Issue
Korean Journal of Chemical Engineering,
Vol.39, No.5, 1097-1106, 2022
Energy metabolism in Chinese hamster ovary (CHO) cells: Productivity and beyond
Chinese hamster ovary (CHO) cell lines have been widely used to produce recombinant proteins. While the biosynthesis of recombinant proteins is energy-intensive, CHO cells exhibit inefficient metabolism, characterized by rapid conversion of glucose to lactate, possibly leading to lower cell growth and productivity of therapeutic proteins. Therefore, it is important to understand and engineer cellular metabolism to increase recombinant protein production. In this review, cellular energy metabolism of CHO cells with respect to protein synthesis is overviewed. Then, genetic and process engineering approaches to enhance metabolic efficiency are described, resulting in the improvement of cell culture performance. Finally, recent modeling technologies for understanding and predicting cellular metabolic behaviors are reviewed. These efforts will aid to further advance the biomanufacturing of therapeutic proteins.
[References]
  1. Walsh G, Nat. Biotechnol., 36, 1136, 2018
  2. Grilo AL, Mantalaris A, Trends Biotechnol., 37, 9, 2019
  3. Zhu MM, Mollet M, Hubert RS, Kyung YS, Zhang GG, Handbook of industrial chemistry and biotechnology, 3rd edition, Springer (2017).
  4. Lai T, Yang Y, Ng SK, Pharmaceuticals, 69, 579, 2013
  5. Pereira S, Kildegaard HF, Andersen MR, Biotechnol. J., 13, e1700499, 2018
  6. Rosano GL, Ceccarelli EA, Front. Microbiol., 5, 172, 2014
  7. Henry MN, MacDonald MA, Orellana CA, Gray PP, Gillard M, Baker K, Nielsen LK, Marcellin E, Mahler S, Martínez VS, Biotechnol. Bioeng., 117, 1187, 2020
  8. Hartley F, Walker T, Chung V, Morten K, Biotechnol. Bioeng., 115, 1890, 2018
  9. Horvat J, Narat M, Spadiut O, Biotechnol. Prog., 36, e3001, 2020
  10. Ivarsson M, Noh H, Morbidelli M, Soos M, Biotechnol. Prog., 31, 347, 2015
  11. Cacciatore JJ, Chasin LA, Leonard EF, Biotechnol. Adv., 28, 673, 2010
  12. Gonzalez MG, Latorre Y, Zuniga R, Aguillon JC, Molina MC, Altamirano C, Crit. Rev. Biotechnol., 39, 665, 2019
  13. Blondeel EJM, Aucoin MG, Biotechnol. Adv., 36, 1505, 2018
  14. Beyer B, Schuster M, Jungbauer A, Lingg N, Biotechnol. J., 13, 1700476, 2018
  15. Martinez VS, Dietmair S, Quek LE, Hodson MP, Gray P, Nielsen LK, Biotechnol. Bioeng., 110, 660, 2013
  16. Young JD, Curr. Opin. Biotechnol., 24, 1108, 2013
  17. Rich PR, Biochem. Soc. Trans., 31, 1095, 2003
  18. Romanova N, Niemann T, Greiner JFW, Kaltschmidt B, Kaltschmidt C, Noll T, Biotechnol. Bioeng., 118, 2348, 2021
  19. Alhuthali S, Kotidis P, Kontoravdi C, Int. J. Mol. Sci., 22, 3290, 2021
  20. Lieske PL, Wei W, Crowe KB, Figueroa B, Zhang L, Biotechnol. J., 15, e1900306, 2020
  21. Liberti MV, Locasale JW, Trends Biochem. Sci., 41, 211, 2016
  22. Heiden MGV, Cantley LC, Thompson CB, Science, 324, 1029, 2009
  23. Warburg O, Cancer Res., 9, 148, 1925
  24. Hume DA, Radik JL, Ferber E, Weidemann MJ, Biochem. J., 174, 703, 1978
  25. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB, Proc. Natl. Acad. Sci., 104, 19345, 2007
  26. Lunt SY, Heiden MGV, Annu. Rev. Cell Dev. Biol., 27, 441, 2011
  27. Zu XL, Guppy M, Biochem. Biophys. Res. Commun., 313, 459, 2004
  28. Locasale JW, Cantley LC, Cell Metab., 14, 443, 2011
  29. Zagari F, Jordan M, Stettler M, Broly H, Wurm FM, N. Biotechnol., 30, 238, 2013
  30. Ghorbaniaghdam A, Chen J, Henry O, Jolicoeur M, PLoS One, 9, e90832, 2014
  31. Ma N, Ellet J, Okediadi C, Hermes P, McCormick E, Casnocha S, Biotechnol. Prog., 25, 1353, 2009
  32. Wahrheit J, Niklas J, Heinzle E, Metab. Eng., 23, 9, 2014
  33. Sun YT, Zhao L, Ye Z, Fan L, Liu XP, Tan WS, Biochem. Eng. J., 81, 126, 2013
  34. Le H, Kabbur S, Pollastrini L, Sun Z, Mills K, Johnson K, Karypis G, Hu WS, J. Biotechnol., 162, 210, 2012
  35. Templeton N, Dean J, Reddy P, Young JD, Biotechnol. Bioeng., 110, 2013, 2013
  36. Yong J, Bischof H, Burgstaller S, Siirin M, Murphy A, Malli R, Kaufman RJ, Elife, 8, e49682, 2019
  37. Klein MC, Zimmermann K, Schorr S, Landini M, Klemens PAW, Altensell J, Jung M, Krause E, Nguyen D, Helms V, Nat. Commun., 9, 3489, 2018
  38. Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, Kim JK, Heo Y, Lee HS, Lee MY, Lee CW, Kang JS, Kim YH, Cell Metab., 31, 267, 2020
  39. Yoo HC, Yu YC, Sung Y, Han JM, Exp. Mol. Med., 52, 1496, 2020
  40. Budge JD, Knight TJ, Povey J, Roobol J, Brown IR, Singh G, Dean A, Turner S, Jaques CM, Young RJ, Racher AJ, Smales CM, Metab. Eng., 57, 203, 2020
  41. Li W, Fan Z, Lin Y, Wang TY, Front. Bioeng. Biotechnol., 9, 646363, 2021
  42. Houten SM, Violante S, Ventura FV, Wanders RJ, Annu. Rev. Physiol., 78, 23, 2016
  43. Gutierrez JM, Feizi A, Li S, Kallehauge TB, Hefzi H, Grav LM, Ley D, Hizal DB, Betenbaugh MJ, Voldborg B, Kildegaard HF, Nat. Commun., 11, 68, 2020
  44. Hiller K, Grote A, Scheer M, Munch R, Jahn D, Nucleic Acids Res., 32, 375, 2004
  45. Fankhauser N, Maser P, Bioinformatics, 21, 1846, 2005
  46. Yang Z, Halim A, Narimatsu Y, Joshi HJ, Steentoft C, Schjoldager KTBG, Schulz MA, Sealover NR, Kayser KJ, Mol. Cell Proteomics., 13, 3224, 2014
  47. Kapp LD, Lorsch JR, Annu. Rev. Biochem., 73, 657, 2004
  48. Noh SM, Sathyamurthy M, Lee GM, Curr. Opin. Chem. Biol., 2, 391, 2013
  49. Tihanyi B, Nyitray L, Drug Discov. Today, 38, 25, 2021
  50. Reinhart LDD, Sommeregger W, Gili A, Schafellner S, Castan A, Kaisermayer C, Kunert R, BMC Proc., 9, 36, 2015
  51. Kim SH, Lee GM, Appl. Microbiol. Biotechnol., 74, 152, 2007
  52. Jeon MK, Yu DY, Lee GM, Appl. Microbiol. Biotechnol., 92, 779, 2011
  53. Noh SM, Park JH, Lim MS, Kim JW, Lee GM, Appl. Microbiol. Biotechnol., 101, 1035, 2017
  54. Irani N, Wirth M, Heuvel JVD, Wagner R, Biotechnol. Bioeng., 66, 238, 1999
  55. Vallee C, Durocher Y, Henry O, J. Biotechnol., 169, 63, 2014
  56. Toussaint C, Henry O, Durocher Y, J. Biotechnol., 217, 122, 2016
  57. Gupta SK, Srivastava SK, Sharma A, Nalage VHH, Salvi D, Kushwaha H, Chitnis NB, Shukla P, PLoS One, 12, e0181455, 2017
  58. Gupta SK, Sharma A, Kushwaha H, Shukla P, Front. Pharmacol., 8, 463, 2017
  59. Wlaschin KF, Hu WS, J. Biotechnol., 131, 168, 2007
  60. Leong DS, Tan JC, Chin CL, Mak SY, Ho YS, Ng SK, Sci. Rep., 7, 45216, 2017
  61. Leong DSZ, Teo BKH, Tan JGL, Kamari H, Yang YS, Zhang P, Ng SK, Sci. Rep., 8, 4037, 2018
  62. Wilkens CA, Altamirano C, Gerdtzen ZP, Biotechnol. Bioprocess Eng., 16, 714, 2011
  63. Torres M, Berrios J, Rigual Y, Latorre Y, Vergara M, Dickson AJ, Altamirano C, Chem. Eng. Sci., 205, 201, 2019
  64. Buchsteiner M, Quek LE, Gray P, Nielsen LK, Biotechnol. Bioeng., 115, 2315, 2018
  65. Moller J, Bhat K, Guhl L, Portner R, Jandt U, Zeng AP, Eng. Life Sci., 21, 100, 2021
  66. Urquiza LT, Martin AEA, James DC, Nagy T, Falconer RJ, Biotechnol. Prog., 36, e2940, 2020
  67. Scorrano L, De Matteis MA, Emr S, Giordano F, Hajnóczky G, Kornmann B, Lackner LL, Levine TP, Pellegrini L, Reinisch K, Nat. Commun., 10, 1287, 2019
  68. Calleja LL, Lecina M, Repullo JL, Albiol J, Sola C, Cairo JJ, Appl. Microbiol. Biotechnol., 99, 9951, 2015
  69. Zalai D, Koczka K, Parta L, Wechselberger P, Klein T, Herwig C, Biotechnol. Prog., 31, 1657, 2015
  70. Osman JBJJ, Varley J, Biotechnol. Bioeng., 79, 398, 2002
  71. Brunner M, Doppler P, Klein T, Herwig C, Fricke J, Eng. Life Sci., 18, 204, 2018
  72. Gagnon M, Hiller G, Luan YT, Kittredge A, DeFelice J, Drapeau D, Biotechnol. Bioeng., 108, 1328, 2011
  73. Mulukutla BC, Kale J, Kalomeris T, Jacobs M, Hiller GW, Biotechnol. Bioeng., 114, 1779, 2017
  74. Calmels C, McCann A, Malphettes L, Andersen MR, Metab Eng., 51, 9, 2019
  75. Yahia BB, Malphettes L, Heinzle E, Appl. Microbiol. Biotechnol., 99, 7009, 2015
  76. Huang Z, Lee DY, Yoon S, Biotechnol. Bioeng., 114, 2717, 2017
  77. Kyriakopoulos S, Ang KS, Lakshmanan M, Huang Z, Yoon S, Gunawan R, Lee DY, Biotechnol. J., 13, e1700229, 2018
  78. Tang P, Xu J, Louey A, Tan Z, Yongky A, Liang S, Li ZJ, Weng Y, Liu S, Crit. Rev. Biotechnol., 40, 265, 2020
  79. Sha S, Huang Z, Wang Z, Yoon S, Curr. Opin. Chem. Eng., 22, 54, 2018
  80. Islam MM, Schroeder WL, Saha R, Curr. Opin. Syst. Biol., 26, 72, 2021
  81. Stalidzans E, Seiman A, Peebo K, Komasilovs V, Pentjuss A, Biochem. Soc. Trans., 46, 261, 2018
  82. Gutierrez JM, Lewis NE, Biotechnol. J., 10, 939, 2015
  83. Rejc Z, Magdevska L, Trselic T, Osolin T, Vodopivec R, Mraz J, Pavliha E, Zimic N, Cvitanović T, Rozman D, Moškon M, Comput. Biol. Med., 88, 150, 2017
  84. Altamirano C, Illanes A, Becerra S, Cairo JJ, Godia F, J. Biotechnol., 125, 547, 2006
  85. Sheikholeslami Z, Jolicoeur M, Henry O, Biotechnol. Prog., 30, 535, 2014
  86. O'Brien CM, Zhang Q, Daoutidis P, Hu WS, Metab Eng., 66, 31, 2021
  87. Yahia BB, Malphettes L, Heinzle E, Metab Eng., 66, 204, 2021
  88. Selvarasu S, Kim DY, Karimi IA, Lee DY, J. Biotechnol., 150, 94, 2010
  89. Zhanga Y, Lin H, Yanga Z, Wanga J, Sun Y, Xu B, Zhao Z, J. Biomed. Inform., 99, 103294, 2019
  90. Schmitt J, Downey B, Beller J, Russell B, Quach A, Lyon D, Curran M, Mulukutla BC, Chu C, Biotechnol. Bioeng., 116, 2223, 2019
  91. Schinn SM, Morrison C, Wei W, Zhang L, Lewis NE, Biotechnol. Bioeng., 118, 2118, 2021
  92. Huang Z, Xu J, Yongkyb A, Morrisa CS, Polancoa AL, Reilyc M, Borysb MC, Lib ZJ, Yoon S, Biochem. Eng. J., 160, 1076938, 2020
  93. Calmels C, Arnoult S, Yahia BB, Malphettes L, Andersen MR, Metab. Eng., 9, e00097, 2019
  94. Huang Z, Yoon S, Processes, 8, 331, 2020
  95. Luo Y, Lovelett RJ, Price JV, Radhakrishnan D, Barnthouse K, Hu P, Schaefer E, Cunningham J, Lee KH, Shivappa RB, Ogunnaike BA, Biotechnol. J., 16, e2000261, 2021
  96. van Rosmalen RP, Smith RW, dos Santos VAPM, Fleck C, Suarez-Diez M, Metab. Eng., 64, 74, 2021
  97. Yeo HC, Hong J, Lakshmanan M, Lee DY, Metab. Eng., 60, 138, 2020