Abstract
The classical view of tumour cell bioenergetics has been recently revised. Then, the definition of the mitochondrial profile is considered of fundamental importance for the development of anti-cancer therapies, but it still needs to be clarified. We investigated two human hepatocellular carcinoma cell lines: the partially differentiated HepG2 and the undifferentiated JHH-6. High resolution respirometry revealed a marked impairment/uncoupling of OXPHOS in JHH-6 compared with HepG2, with the phosphorylation system limiting the capacity for electron transport much more in JHH-6. Blocking glycolysis or mitochondrial ATP synthase we demonstrated that in JHH-6 ATP synthase functions in reverse and consumes glycolytic ATP, thereby sustaining ΔΨm. A higher expression level of ATP synthase Inhibitor Factor 1 (IF1), a higher extent of IF1 bound to ATP synthase and a lower ATPase/synthase capacity were documented in JHH-6. Thus, here IF1 appears to down-regulate the reverse mode of ATPsynthase activity, thereby playing a crucial role in controlling energy waste and ΔΨm. These results, while confirming the over-expression of IF1 in cancer cells, are the first to indicate an inverse link between cell differentiation status and IF1 (expression level and regulatory function).
Similar content being viewed by others
References
Arismendi-Morillo G (2009) Int J Biochem Cell Biol 41:2062–2068
Bellance N, Benard G, Furt F, Begueret H, Smolkova K, Passerieux E, Delage JP, Baste JM, Moreau P, Rossignol R (2009) Int J Biochem Cell Biol 41:2566–2577
Bravo C, Minauro-Sanmiguel F, Morales-Rios E, Rodriguez-Zavala JS, Garcia JJ (2004) J Bioenerg Biomembr 36:257–264
Campanella M, Parker N, Tan CH, Hall AM, Duchen MR (2009) Trends Biochem Sci 34:343–350
Chen C, Ko Y, Delannoy M, Ludtke SJ, Chiu W, Pedersen PL (2004) J Biol Chem 279:31761–31768
Chernyak BV, Dukhovich VF, Khodjaev E (1991) Arch Biochem Biophys 286:604–609
Chevrollier A, Loiseau D, Chabi B, Renier G, Douay O, Malthiery Y, Stepien G (2005) J Bioenerg Biomembr 37:307–316
Chevrollier A, Loiseau D, Stepien G, Reynier P (2010) Biochim Biophys Acta. (in press)
Chinopoulos C, Adam-Vizi V (2010) Biochim Biophys Acta 1802:221–227
Chinopoulos C, Vajda S, Csanady L, Mandi M, Mathe K, Adam-Vizi V (2009) Biophys J 96:2490–2504
Comelli M, Lippe G, Mavelli I (1994) FEBS Lett 352:71–75
Contessi S, Comelli M, Cmet S, Lippe G, Mavelli I (2007) J Bioenerg Biomembr 39:291–300
Cossarizza A, Salvioli S (2001) Current protocols in cytometry Chapter 9: unit 9.14
Cuezva JM, Krajewska M, de Heredia ML, Krajewski S, Santamaria G, Kim H, Zapata JM, Marusawa H, Chamorro M, Reed JC (2002) Cancer Res 62:6674–6681
Cuezva JM, Ortega AD, Willers I, Sánchez-Cenizo L, Aldea M, Sánchez-Aragó M (2009) Biochim Biophys Acta 1792:1145–1158
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB (2008) Cell Metab 7:11–20
Di Pancrazio F, Mavelli I, Isola M, Losano G, Pagliaro P, Harris DA, Lippe G (2004) Biochim Biophys Acta 1659:52–62
Di Pietro A, Penin F, Julliard JH, Godinot C, Gautheron DC (1988) Biochem Biophys Res Commun 152:1319–1325
Frezza C, Gottlieb E (2009) Semin Cancer Biol 19:4–11
Giorgio V, Bisetto E, Soriano ME, Dabbeni-Sala F, Basso E, Petronilli V, Forte MA, Bernardi P, Lippe G (2009) J Biol Chem 284:33982–33988
Gnaiger E (2008) Mitochondrial dysfunction in drug-induced toxicity: 327–352
Grassi G, Scaggiante B, Farra R, Dapas B, Agostini F, Baiz D, Rosso N, Tiribelli C (2007) Biochimie 89:1544–1552
Green DW, Grover GJ (2000) Biochim Biophys Acta 1458:343–355
Grover GJ, Atwal KS, Sleph PG, Wang FL, Monshizadegan H, Monticello T, Green DW (2004) Am J Physiol Heart Circ Physiol 287:H1747–H1755
Hanahan D, Weinberg RA (2000) Cell 100:57–70
Harris DA, Das AM (1991) Biochem J 280:561–573
Hernlund E, Hjerpe E, Avall-Lundqvist E, Shoshan M (2009) Mol Cancer Ther 8:1916–1923
Ihrlund LS, Hernlund E, Khan O, Shoshan MC (2008) Mol Oncol 2:94–101
Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) Science 320:661–664
Kim HK, Park WS, Kang SH, Warda M, Kim N, Ko JH, Ael B, Han J (2007) Am J Physiol Cell Physiol 293:C761–C771
Kroemer G, Pouyssegur J (2008) Cancer Cell 13:472–482
Kurtoglu M, Lampidis TJ (2009) Mol Nutr Food Res 53:68–75
Lippe G, Bisetto E, Comelli M, Contessi S, Di Pancrazio F, Mavelli I (2009) J Bioenerg Biomembr 41:151–157
Loiseau D, Morvan D, Chevrollier A, Demidem A, Douay O, Reynier P, Stepien G (2009) Mol Carcinog 48:733–741
López-RÃos F, Sánchez-Aragó M, GarcÃa E, Ortega AD, Berrendero JR, Pozo-RodrÃguez F, López-Encuentra A, BallestÃn C, Cuezva JM (2007) Cancer Res 67:9013–9017
Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y (2007) Toxicol Sci 97:539–547
Mathupala SP, Ko YH, Pedersen PL (2010) Biochim Biophys Acta 1797:1225–1230
McKenzie M, Liolitsa D, Akinshina N, Campanella M, Sisodiya S, Hargreaves I, Nirmalananthan N, Sweeney MG, Abou-Sleiman PM, Wood NW, Hanna MG, Duchen MR (2007) J Biol Chem 282:36845–36852
Modica-Napolitano JS, Aprille JR (2001) Adv Drug Deliv Rev 49:63–70
Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) FEBS J 274:1393–1418
Oliva CR, Nozell SE, Diers A, McClugage SG, Sarkaria JN, Markert JM, Darley-Usmar VM, Bailey SM, Gillespie GY, Landar A, Griguer CE (2010) J Biol Chem 285:39759–39767
Paumard P, Vaillier J, Coulary B, Schaeffer J, Soubannier V, Mueller DM, Brethes D, di Rago JP, Velours J (2002) EMBO J 21:221–230
Penna C, Pagliaro P, Rastaldo R, Di Pancrazio F, Lippe G, Gattullo D, Mancardi D, Samaja M, Losano G, Mavelli I (2004) Am J Physiol 287:H2192–H2200
Putignani L, Raffa S, Pescosolido R, Aimati L, Signore F, Torrisi MR, Grammatico P (2008) Breast Cancer Res Treat 110:439–452
Rouslin W, Broge CW (1996) J Biol Chem 271:23638–23641
Sanchez-Arago M, Chamorro M, Cuezva JM (2010) Carcinogenesis 31:567–576
Sanchez-Cenizo L, Formentini L, Aldea M, Ortega AD, Garcia-Huerta P, Sanchez-Arago M, Cuezva JM (2010) J Biol Chem 285:25308–25313
Shaw RJ (2006) Curr Opin Cell Biol 18:598–608
Simonnet H, Alazard N, Pfeiffer K, Gallou C, Beroud C, Demont J, Bouvier R, Schagger H, Godinot C (2002) Carcinogenesis 23:759–768
Solaini G, Sgarbi G, Baracca A (2010) Biochim Biophys Acta (in press)
Srere PA (1969) Methods Enzymol 13:3–5
Warburg O (1956) Science 123:309–314
Willers IM, Cuezva JM (2010) Biochim Biophys Acta (in press)
Zu XL, Guppy M (2004) Biochem Biophys Res Commun 313:459–465
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Domenis, R., Comelli, M., Bisetto, E. et al. Mitochondrial bioenergetic profile and responses to metabolic inhibition in human hepatocarcinoma cell lines with distinct differentiation characteristics. J Bioenerg Biomembr 43, 493–505 (2011). https://doi.org/10.1007/s10863-011-9380-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10863-011-9380-5