion Channels and Tubulin: Bioenergetic Controllers in Cancer Cells

  • Chapter
  • First Online:
Molecular Basis for Mitochondrial Signaling

Part of the book series: Biological and Medical Physics, Biomedical Engineering ((BIOMEDICAL))

  • 968 Accesses

Abstract

The Warburg phenotype is characterized by enhanced glycolysis and suppression of mitochondrial metabolism. Sustained glycolysis depends on a low cytosolic ATP/ADP ratio that, in turn, occurs when mitochondrial metabolism is decreased. We propose that the voltage-dependent anion channel (VDAC) is a global controller of cancer cell bioenergetics. VDAC located in the mitochondrial outer membrane allows the flux of respiratory substrates, ADP, and Pi into mitochondria and the release of mitochondrial ATP to the cytosol. The tricarboxylic acid cycle generates NADH from the oxidation of respiratory substrates. NADH enters the respiratory chain to generate a proton motive force that maintains mitochondrial membrane potential (ΔΨ) and is utilized to generate ATP. The respiratory chain is also the major cellular source of mitochondrial reactive oxygen species (ROS). α-β tubulin heterodimers decrease VDAC conductance in lipid bilayers. Free tubulin by closing VDAC limits the ingress of respiratory substrates and ATP, thereby decreasing mitochondrial ΔΨ in tumor cells. By this mechanism, fluctuations of free tubulin dynamically regulate VDAC conductance and globally control mitochondrial metabolism, the intracellular flow of energy, and ROS formation. Erastin, a VDAC-binding molecule lethal to certain types of cancer cells, and erastin-like compounds identified in a small molecule screening antagonize the inhibitory effect of tubulin on VDAC. Blockage of tubulin inhibition of VDAC opens the channel to increase mitochondrial metabolism and subsequently decrease glycolysis. Mitochondrial hyperpolarization after VDAC opening also leads to oxidative stress and mitochondrial dysfunction, bioenergetic failure, and cell death. In summary, antagonism of VDAC-tubulin interaction promotes cell death by a “double hit model” characterized by reversion of the pro-proliferative Warburg phenotype and promotion of oxidative stress.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Al Jamal JA (2005) Involvement of porin N,N-dicyclohexylcarbodiimide-reactive domain in hexokinase binding to the outer mitochondrial membrane. Protein J 24(1):1–8. Available from: PM:15756812

    Article  Google Scholar 

  • Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V (2004) In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem J 377(Pt 2):347–355

    Article  Google Scholar 

  • Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P (2003) Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res 92(8):873–880

    Article  Google Scholar 

  • Beckner ME, Gobbel GT, Abounader R, Burovic F, Agostino NR, Laterra J, Pollack IF (2005) Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis. Lab Investig 85(12):1457–1470. Available from: PM:16170333

    Google Scholar 

  • Bera AK, Ghosh S, Das S (1995) Mitochondrial VDAC can be phosphorylated by cyclic AMP-dependent protein kinase. Biochem Biophys Res Commun 209(1):213–217. Available from: PM:7537039

    Article  Google Scholar 

  • Bhat TA, Kumar S, Chaudhary AK, Yadav N, Chandra D (2015) Restoration of mitochondria function as a target for cancer therapy. Drug Discov Today 20(5):635–643. Available from: PM:25766095

    Article  Google Scholar 

  • Blachly-Dyson E, Forte M (2001) VDAC channels. IUBMB Life 52(3–5):113–118

    Google Scholar 

  • Bouzier AK, Voisin P, Goodwin R, Canioni P, Merle M (1998) Glucose and lactate metabolism in C6 glioma cells: evidence for the preferential utilization of lactate for cell oxidative metabolism. Dev Neurosci 20(4–5):331–338. Available from: PM:9778569

    Article  Google Scholar 

  • Brand MD (2005) The efficiency and plasticity of mitochondrial energy transduction. Biochem Soc Trans 33(Pt 5):897–904. Available from: PM:16246006

    Article  Google Scholar 

  • Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45(7–8):466–472. Available from: PM:20064600

    Article  Google Scholar 

  • Cairns RA (2015) Drivers of the Warburg phenotype. Cancer J 21(2):56–61. Available from: PM:25815844

    Article  Google Scholar 

  • Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B, Ficarro SB, Polak K, Tondera D, Gounarides J, Yin H, Zhou F, Green MR, Chen L, Monti S, Marto JA, Shipp MA, Danial NN (2012) Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22(4):547–560. Available from: PM:23079663

    Article  Google Scholar 

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

    Google Scholar 

  • 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(38):36027–36031

    Article  Google Scholar 

  • Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY, Sontheimer H (2005) Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci 25(31):7101–7110. Available from: PM:16079392

    Article  Google Scholar 

  • Clavell LA, Gelber RD, Cohen HJ, Hitchcock-Bryan S, Cassady JR, Tarbell NJ, Blattner SR, Tantravahi R, Leavitt P, Sallan SE (1986) Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 315(11):657–663. Available from: PM:2943992

    Article  Google Scholar 

  • Clerkin JS, Naughton R, Quiney C, Cotter TG (2008) Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett 266(1):30–36. Available from: PM:18372105

    Article  Google Scholar 

  • Colombini M (1980) Structure and mode of action of a voltage dependent anion-selective channel (VDAC) located in the outer mitochondrial membrane. Ann NY Acad Sci 341:552–563. Available from: PM:6249159

    Article  ADS  Google Scholar 

  • Colombini M (2004) VDAC: the channel at the interface between mitochondria and the cytosol. Mol Cell Biochem 256–257(1–2):107–115

    Article  Google Scholar 

  • Colombini M (2012) VDAC structure, selectivity, and dynamics. Biochim Biophys Acta 1818(6):1457–1465. Available from: PM:22240010

    Article  Google Scholar 

  • Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, Walters H, Tantawy MN, Fu A, Manning HC, Horton JD, Hammer RE, McKnight SL, Tu BP (2014) Acetate dependence of tumors. Cell 159(7):1591–1602. Available from: PM:25525877

    Article  Google Scholar 

  • Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, Grabocka E, Nofal M, Drebin JA, Thompson CB, Rabinowitz JD, Metallo CM, Vander Heiden MG, Bar-Sagi D (2013) Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497(7451):633–637. Available from: PM:23665962

    Article  ADS  Google Scholar 

  • Conklin KA (2004) Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther 3(4):294–300. Available from: PM:15523100

    Article  Google Scholar 

  • Dang CV (2012) Links between metabolism and cancer. Genes Dev 26(9):877–890. Available from: PM:22549953

    Article  Google Scholar 

  • Das S, Wong R, Rajapakse N, Murphy E, Steenbergen C (2008) Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res 103(9):983–991. Available from: PM:18802025

    Article  Google Scholar 

  • De Pinto V, Guarino F, Guarnera A, Messina A, Reina S, Tomasello FM, Palermo V, Mazzoni C (2010) Characterization of human VDAC isoforms: a peculiar function for VDAC3? Biochim Biophys Acta 1797(6–7):1268–1275. Available from: PM:20138821

    Article  Google Scholar 

  • DeBerardinis RJ, Cheng T (2010) Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29(3):313–324. Available from: PM:19881548

    Article  Google Scholar 

  • DeBerardinis RJ, Sayed N, Ditsworth D, Thompson CB (2008) Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 18(1):54–61. Available from: PM:18387799

    Article  Google Scholar 

  • DeHart DN, Gooz M, Lemasters JJ, Maldonado EN (2015) Small anti-Warburg molecules kill hepatocarcinoma cells by opening voltage dependent anion channels and promoting mitochondrial oxidative stress. The Liver Meeting 2015, San Francisco. Ref Type: Abstract

    Google Scholar 

  • Doherty JR, Cleveland JL (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123(9):3685–3692. Available from: PM:23999443

    Article  Google Scholar 

  • Dolma S, Lessnick SL, Hahn WC, Stockwell BR (2003) Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3(3):285–296. Available from: PM:12676586

    Article  Google Scholar 

  • Eason K, Sadanandam A (2016) Molecular or metabolic reprograming: what triggers tumor subtypes? Cancer Res 76(18):5195–5200. Available from: PM:27635042

    Article  Google Scholar 

  • Faber M, Coudray C, Hida H, Mousseau M, Favier A (1995) Lipid peroxidation products, and vitamin and trace element status in patients with cancer before and after chemotherapy, including adriamycin. A preliminary study. Biol Trace Elem Res 47(1–3):117–123. Available from: PM:7779537

    Article  Google Scholar 

  • Fridovich I (1997) Superoxide anion radical (O2-.), superoxide dismutases, and related matters. J Biol Chem 272(30):18515–18517. Available from: PM:9228011

    Article  Google Scholar 

  • Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892. Available from: PM:22397650

    Article  Google Scholar 

  • Giles GI (2006) The redox regulation of thiol dependent signaling pathways in cancer. Curr Pharm Des 12(34):4427–4443. Available from: PM:17168752

    Article  Google Scholar 

  • Gincel D, Silberberg SD, Shoshan-Barmatz V (2000) Modulation of the voltage-dependent anion channel (VDAC) by glutamate. J Bioenerg Biomembr 32(6):571–583. Available from: PM:15254371

    Article  Google Scholar 

  • Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D (2010) Diabetes and cancer: a consensus report. CA Cancer J Clin 60(4):207–221. Available from: PM:20554718.

    Article  Google Scholar 

  • Griguer CE, Oliva CR, Gillespie GY (2005) Glucose metabolism heterogeneity in human and mouse malignant glioma cell lines. J Neurooncol 74(2):123–133. Available from: PM:16193382

    Article  Google Scholar 

  • Guppy M, Leedman P, Zu X, Russell V (2002) Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J 364(Pt 1):309–315. Available from: PM:11988105

    Article  Google Scholar 

  • Hahn AT, Jones JT, Meyer T (2009) Quantitative analysis of cell cycle phase durations and PC12 differentiation using fluorescent biosensors. Cell Cycle 8(7):1044–1052. Available from: PM:19270522

    Article  Google Scholar 

  • Han D, Antunes F, Canali R, Rettori D, Cadenas E (2003) Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278(8):5557–5563. Available from: PM:12482755

    Article  Google Scholar 

  • Hiller S, Abramson J, Mannella C, Wagner G, Zeth K (2010) The 3D structures of VDAC represent a native conformation. Trends Biochem Sci 35(9):514–521. Available from: PM:20708406

    Article  Google Scholar 

  • Holmuhamedov E, Lemasters JJ (2009) Ethanol exposure decreases mitochondrial outer membrane permeability in cultured rat hepatocytes. Arch Biochem Biophys 481(2):226–233. Available from: PM:19014900

    Article  Google Scholar 

  • Huang H, Shah K, Bradbury NA, Li C, White C (2014) Mcl-1 promotes lung cancer cell migration by directly interacting with VDAC to increase mitochondrial Ca2+ uptake and reactive oxygen species generation. Cell Death Dis 5:e1482. Available from: PM:25341036

    Article  Google Scholar 

  • Jara JA, Lopez-Munoz R (2015) Metformin and cancer: between the bioenergetic disturbances and the antifolate activity. Pharmacol Res 101:102–108. Available from: PM:26277279

    Article  Google Scholar 

  • Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120(5):649–661

    Article  Google Scholar 

  • Keenan MM, Chi JT (2015) Alternative fuels for cancer cells. Cancer J 21(2):49–55. Available from: PM:25815843

    Article  Google Scholar 

  • Keibler MA, Wasylenko TM, Kelleher JK, Iliopoulos O, Vander Heiden MG, Stephanopoulos G (2016) Metabolic requirements for cancer cell proliferation. Cancer Metab 4:16. Available from: PM:27540483

    Article  Google Scholar 

  • Kennedy KM, Scarbrough PM, Ribeiro A, Richardson R, Yuan H, Sonveaux P, Landon CD, Chi JT, Pizzo S, Schroeder T, Dewhirst MW (2013) Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. PLoS One 8(9):e75154. Available from: PM:24069390

    Article  ADS  Google Scholar 

  • Kilburn DG, Lilly MD, Webb FC (1969) The energetics of mammalian cell growth. J Cell Sci 4(3):645–654. Available from: PM:5817088

    Google Scholar 

  • Kreis W, Baker A, Ryan V, Bertasso A (1980) Effect of nutritional and enzymatic methionine deprivation upon human normal and malignant cells in tissue culture. Cancer Res 40(3):634–641. Available from: PM:6937240

    Google Scholar 

  • Ladner C, Ehninger G, Gey KF, Clemens MR (1989) Effect of etoposide (VP16-213) on lipid peroxidation and antioxidant status in a high-dose radiochemotherapy regimen. Cancer Chemother Pharmacol 25(3):210–212. Available from: PM:2513140

    Article  Google Scholar 

  • Lee AC, Zizi M, Colombini M (1994) Beta-NADH decreases the permeability of the mitochondrial outer membrane to ADP by a factor of 6. J Biol Chem 269(49):30974–30980

    Google Scholar 

  • Lemasters JJ, Holmuhamedov E (2006) Voltage-dependent anion channel (VDAC) as mitochondrial governator – thinking outside the box. Biochim Biophys Acta 1762(2):181–190. Available from: PM:16307870

    Article  Google Scholar 

  • Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32(9):1620–1625. Available from: PM:19564453

    Article  Google Scholar 

  • Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41(3):211–218. Available from: PM:26778478

    Article  Google Scholar 

  • Liemburg-Apers DC, Schirris TJ, Russel FG, Willems PH, Koopman WJ (2015) Mitoenergetic dysfunction triggers a rapid compensatory increase in steady-state glucose flux. Biophys J 109(7):1372–1386. Available from: PM:26445438

    Article  Google Scholar 

  • Lim HY, Ho QS, Low J, Choolani M, Wong KP (2011) Respiratory competent mitochondria in human ovarian and peritoneal cancer. Mitochondrion 11(3):437–443. Available from: PM:21211574

    Article  Google Scholar 

  • Liou GY, Storz P (2010) Reactive oxygen species in cancer. Free Radic Res 44(5):479–496. Available from: PM:20370557

    Article  Google Scholar 

  • Locasale JW, Cantley LC (2010) Altered metabolism in cancer. BMC Biol 8:88. Available from: PM:20598111

    Article  Google Scholar 

  • Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27:441–464. Available from: PM:21985671

    Article  Google Scholar 

  • Maldonado EN, Lemasters JJ (2012) Warburg revisited: regulation of mitochondrial metabolism by voltage-dependent anion channels in cancer cells. J Pharmacol Exp Ther 342(3):637–641. Available from: PM:22700429

    Article  Google Scholar 

  • Maldonado EN, Lemasters JJ (2014) ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect. Mitochondrion 19(Pt A):78–84. Available from: PM:25229666

    Article  Google Scholar 

  • Maldonado EN, Patnaik J, Mullins MR, Lemasters JJ (2010) Free tubulin modulates mitochondrial membrane potential in cancer cells. Cancer Res 70(24):10192–10201. Available from: PM:21159641

    Article  Google Scholar 

  • Maldonado EN, Sheldon KL, DeHart DN, Patnaik J, Manevich Y, Townsend DM, Bezrukov SM, Rostovtseva TK, Lemasters JJ (2013) Voltage-dependent anion channels modulate mitochondrial metabolism in cancer cells: regulation by free tubulin and erastin. J Biol Chem 288(17):11920–11929. Available from: PM:23471966

    Article  Google Scholar 

  • Maldonado EN, DeHart DN, Patnaik J, Klatt SC, Beck GM, Lemasters JJ (2016) ATP/ADP turnover and import of glycolytic ATP into mitochondria in cancer cells is independent of the adenine nucleotide translocator. J Biol Chem 291:19642. Available from: PM:27458020

    Article  Google Scholar 

  • Marengo B, Nitti M, Furfaro AL, Colla R, Ciucis CD, Marinari UM, Pronzato MA, Traverso N, Domenicotti C (2016) Redox homeostasis and cellular antioxidant systems: crucial players in cancer growth and therapy. Oxid Med Cell Longev 2016:6235641. Available from: PM:27418953

    Article  Google Scholar 

  • Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, Nannepaga S, Piccirillo SG, Kovacs Z, Foong C, Huang Z, Barnett S, Mickey BE, DeBerardinis RJ, Tu BP, Maher EA, Bachoo RM (2014) Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159(7):1603–1614. Available from: PM:25525878

    Article  Google Scholar 

  • Mathupala SP, Ko YH, Pedersen PL (2010) The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta 1797(6–7):1225–1230. Available from: PM:20381449

    Article  Google Scholar 

  • Meiser J, Vazquez A (2016) Give it or take it: the flux of one-carbon in cancer cells. FEBS J 283:3695. Available from: PM:27042806

    Article  Google Scholar 

  • Mor I, Cheung EC, Vousden KH (2011) Control of glycolysis through regulation of PFK1: old friends and recent additions. Cold Spring Harb Symp Quant Biol 76:211–216. Available from: PM:22096029

    Article  Google Scholar 

  • Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274(6):1393–1418. Available from: PM:17302740

    Article  Google Scholar 

  • Moreno-Sanchez R, Marin-Hernandez A, Saavedra E, Pardo JP, Ralph SJ, Rodriguez-Enriquez S (2014) Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism. Int J Biochem Cell Biol 50:10–23. Available from: PM:24513530

    Article  Google Scholar 

  • Morgan B, Sobotta MC, Dick TP (2011) Measuring E(GSH) and H2O2 with roGFP2-based redox probes. Free Radic Biol Med 51(11):1943–1951. Available from: PM:21964034

    Article  Google Scholar 

  • Muller FL, Liu Y, Van RH (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 279(47):49064–49073. Available from: PM:15317809

    Article  Google Scholar 

  • Nakashima RA, Paggi MG, Pedersen PL (1984) Contributions of glycolysis and oxidative phosphorylation to adenosine 5′-triphosphate production in AS-30D hepatoma cells. Cancer Res 44(12 Pt 1):5702–5706

    Google Scholar 

  • Nakashima RA, Paggi MG, Scott LJ, Pedersen PL (1988) Purification and characterization of a bindable form of mitochondrial bound hexokinase from the highly glycolytic AS-30D rat hepatoma cell line. Cancer Res 48(4):913–919. Available from: PM:3338084

    Google Scholar 

  • Palmieri F, Pierri CL (2010) Mitochondrial metabolite transport. Essays Biochem 47:37–52. Available from: PM:20533899

    Article  Google Scholar 

  • Panieri E, Santoro MM (2016) ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis 7(6):e2253. Available from: PM:27277675

    Article  Google Scholar 

  • Pastorino JG, Hoek JB (2003) Hexokinase II: the integration of energy metabolism and control of apoptosis. Curr Med Chem 10(16):1535–1551

    Article  Google Scholar 

  • Pedersen PL (1978) Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 22:190–274. Available from: PM:149996

    Article  Google Scholar 

  • Pelicano H, Martin DS, Xu RH, Huang P (2006) Glycolysis inhibition for anticancer treatment. Oncogene 25(34):4633–4646. Available from: PM:16892078

    Article  Google Scholar 

  • Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA, Brand MD (2012) Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem 287(32):27255–27264. Available from: PM:22689576

    Article  Google Scholar 

  • Rich PR (2003) The molecular machinery of Keilin’s respiratory chain. Biochem Soc Trans 31(Pt 6):1095–1105. Available from: PM:14641005

    Article  Google Scholar 

  • Rich PR, Marechal A (2010) The mitochondrial respiratory chain. Essays Biochem 47:1–23. Available from: PM:20533897

    Article  Google Scholar 

  • Robinson GL, Dinsdale D, MacFarlane M, Cain K (2012) Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL. Oncogene 31(48):4996–5006. Available from: PM:22310286

    Article  Google Scholar 

  • Rodriguez-Enriquez S, Carreno-Fuentes L, Gallardo-Perez JC, Saavedra E, Quezada H, Vega A, Marin-Hernandez A, Olin-Sandoval V, Torres-Marquez ME, Moreno-Sanchez R (2010) Oxidative phosphorylation is impaired by prolonged hypoxia in breast and possibly in cervix carcinoma. Int J Biochem Cell Biol 42(10):1744–1751. Available from: PM:20654728

    Article  Google Scholar 

  • Rostovtseva TK, Antonsson B, Suzuki M, Youle RJ, Colombini M, Bezrukov SM (2004) Bid, but not Bax, regulates VDAC channels. J Biol Chem 279(14):13575–13583

    Article  Google Scholar 

  • Rostovtseva TK, Sheldon KL, Hassanzadeh E, Monge C, Saks V, Bezrukov SM, Sackett DL (2008) Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc Natl Acad Sci USA 105(48):18746–18751. Available from: PM:19033201

    Article  ADS  Google Scholar 

  • Sampson MJ, Lovell RS, Craigen WJ (1997) The murine voltage-dependent anion channel gene family. Conserved structure and function. J Biol Chem 272(30):18966–18973. Available from: PM:9228078

    Article  Google Scholar 

  • Sampson MJ, Decker WK, Beaudet AL, Ruitenbeek W, Armstrong D, Hicks MJ, Craigen WJ (2001) Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J Biol Chem 276(42):39206–39212. Available from: PM:11507092

    Article  Google Scholar 

  • Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, Kaluarachchi K, Bornmann W, Duvvuri S, Taegtmeyer H, Andreeff M (2010) Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest 120(1):142–156. Available from: PM:20038799

    Article  Google Scholar 

  • Schenkel LC, Bakovic M (2014) Formation and regulation of mitochondrial membranes. Int J Cell Biol 2014:709828. Available from: PM:24578708

    Article  Google Scholar 

  • Schredelseker J, Paz A, Lopez CJ, Altenbach C, Leung CS, Drexler MK, Chen JN, Hubbell WL, Abramson J (2014) High resolution structure and double electron-electron resonance of the zebrafish voltage-dependent anion channel 2 reveal an oligomeric population. J Biol Chem 289(18):12566–12577. Available from: PM:24627492

    Article  Google Scholar 

  • Schwenke WD, Soboll S, Seitz HJ, Sies H (1981) Mitochondrial and cytosolic ATP/ADP ratios in rat liver in vivo. Biochem J 200(2):405–408. Available from: PM:7340839

    Article  Google Scholar 

  • Scott L, Lamb J, Smith S, Wheatley DN (2000) Single amino acid (arginine) deprivation: rapid and selective death of cultured transformed and malignant cells. Br J Cancer 83(6):800–810. Available from: PM:10952786

    Article  Google Scholar 

  • Scott DA, Richardson AD, Filipp FV, Knutzen CA, Chiang GG, Ronai ZA, Osterman AL, Smith JW (2011) Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J Biol Chem 286(49):42626–42634. Available from: PM:21998308

    Article  Google Scholar 

  • Sheen JH, Zoncu R, Kim D, Sabatini DM (2011) Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 19(5):613–628. Available from: PM:21575862

    Article  Google Scholar 

  • Singleterry J, Sreedhar A, Zhao Y (2014) Components of cancer metabolism and therapeutic interventions. Mitochondrion 17C:50–55. Available from: PM:24910195

    Article  Google Scholar 

  • Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, Hurren R, Jitkova Y, Gronda M, Maclean N, Lai CK, Eberhard Y, Bartoszko J, Spagnuolo P, Rutledge AC, Datti A, Ketela T, Moffat J, Robinson BH, Cameron JH, Wrana J, Eaves CJ, Minden MD, Wang JC, Dick JE, Humphries K, Nislow C, Giaever G, Schimmer AD (2011) Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20(5):674–688. Available from: PM:22094260

    Article  Google Scholar 

  • Skulachev VP (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys 29(2):169–202. Available from: PM:8870073

    Article  Google Scholar 

  • Smolkova K, Bellance N, Scandurra F, Genot E, Gnaiger E, Plecita-Hlavata L, Jezek P, Rossignol R (2010) Mitochondrial bioenergetic adaptations of breast cancer cells to aglycemia and hypoxia. J Bioenerg Biomembr 42(1):55–67. Available from: PM:20084539

    Article  Google Scholar 

  • Son Y, Cheong YK, Kim NH, Chung HT, Kang DG, Pae HO (2011) Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways? J Signal Transduct 2011:792639. Available from: PM:21637379

    Article  Google Scholar 

  • Song J, Colombini M (1996) Indications of a common folding pattern for VDAC channels from all sources. J Bioenerg Biomembr 28(2):153–161. Available from: PM:9132414

    Article  Google Scholar 

  • Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118(12):3930–3942. Available from: PM:19033663

    Google Scholar 

  • Sullivan LB, Chandel NS (2014) Mitochondrial reactive oxygen species and cancer. Cancer Metab 2:17. Available from: PM:25671107

    Article  Google Scholar 

  • Suski JM, Lebiedzinska M, Bonora M, Pinton P, Duszynski J, Wieckowski MR (2012) Relation between mitochondrial membrane potential and ROS formation. Methods Mol Biol 810:183–205. Available from: PM:22057568

    Article  Google Scholar 

  • Sutendra G, Michelakis ED (2013) Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol 3:38. Available from: PM:23471124

    Article  Google Scholar 

  • Timohhina N, Guzun R, Tepp K, Monge C, Varikmaa M, Vija H, Sikk P, Kaambre T, Sackett D, Saks V (2009) Direct measurement of energy fluxes from mitochondria into cytoplasm in permeabilized cardiac cells in situ: some evidence for mitochondrial interactosome. J Bioenerg Biomembr 41(3):259–275. Available from: PM:19597977

    Article  Google Scholar 

  • Tribble DL, Jones DP, Edmondson DE (1988) Effect of hypoxia on tert-butylhydroperoxide-induced oxidative injury in hepatocytes. Molec Pharmacol 34:413–420

    Google Scholar 

  • Tsujimoto Y, Shimizu S (2000) VDAC regulation by the Bcl-2 family of proteins. Cell Death Differ 7(12):1174–1181. Available from: PM:11175254

    Article  Google Scholar 

  • Ujwal R, Cascio D, Colletier JP, Faham S, Zhang J, Toro L, Ping P, Abramson J (2008) The crystal structure of mouse VDAC1 at 2.3 A resolution reveals mechanistic insights into metabolite gating. Proc Natl Acad Sci USA 105(46):17742–17747. Available from: PM:18988731

    Article  ADS  Google Scholar 

  • Ushio-Fukai M, Nakamura Y (2008) Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett 266(1):37–52. Available from: PM:18406051

    Article  Google Scholar 

  • Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB (2000) Outer mitochondrial membrane permeability can regulate coupled respiration and cell survival. Proc Natl Acad Sci USA 97(9):4666–4671

    Article  ADS  Google Scholar 

  • Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M (2001) Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem 276(22):19414–19419

    Article  Google Scholar 

  • Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26(1):1–14. Available from: PM:17434122

    Article  Google Scholar 

  • Venditti P, Di SL, Di MS (2013) Mitochondrial metabolism of reactive oxygen species. Mitochondrion 13(2):71–82. Available from: PM:23376030

    Article  Google Scholar 

  • Walker JE (2013) The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans 41(1):1–16. Available from: PM:23356252

    Article  Google Scholar 

  • Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18(3):207–219. Available from: PM:20832749

    Article  Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314. Available from: PM:13298683

    Article  ADS  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530. Available from: PM:19872213

    Article  Google Scholar 

  • Weijl NI, Hopman GD, Wipkink-Bakker A, Lentjes EG, Berger HM, Cleton FJ, Osanto S (1998) Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol 9(12):1331–1337. Available from: PM:9932164

    Article  Google Scholar 

  • Weinberg SE, Chandel NS (2015) Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol 11(1):9–15. Available from: PM:25517383

    Article  Google Scholar 

  • Weinhouse S (1956) On respiratory impairment in cancer cells. Science 124(3215):267–269. Available from: PM:13351638

    Article  ADS  Google Scholar 

  • Wikstrom M, Sharma V, Kaila VR, Hosler JP, Hummer G (2015) New perspectives on proton pumping in cellular respiration. Chem Rev 115(5):2196–2221. Available from: PM:25694135

    Article  Google Scholar 

  • Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N, Cairns R, Hawkins C, Guha A (2011) Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J Exp Med 208(2):313–326. Available from: PM:21242296

    Article  Google Scholar 

  • Yagoda N, von Rechenberg RM, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, Smith R, Lessnick SL, Sahasrabudhe S, Stockwell BR (2007) RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447(7146):864–868. Available from: PM:17568748

    Article  ADS  Google Scholar 

  • Yun J, Johnson JL, Hanigan CL, Locasale JW (2012) Interactions between epigenetics and metabolism in cancers. Front Oncol 2:163. Available from: PM:23162793

    Article  Google Scholar 

  • Zhang Y, Marcillat O, Giulivi C, Ernster L, Davies KJ (1990) The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J Biol Chem 265(27):16330–16336. Available from: PM:2168888

    Google Scholar 

  • Zhang X, Fryknas M, Hernlund E, Fayad W, De MA, Olofsson MH, Gogvadze V, Dang L, Pahlman S, Schughart LA, Rickardson L, D'Arcy P, Gullbo J, Nygren P, Larsson R, Linder S (2014) Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun 5:3295. Available from: PM:24548894

    Google Scholar 

  • Zhu A, Lee D, Shim H (2011) Metabolic positron emission tomography imaging in cancer detection and therapy response. Semin Oncol 38(1):55–69. Available from: PM:21362516

    Article  Google Scholar 

  • Zizi M, Forte M, Blachly-Dyson E, Colombini M (1994) NADH regulates the gating of VDAC, the mitochondrial outer membrane channel. J Biol Chem 269(3):1614–1616. Available from: PM:7507479

    Google Scholar 

Download references

Funding

R01CA184456, GM103542 and ACS 13-041-01-IRG to ENM, T32DK083262 to DND, and R21 AA021191, AA022815 and DK073336 to JJL.

Supported in part by the Cell & Molecular Imaging Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313) and the Shared Instrumentation Grant S10 OD018113.

Author information

Authors and Affiliations

  1. Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, DD506 Drug Discovery Building, 70 President Street, MSC 139, Charleston, SC, 29425, USA

    Eduardo N. Maldonado & John J. Lemasters

  2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    Eduardo N. Maldonado & John J. Lemasters

  3. Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, 29425, USA

    Eduardo N. Maldonado & John J. Lemasters

  4. Departments of Drug Discovery and Biomedical Sciences and the Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    David N. DeHart

  5. Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA

    John J. Lemasters

  6. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russian Federation

    John J. Lemasters

Authors
  1. Eduardo N. Maldonado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David N. DeHart
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John J. Lemasters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eduardo N. Maldonado .

Editor information

Editors and Affiliations

  1. Section on Molecular Transport, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Tatiana K. Rostovtseva

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Maldonado, E.N., DeHart, D.N., Lemasters, J.J. (2017). Voltage-Dependent Anion Channels and Tubulin: Bioenergetic Controllers in Cancer Cells. In: Rostovtseva, T. (eds) Molecular Basis for Mitochondrial Signaling. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-55539-3_5

Download citation

Publish with us

Policies and ethics

Search

Navigation