BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Long-term depletion of cereblon induces mitochondrial dysfunction in cancer cells

  • Park, Seulki (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Kim, Kidae (Division of Biomedical Informatics, Center for Genome Science, National Institute of Health, KCDC) ;
  • Haam, Keeok (Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Ban, Hyun Seung (Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Jung-Ae (Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology) ;
  • Park, Byoung Chul (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Park, Sung Goo (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Kim, Sunhong (Drug Discovery Center, LG Chem) ;
  • Kim, Jeong-Hoon (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
  • Received : 2020.10.05
  • Accepted : 2020.12.30
  • Published : 2021.06.30
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Abstract

Cereblon (CRBN) is a multi-functional protein that acts as a substrate receptor of the E3 ligase complex and a molecular chaperone. While CRBN is proposed to function in mitochondria, its specific roles are yet to be established. Here, we showed that knockdown of CRBN triggers oxidative stress and calcium overload in mitochondria, leading to disruption of mitochondrial membrane potential. Notably, long-term CRBN depletion using PROteolysis TArgeting Chimera (PROTAC) induced irreversible mitochondrial dysfunction, resulting in cell death. Our collective findings indicate that CRBN is required for mitochondrial homeostasis in cells.

Keywords

Acknowledgement

This work was supported by a grant (CAP-15-11-KRICT) from the National Research Council of Science and Technology, Ministry of Science, ICT, and Future Planning, a grant (NRF-2019M3E5D4069882) from the National Research Foundation, Ministry of Science and ICT and Future Planning, and a grant from the KRIBB Initiative Program.

References

  1. Friedman JR and Nunnari J (2014) Mitochondrial form and function. Nature 505, 335-343 https://doi.org/10.1038/nature12985
  2. Huttemann M, Lee I, Samavati L, Yu H and Doan JW (2007) Regulation of mitochondrial oxidative phosphorylation through cell signaling. Biochim Biophys Acta 1773, 1701-1720 https://doi.org/10.1016/j.bbamcr.2007.10.001
  3. Lim JW, Lee J and Pae AN (2020) Mitochondrial dysfunction and Alzheimer's disease: prospects for therapeutic intervention. BMB Rep 53, 47-55 https://doi.org/10.5483/BMBRep.2020.53.1.279
  4. Belhadj Slimen I, Najar T, Ghram A, Dabbebi H, Ben Mrad M and Abdrabbah M (2014) Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review. Int J Hyperthermia 30, 513-523 https://doi.org/10.3109/02656736.2014.971446
  5. Shokolenko I, Venediktova N, Bochkareva A, Wilson GL and Alexeyev MF (2009) Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res 37, 2539-2548 https://doi.org/10.1093/nar/gkp100
  6. Ott M, Gogvadze V, Orrenius S and Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12, 913-922 https://doi.org/10.1007/s10495-007-0756-2
  7. Ni H-M, Williams JA and Ding W-X (2015) Mitochondrial dynamics and mitochondrial quality control. Redox Biol 4, 6-13 https://doi.org/10.1016/j.redox.2014.11.006
  8. Ishii T, Miyazawa M, Hartman PS and Ishii N (2011) Mitochondrial superoxide anion (O 2·-) inducible. BMB Rep 44, 298-305 https://doi.org/10.5483/BMBRep.2011.44.5.298
  9. Bota DA and Davies KJ (2016) Mitochondrial Lon protease in human disease and aging: including an etiologic classification of Lon-related diseases and disorders. Free Radix Biol Med 100, 188-198 https://doi.org/10.1016/j.freeradbiomed.2016.06.031
  10. Davalli P, Mitic T, Caporali A, Lauriola A and D'Arca D (2016) ROS, cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid Med Cell Longev 2016, 3565127 https://doi.org/10.1155/2016/3565127
  11. Kataoka K, Asahi T and Sawamura N (2016) Mitochondrial cereblon functions as a Lon-type protease. Sci Rep 6, 29986 https://doi.org/10.1038/srep29986
  12. Kim MJ, Min Y, Shim J-H, Chun E and Lee K-Y (2019) CRBN is a negative regulator of bactericidal activity and autophagy activation through inhibiting the ubiquitination of ECSIT and BECN1. Front Immunol 10, 3389
  13. Zhou L and Xu G (2019) Cereblon attenuates DNA damage-induced apoptosis by regulating the transcription-independent function of p53. Cell Death Dis 10, 1-13 https://doi.org/10.1038/s41419-018-1236-z
  14. Kamogashira T, Hayashi K, Fujimoto C, Iwasaki S and Yama-soba T (2017) Functionally and morphologically damaged mitochondria observed in auditory cells under senescence-inducing stress. NPJ Aging Mech Dis 3, 1-11 https://doi.org/10.1038/s41514-016-0001-8
  15. Gunter T, Buntinas L, Sparagna G, Eliseev R and Gunter K (2000) Mitochondrial calcium transport: mechanisms and functions. Cell calcium 28, 285-296 https://doi.org/10.1054/ceca.2000.0168
  16. Gorlach A, Bertram K, Hudecova S and Krizanova O (2015) Calcium and ROS: a mutual interplay. Redox Biol 6, 260-271 https://doi.org/10.1016/j.redox.2015.08.010
  17. Fonteriz RI, de la Fuente S, Moreno A, Lobaton CD, Montero M and Alvarez J (2010) Monitoring mitochondrial [Ca2+] dynamics with rhod-2, ratiometric pericam and aequorin. Cell calcium 48, 61-69 https://doi.org/10.1016/j.ceca.2010.07.001
  18. Lazarowski ER and Boucher RC (2001) UTP as an extra-cellular signaling molecule. Physiology 16, 1-5 https://doi.org/10.1152/physiologyonline.2001.16.1.1
  19. Kim K, Lee DH, Park S et al (2019) Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera. Sci Rep 9, 1-14 https://doi.org/10.1038/s41598-018-37186-2
  20. Yamamoto H, Itoh N, Kawano S et al (2011) Dual role of the receptor Tom20 in specificity and efficiency of protein import into mitochondria. Proc Natl Acad Sci U S A 108, 91-96 https://doi.org/10.1073/pnas.1014918108
  21. Miyazono Y, Hirashima S, Ishihara N, Kusukawa J, Nakamura K-i and Ohta K (2018) Uncoupled mitochondria quickly shorten along their long axis to form indented spheroids, instead of rings, in a fission-independent manner. Sci Rep 8, 1-14 https://doi.org/10.1038/s41598-017-17765-5
  22. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE and Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160, 189-200 https://doi.org/10.1083/jcb.200211046
  23. Cao X, Zhao S, Liu D et al (2011) ROS-Ca2+ is associated with mitochondria permeability transition pore involved in surfactin-induced MCF-7 cells apoptosis. Chem Biol Ineract 190, 16-27 https://doi.org/10.1016/j.cbi.2011.01.010
  24. Baumgartner HK, Gerasimenko JV, Thorne C et al (2009) Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening. J Biol Chem 284, 20796-20803 https://doi.org/10.1074/jbc.M109.025353
  25. Pinti M, Gibellini L, Liu Y, Xu S, Lu B and Cossarizza A (2015) Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer. Cell Mol Life Sci 72, 4807-4824 https://doi.org/10.1007/s00018-015-2039-3
  26. Lee KM, Yang S-J, Kim YD et al (2013) Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice. Diabetes 62, 1855-1864 https://doi.org/10.2337/db12-1030
  27. Lee KM, Jo S, Kim H, Lee J and Park C-S (2011) Functional modulation of AMP-activated protein kinase by cereblon. Biochim Biophys Acta 1813, 448-455 https://doi.org/10.1016/j.bbamcr.2011.01.005
  28. Hardie DG, Ross FA and Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13, 251-262 https://doi.org/10.1038/nrm3311
  29. Herzig S and Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19, 121 https://doi.org/10.1038/nrm.2017.95
  30. Mungai PT, Waypa GB, Jairaman A et al (2011) Hypoxia triggers AMPK activation through reactive oxygen speciesmediated activation of calcium release-activated calcium channels. Mol Cell Biol 31, 3531-3545 https://doi.org/10.1128/MCB.05124-11
  31. Vives-Bauza C, Zhou C, Huang Y et al (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 107, 378-383 https://doi.org/10.1073/pnas.0911187107