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Long-term depletion of cereblon induces mitochondrial dysfunction in cancer cells

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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.

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.

참고문헌 (31)

  1. Friedman JR, "Mitochondrial form and function", Nature, 505, pp.335~343 (2014)
  2. Hüttemann M, "Regulation of mitochondrial oxidative phosphorylation through cell signaling", Biochim Biophys Acta, 1773, pp.1701~1720 (2007)
  3. Ji Woong Lim, "Mitochondrial dysfunction and Alzheimer’s disease: prospects for therapeutic intervention", BMB Reports, 53(1), pp.47~55 (2020), 생화학분자생물학회[DOI]
  4. Belhadj Slimen I, "Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review", Int J Hyperthermia, 30, pp.513~523 (2014)
  5. Shokolenko I, "Oxidative stress induces degradation of mitochondrial DNA", Nucleic Acids Res, 37, pp.2539~2548 (2009)
  6. Ott M, "Mitochondria, oxidative stress and cell death", Apoptosis, 12, pp.913~922 (2007)
  7. Ni H-M, "Mitochondrial dynamics and mitochondrial quality control", Redox Biol, 4, pp.6~13 (2015)
  8. Takamasa Ishii, "Mitochondrial superoxide anion (O₂ •-) inducible “mev-1” animal models for aging research", BMB Reports, 44(5), pp.298~305 (2011), 생화학분자생물학회
  9. Bota DA, "Mitochondrial Lon protease in human disease and aging : including an etiologic classification of Lon-related diseases and disorders", Free Radix Biol Med, 100, pp.188~198 (2016)
  10. Davalli P, "ROS, cell senescence, and novel molecular mechanisms in aging and age-related diseases", Oxid Med Cell Longev, 2016, pp.3565127~ (2016)
  11. Kataoka K, "Mitochondrial cereblon functions as a Lon-type protease", Sci Rep, 6, pp.29986~ (2016)
  12. Kim MJ, "CRBN is a negative regulator of bactericidal activity and autophagy activation through inhibiting the ubiquitination of ECSIT and BECN1", Front Immunol, 10, pp.3389~ (2019)
  13. Zhou L, "Cereblon attenuates DNA damageinduced apoptosis by regulating the transcription-independent function of p53", Cell Death Dis, 10, pp.1~13 (2019)
  14. Kamogashira T, "Functionally and morphologically damaged mitochondria observed in auditory cells under senescenceinducing stress", NPJ Aging Mech Dis, 3, pp.1~11 (2017)
  15. Gunter T, "Mitochondrial calcium transport : mechanisms and functions", Cell calcium, 28, pp.285~296 (2000)
  16. Görlach A, "Calcium and ROS : a mutual interplay", Redox Biol, 6, pp.260~271 (2015)
  17. dynamics with rhod-2, ratiometric pericam and aequorin, "Cell calcium", 2010, 61~69
  18. Lazarowski ER, "UTP as an extracellular signaling molecule", Physiology, 16, pp.1~5 (2001)
  19. Kim K, "Disordered region of cereblon is required for efficient degradation by proteolysistargeting chimera", Sci Rep, 9, pp.1~14 (2019)
  20. Yamamoto H, "Dual role of the receptor Tom20 in specificity and efficiency of protein import into mitochondria", Proc Natl Acad Sci U S A, 108, pp.91~96 (2011)
  21. Miyazono Y, "Uncoupled mitochondria quickly shorten along their long axis to form indented spheroids, instead of rings, in a fission-independent manner", Sci Rep, 8, pp.1~14 (2018)
  22. Chen H, "Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development", J Cell Biol, 160, pp.189~200 (2003)
  23. Cao X, "ROS-Ca2+ is associated with mitochondria permeability transition pore involved in surfactin-induced MCF-7 cells apoptosis", Chem Biol Ineract, 190, pp.16~27 (2011)
  24. Baumgartner HK, "Calcium elevation in mitochondria is the main Ca2+requirement for mitochondrial permeability transition pore(mPTP)opening", J Biol Chem, 284, pp.20796~20803 (2009)
  25. Pinti M, "Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer", Cell Mol Life Sci, 72, pp.4807~4824 (2015)
  26. Lee KM, "Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice", Diabetes, 62, pp.1855~1864 (2013)
  27. Lee KM, "Functional modulation of AMP-activated protein kinase by cereblon", Biochim Biophys Acta, 1813, pp.448~455 (2011)
  28. Hardie DG, "AMPK : a nutrient and energy sensor that maintains energy homeostasis", Nat Rev Mol Cell Biol, 13, pp.251~262 (2012)
  29. Herzig S, "AMPK : guardian of metabolism and mitochondrial homeostasis", Nat Rev Mol Cell Biol, 19, pp.121~ (2018)
  30. Mungai PT, "Hypoxia triggers AMPK activation through reactive oxygen speciesmediated activation of calcium release-activated calcium channels", Mol Cell Biol, 31, pp.3531~3545 (2011)
  31. Vives-Bauza C, "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy", Proc Natl Acad Sci U S A, 107, pp.378~383 (2010)

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