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Mitochondrial Lon Protease and Cancer

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Mitochondrial DNA and Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1038))

Abstract

ATP-dependent Lon protease of mitochondrial matrix is encoded by nuclear DNA and highly evolutionarily conserved throughout all organisms, which is involved in the quality control of proteins by selective degradation of misfolded, oxidized, and short-lived regulatory proteins within mitochondrial matrix, maintenance of mitochondrial genome (mtDNA), and folding of mitochondria proteins. Various stimuli such as hypoxia and oxidative and ER stress lead to upregulation of Lon expression. Inhibition of protease activity or downregulation of Lon promotes cancer cell death and enhances sensitivity of cancer cells to anticancer drugs through metabolic reprogramming, thus reducing the viability of cancer cell in tumor microenvironment and epithelial to mesenchymal transition (EMT). Moreover, mitochondrial ATP-dependent Lon protease may serve as a potential biomarker for cancer diagnosis and novel target for the development of anticancer drugs and for predicting of the efficiency and effectiveness of chemotherapy of a variety of cancers.

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References

  1. Venkatesh S, Lee J, Singh K, Lee I, Suzuki CK. Multitasking in the mitochondrion by the ATP-dependent Lon protease. Biochim Biophys Acta. 2012;1823(1):56–66.

    Article  CAS  PubMed  Google Scholar 

  2. Pinti M, Gibellini L, Liu Y, Xu S, Lu B, Cossarizza A. Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer. Cell Mol Life Sci. 2015;72(24):4807–24.

    Article  CAS  PubMed  Google Scholar 

  3. Bao L, Diao H, Dong N, Su X, Wang B, Mo Q, Yu H, Wang X, Chen C. Histone deacetylase inhibitor induces cell apoptosis and cycle arrest in lung cancer cells via mitochondrial injury and p53 up-acetylation. Cell Biol Toxicol. 2016;32(6):469–82. PMID: 27423454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Liu T, Lu B, Lee I, Ondrovicova G, Kutejova E, Suzuki CK. DNA and RNA binding by the mitochondrial lon protease is regulated by nucleotide and protein substrate. J Biol Chem. 2004;279(14):13902–10.

    Article  CAS  PubMed  Google Scholar 

  5. Lu B, Lee J, Nie X, Li M, Morozov YI, Venkatesh S, Bogenhagen DF, Temiakov D, Suzuki CK. Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease. Mol Cell. 2013;49(1):121–32.

    Article  CAS  PubMed  Google Scholar 

  6. Quiros PM, Espanol Y, Acin-Perez R, Rodriguez F, Barcena C, Watanabe K, Calvo E, Loureiro M, Fernandez-Garcia MS, Fueyo A, Vazquez J, Enriquez JA, Lopez-Otin C. ATPdependent Lon protease controls tumor bioenergetics by reprogramming mitochondrial activity. Cell Rep. 2014;8(2):542–56.

    Article  CAS  PubMed  Google Scholar 

  7. Lu B, Yadav S, Shah PG, Liu T, Tian B, Pukszta S, Villaluna N, Kutejova E, Newlon CS, Santos JH, Suzuki CK. Roles for the human ATP-dependent Lon protease in mitochondrial DNA maintenance. J Biol Chem. 2007;282(24):17363–74.

    Article  CAS  PubMed  Google Scholar 

  8. Vedi M, Sabina EP. Assessment of hepatoprotective and nephroprotective potential of withaferin A on bromobenzene-induced injury in Swiss albino mice: possible involvement of mitochondrial dysfunction and inflammation. Cell Biol Toxicol. 2016;32(5):373–90. PMID: 27250656

    Article  CAS  PubMed  Google Scholar 

  9. Bulteau AL, Szweda LI, Friguet B. Mitochondrial protein oxidation and degradation in response to oxidative stress and aging. Exp Gerontol. 2006;41(7):653–7.

    Article  CAS  PubMed  Google Scholar 

  10. Goard CA, Schimmer AD. Mitochondrial matrix proteases as novel therapeutic targets in malignancy. Oncogene. 2014;33(21):2690–9.

    Article  CAS  PubMed  Google Scholar 

  11. Bulteau AL, Bayot A. Mitochondrial proteases and cancer. Biochim Biophys Acta. 2011;1807(6):595–601.

    Article  CAS  PubMed  Google Scholar 

  12. Swamy KH, Goldberg AL. Escherichia coli contains eight soluble proteolytic activities, one being ATP dependent. Nature. 1981;292(5824):652–4.

    Article  CAS  PubMed  Google Scholar 

  13. Amerik A, Petukhova GV, Grigorenko VG, Lykov IP, Yarovoi SV, Lipkin VM, Gorbalenya AE. Cloning and sequence analysis of cDNA for a human homolog of eubacterial ATPdependent Lon proteases. FEBS Lett. 1994;340(1–2):25–8.

    Article  CAS  PubMed  Google Scholar 

  14. Howard-Flanders P, Simson E, Theriot L. The excision of thymine dimers from DNA, filament formation and sensitivity to ultraviolet light in Escherichia coli K-12. Mutat Res. 1964;106:219–26.

    Article  CAS  PubMed  Google Scholar 

  15. Seo JB, Jung SR, Hille B, Koh DS, Extracellular ATP. Protects pancreatic duct epithelial cells from alcohol-induced damage through P2Y1 receptor-cAMP signal pathway. Cell Biol Toxicol. 2016;32(3):229–47. PMID: 27197531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Charette MF, Henderson GW, Markovitz A. ATP hydrolysis-dependent protease activity of the lon (capR) protein of Escherichia coli K-12. Proc Natl Acad Sci U S A. 1981;78:4728–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chung CH, Goldberg AL. The product of the lon (capR) gene in Escherichia coli is the ATP-dependent protease, protease La. Proc Natl Acad Sci U S A. 1981;78:4931–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Suzuki CK, Suda K, Wang N, Schatz G. Requirement for the yeast gene LON in intramitochondrial proteolysis and maintenance of respiration. Science. 1994;264(5156):273–6.

    Article  CAS  PubMed  Google Scholar 

  19. Park SC, Jia B, Yang JK, Van DL, Shao YG, Han SW, Jeon YJ, Chung CH, Cheong GW. Oligomeric structure of the ATP-dependent protease La (Lon) of Escherichia coli. Mol Cells. 2006;21(1):129–34.

    CAS  PubMed  Google Scholar 

  20. Vieux EF, Wohlever ML, Chen JZ, Sauer RT, Baker TA. Distinct quaternary structures of the AAA? Lon protease control substrate degradation. Proc Natl Acad Sci U S A. 2013;110(22):E2002–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schmidt R, Decatur AL, Rather PN, Moran CP Jr, Losick R. Bacillus subtilis lon protease prevents inappropriate transcription of genes under the control of the sporulation transcription factor sigma G. J Bacteriol. 1994;176(21):6528–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Van Dyck L, Langer T. ATP-dependent proteases controlling mitochondrial function in the yeast Saccharomyces cerevisiae. Cell Mol Life Sci. 1999;56(9–10):825–42.

    Article  PubMed  Google Scholar 

  23. Opperman CM, Sishi BJ. Tumor necrosis factor alpha stimulates p62 accumulation and enhances proteasome activity independently of ROS. Cell Biol Toxicol. 2015;31(2):83–94. PMID: 25761618

    Article  CAS  PubMed  Google Scholar 

  24. Gottesman S, Wickner S, Maurizi MR. Protein quality control: triage by chaperones and proteases. Genes Dev. 1997;11(7):815–23.

    Article  CAS  PubMed  Google Scholar 

  25. Ganta KK, Mandal A, Chaubey B. Depolarization of mitochondrial membrane potential is the initial event in non-nucleoside reverse transcriptase inhibitor efavirenz induced cytotoxicity. Cell Biol Toxicol. 2017;33(1):69–82. PMID: 27639578

    Article  PubMed  Google Scholar 

  26. Robertson GT, Kovach ME, Allen CA, Ficht TA, Roop RM 2nd. The Brucella abortus Lon functions as a generalized stress response protease and is required for wild-type virulence in BALB/c mice. Mol Microbiol. 2000;35(3):577–88.

    Article  CAS  PubMed  Google Scholar 

  27. Wang N, Gottesman S, Willingham MC, Gottesman MM, Maurizi MR. A human mitochondrial ATP-dependent protease that is highly homologous to bacterial Lon protease. Proc Natl Acad Sci U S A. 1993;90:11247–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. GK F, Smith MJ, Markovitz DM. Bacterial protease Lon is a site-specific DNA-binding protein. J Biol Chem. 1997;272(1):534–8.

    Article  Google Scholar 

  29. Rigas S, Daras G, Laxa M, Marathias N, Fasseas C, Sweetlove LJ, Hatzopoulos P. Role of Lon1 protease in post-germinative growth and maintenance of mitochondrial function in Arabidopsis thaliana. New Phytol. 2009;181(3):588–600.

    Article  CAS  PubMed  Google Scholar 

  30. Adam C, Picard M, Dequard-Chablat M, Sellem CH, Hermann-Le Denmat S, Contamine V. Biological roles of the Podospora anserina mitochondrial Lon protease and the importance of its N-domain. PLoS One. 2012;7(5):e38138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Coleman JL, Katona LI, Kuhlow C, Toledo A, Okan NA, Tokarz R, Benach JL. Evidence that two ATP-dependent (Lon) proteases in Borrelia burgdorferi serve differentfunctions. PLoS Pathog. 2009;5(11):e1000676.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Teichmann U, van Dyck L, Guiard B, Fischer H, Glockshuber R, Neupert W, Langer T. Substitution of PIM1 protease in mitochondria by Escherichia coli Lon protease. J Biol Chem. 1996;271(17):10137–42.

    Article  CAS  PubMed  Google Scholar 

  33. Jonas K, Liu J, Chien P, Laub MT. Proteotoxic stress induces a cell-cycle arrest by stimulating Lon to degrade the replication initiator DnaA. Cell. 2013;154:623–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Granot Z, Kobiler O, Melamed-Book N, Eimerl S, Bahat A, Lu B, Braun S, Maurizi MR, Suzuki CK, Oppenheim AB, Orly J. Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors. Mol Endocrinol. 2007;21(9):2164–77.

    Article  CAS  PubMed  Google Scholar 

  35. Granot Z, Geiss-Friedlander R, Melamed-Book N, Eimerl S, Timberg R, Weiss AM, Hales KH, Hales DB, Stocco DM, Orly J. Proteolysis of normal and mutated steroidogenic acute regulatory proteins in the mitochondria: the fate of unwanted proteins. Mol Endocrinol. 2003;17(12):2461–76.

    Article  CAS  PubMed  Google Scholar 

  36. Bota DA, Davies KJ. Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism. Nat Cell Biol. 2002;4(9):674–80.

    Article  CAS  PubMed  Google Scholar 

  37. Bernstein SH, Venkatesh S, Li M, Lee J, Lu B, Hilchey SP, Morse KM, Metcalfe HM, Skalska J, Andreeff M, Brookes PS, Suzuki CK. The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood. 2012;119(14):3321–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gibellini L, Pinti M, Bartolomeo R, De Biasi S, Cormio A, Musicco C, Carnevale G, Pecorini S, Nasi M, De Pol A, Cossarizza A. Inhibition of Lon protease by triterpenoids alters mitochondria and is associated to cell death in human cancer cells. Oncotarget. 2015;6(28):25466–83.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bayot A, Basse N, Lee I, Gareil M, Pirotte B, Bulteau AL, Friguet B, Reboud-Ravaux M. Towards the control of intracellular protein turnover: mitochondrial Lon protease inhibitors versus proteasome inhibitors. Biochimie. 2008;90(2):260–9.

    Article  CAS  PubMed  Google Scholar 

  40. Wang HM, Cheng KC, Lin CJ, Hsu SW, Fang WC, Hsu TF, Chiu CC, Chang HW, Hsu CH, Lee AY. Obtusilactone A and (−)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints. Cancer Sci. 2010;101(12):2612–20.

    Article  CAS  PubMed  Google Scholar 

  41. Lan L, Guo M, Ai Y, Chen F, Zhang Y, Xia L, Huang D, Niu L, Zheng Y, Suzuki CK, Zhang Y, Liu Y, Lu B. Tetramethylpyrazine blocks TFAM degradation and up-regulates mitochondrial DNA copy number by interacting with TFAM. Biosci Rep. 2017;37(3):pii: BSR20170319. https://doi.org/10.1042/BSR20170319.

    Article  Google Scholar 

  42. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011;10(9):671–84. https://doi.org/10.1038/nrd3504.

    Article  CAS  PubMed  Google Scholar 

  43. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95. https://doi.org/10.1038/nrc2981.

    Article  CAS  PubMed  Google Scholar 

  44. Zhu LZ, Hou YJ, Zhao M, Yang MF, XT F, Sun JY, XY F, Shao LR, Zhang HF, Fan CD, Gao HL, Sun BL. Caudatin induces caspase-dependent apoptosis in human glioma cells with involvement of mitochondrial dysfunction and reactive oxygen species generation. Cell Biol Toxicol. 2016;32(4):333–45. PMID: 27184666

    Article  CAS  PubMed  Google Scholar 

  45. Nie X, Li M, Lu B, Zhang Y, Lan L, Chen L, Lu J. Downregulating overexpressed human Lon in cervical cancer suppresses cell proliferation and bioenergetics. PLoS One. 2013;8(11):e81084.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Liu Y, Lan L, Huang K, Wang R, Xu C, Shi Y, Wu X, Wu Z, Zhang J, Chen L, Wang L, Yu X, Zhu H, Lu B. Inhibition of Lon blocks cell proliferation, enhances chemosensitivity by promoting apoptosis and decreases cellular bioenergetics of bladder cancer: potential roles of Lon as a prognostic marker and therapeutic target in baldder cancer. Oncotarget. 2014;5(22):11209–24.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  48. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129(1):111–22.

    Article  CAS  PubMed  Google Scholar 

  49. Cheng CW, Kuo CY, Fan CC, Fang WC, Jiang SS, Lo YK, Wang TY, Kao MC, Lee AY. Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis. 2013;4:e681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Di K, Lomeli N, Wood SD, Vanderwal CD, Bota DA. Mitochondrial Lon is over-expressed in high-grade gliomas, and mediates hypoxic adaptation: potential role of Lon as a therapeutic target in glioma. Oncotarget. 2016;7(47):77457–67.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Many thanks to Carolyn K. Suzuki and the members in my laboratory. This study has been supported by grants from the National Basic Research Program of China (973 Program, No. 2013CB531700), National Natural Science Foundation of China (No. 31070710, No. 31171345, No. 31570772, No. 31771543), and Zhejiang Qianjiang Talent Project B (No. 2010R10045) to BL.

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  1. Institute of Biophysics, Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Bin Lu

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Correspondence to Bin Lu .

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  1. Liaoning Province Key Laboratory of Cancer Metabolomics, Jinzhou Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China

    Hongzhi Sun

  2. Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Medical College, Shanghai, China

    Xiangdong Wang

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Lu, B. (2017). Mitochondrial Lon Protease and Cancer. In: Sun, H., Wang, X. (eds) Mitochondrial DNA and Diseases. Advances in Experimental Medicine and Biology, vol 1038. Springer, Singapore. https://doi.org/10.1007/978-981-10-6674-0_12

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