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Quercetin Protects Yeast Saccharomyces cerevisiae pep4 Mutant from Oxidative and Apoptotic Stress and Extends Chronological Lifespan

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Abstract

The yeast Saccharomyces cerevisiae PEP4 gene encodes vacuolar endopeptidase proteinase A (Pep4p), which is a homolog of the human CTSD gene that encodes cathepsin D. Mutation of CTSD gene in human resulted in a number of neurodegenerative diseases. In this study, we have shown that yeast pep4 mutant cells are highly sensitive to oxidative and apoptotic stress induced by hydrogen peroxide and acetic acid, respectively. pep4∆ cells also showed accumulation of reactive oxygen species (ROS), apoptotic markers, and reduced chronological lifespan. In contrast, quercetin pretreatment protected the pep4 mutant from oxidative and apoptotic stress-induced sensitivity by scavenging ROS and reducing apoptotic markers. The percentage viability of quercetin-treated pep4∆ cells was more pronounced and increased stress resistance against oxidant, apoptotic, and heat stress during chronological aging. From our experimental results, we concluded that quercetin protects yeast pep4 mutant cells from oxidative stress and apoptosis, thereby increasing viability during chronological aging.

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References

  1. Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120(4):483–495

    Article  CAS  PubMed  Google Scholar 

  2. Bassett DE Jr, Boguski MS, Hieter P (1996) Yeast genes and human disease. Nature 379(6566):589–590

    Article  CAS  PubMed  Google Scholar 

  3. Bayliak MM, Burdylyuk NI, Lushchak VI (2016) Quercetin increases stress resistance in the yeast Saccharomyces cerevisiae not only as an antioxidant. Ann Microbiol 66(2):569–576

    Article  CAS  Google Scholar 

  4. Belinha I, Amorim MA, Rodrigues P, de Freitas V, Moradas-Ferreira P, Mateus N, Costa V (2007) Quercetin increases oxidative stress resistance and longevity in Saccharomyces cerevisiae. J Agric Food Chem 55(6):2446–2451

    Article  CAS  PubMed  Google Scholar 

  5. Carmona-Gutiérrez D, Bauer MA, Ring J, Knauer H, Eisenberg T, Büttner S, Ruckenstuhl C, Reisenbichler A, Magnes C, Rechberger GN, Birner-Gruenberger R, Jungwirth H, Fröhlich KU, Sinner F, Kroemer G, Madeo F (2011) The propeptide of yeast cathepsin D inhibits programmed necrosis. Cell Death Dis 2:161

    Article  Google Scholar 

  6. Castino R, Davies J, Beaucourt S, Isidoro C, Murphy D (2005) Autophagy is a prosurvival mechanism in cells expressing an autosomal dominant familial neurohypophyseal diabetes insipidus mutant vasopressin transgene. FASEB J 19(8):1021–1023

    Article  CAS  PubMed  Google Scholar 

  7. Chen TJ, Jeng JY, Lin CW, Wu CY, Chen YC (2006) Quercetin inhibition of ROS-dependent and -independent apoptosis in rat glioma C6 cells. Toxicology 223(1–2):113–126

    Article  CAS  PubMed  Google Scholar 

  8. Diment S, Martin KJ, Stahl PD (1989) Cleavage of parathyroid hormone in macrophage endosomes illustrates a novel pathway for intracellular processing of proteins. J Biol Chem 264(23):13403–13406

    CAS  PubMed  Google Scholar 

  9. Dupre S, Haguenauer-Tsapis R (2001) Deubiquitination step in the endocytic pathway of yeast plasma membrane proteins: crucial role of Doa4p ubiquitin isopeptidase. Mol Cell Biol 21(14):4482–4494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. He Z, Ma WY, Hashimoto T, Bode AM, Yang CS, Dong Z (2003) Induction of apoptosis by caffeine is mediated by the p53, Bax, and caspase 3 pathways. Cancer Res 63(15):4396–4401

    CAS  PubMed  Google Scholar 

  11. Herker E, Jungwirth H, Lehmann KA, Maldener C, Fröhlich KU, Wissing S, Buttner S, Fehr M, Sigrist S, Madeo F (2004) Chronological aging leads to apoptosis in yeast. J Cell Biol 164(4):501–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jones EW, Zubenko GS, Parker RR (1982) PEP4 gene function is required for expression of several vacuolar hydrolases in Saccharomyces cerevisiae. Genetics 102(4):665–677

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Khurana V, Lindquist S (2010) Modelling neurodegeneration in Saccharomyces cerevisiae: why cook with baker’s yeast? Nat Rev Neurosci 11(6):436–449

    Article  CAS  PubMed  Google Scholar 

  14. Koning AJ, Lum PY, Williams JM, Wright R (1993) DiOC6 staining reveals organelle structure and dynamics in living yeast cells. Cell Motil Cytoskelet 25(2):111–128

    Article  CAS  Google Scholar 

  15. Liang Q, Ouyang X, Schneider L, Zhang J (2011) Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons. Mol Neurodegener 6:37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu P, Zou D, Yi L, Chen M, Gao Y, Zhou R, Zhang Q, Zhou Y, Zhu J, Chen K, Mi M (2015) Quercetin ameliorates hypobaric hypoxia-induced memory impairment through mitochondrial and neuron function adaptation via the PGC-1alpha pathway. Restor Neurol Neurosci 33(2):143–157

    CAS  PubMed  Google Scholar 

  17. Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M (2004) Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions. J Cell Sci 117(Pt 21):5155–5164

    Article  CAS  PubMed  Google Scholar 

  18. Ludovico P, Sousa MJ, Silva MT, Leao C, Corte-Real M (2001) Saccharomyces cerevisiae commits to a programmed cell death process in response to acetic acid. Microbiology 147(Pt 9):2409–2415

    Article  CAS  PubMed  Google Scholar 

  19. Ludovico P, Rodrigues F, Almeida A, Silva MT, Barrientos A, Corte-Real M (2002) Cytochrome c release and mitochondria involvement in programmed cell death induced by acetic acid in Saccharomyces cerevisiae. Mol Biol Cell 13(8):2598–2606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Madeo F, Frohlich E, Frohlich KU (1997) A yeast mutant showing diagnostic markers of early and late apoptosis. J Cell Biol 139(3):729–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Marques M, Mojzita D, Amorim MA, Almeida T, Hohmann S, Moradas-Ferreira P, Costa V (2006) The Pep4p vacuolar proteinase contributes to the turnover of oxidized proteins but PEP4 overexpression is not sufficient to increase chronological lifespan in Saccharomyces cerevisiae. Microbiology 152(Pt 12):3595–3605

    Article  CAS  PubMed  Google Scholar 

  22. Mazzoni C, Herker E, Palermo V, Jungwirth H, Eisenberg T, Madeo F, Falcone C (2005) Yeast caspase 1 links messenger RNA stability to apoptosis in yeast. EMBO Rep 6(11):1076–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mendes V, Vilaça R, de Freitas V, Ferreira PM, Mateus N, Costa V (2015) Effect of myricetin, pyrogallol, and phloroglucinol on yeast resistance to oxidative stress. Oxid Med Cell Longev. https://doi.org/10.1155/2015/782504

    Google Scholar 

  24. Mole SE, Zhong NA, Sarpong A, Logan WP, Hofmann S, Yi W, Franken PF, van Diggelen OP, Breuning MH, Moroziewicz D, Ju W, Salonen T, Holmberg V, Järvelä I, Taschner PE (2001) New mutations in the neuronal ceroid lipofuscinosis genes. Eur J Paediatr Neurol 5(Suppl A):7–10

    Article  PubMed  Google Scholar 

  25. Mutka AL, Haapanen A, Kakela R, Lindfors M, Wright AK, Inkinen T, Hermansson M, Rokka A, Corthals G, Jauhiainen M, Gillingwater TH, Ikonen E, Tyynela J (2010) Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain. J Neurochem 112(1):193–203

    Article  CAS  PubMed  Google Scholar 

  26. Pereira C, Chaves S, Alves S, Salin B, Camougrand N, Manon S, Sousa MJ, Corte-Real M (2010) Mitochondrial degradation in acetic acid-induced yeast apoptosis: the role of Pep4 and the ADP/ATP carrier. Mol Microbiol 76(6):1398–1410

    Article  CAS  PubMed  Google Scholar 

  27. Pereira H, Azevedo F, Rego A, Sousa MJ, Chaves SR, Corte-Real M (2013) The protective role of yeast cathepsin D in acetic acid-induced apoptosis depends on ANT (Aac2p) but not on the voltage-dependent channel (Por1p). FEBS Lett 587(2):200–205

    Article  CAS  PubMed  Google Scholar 

  28. Phaniendra A, Jestadi DB, Periyasamy L (2015) Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem 30(1):11–26

    Article  CAS  PubMed  Google Scholar 

  29. Qiao L, Hamamichi S, Caldwell KA, Caldwell GA, Yacoubian TA, Wilson S, Xie ZL, Speake LD, Parks R, Crabtree D, Liang Q, Crimmins S, Schneider L, Uchiyama Y, Iwatsubo T, Zhou Y, Peng L, Lu Y, Standaert DG, Walls KC, Shacka JJ, Roth KA, Zhang J (2008) Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 1(1):1–18

    Article  CAS  Google Scholar 

  30. Rice-Evans CA, Miller NJ, Bolwell PG, Bramley PM, Pridham JB (1995) The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res 22(4):375 – 83

    Article  CAS  PubMed  Google Scholar 

  31. Sayad A, Noruzinia M, Zamani M, Harirchian MH, Kazemnejad A (2014) Association study of cathepsin D gene polymorphism in Iranian patients with sporadic late-onset Alzheimer’s disease. Dement Geriatr Cogn Disord 37(5–6):257–264

    Article  CAS  PubMed  Google Scholar 

  32. Siintola E, Partanen S, Stromme P, Haapanen A, Haltia M, Maehlen J, Lehesjoki AE, Tyynela J (2006) Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129(Pt 6):1438–1445

    Article  PubMed  Google Scholar 

  33. Smith DL Jr, McClure JM, Matecic M, Smith JS (2007) Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins. Aging Cell 6(5):649–662

    Article  CAS  PubMed  Google Scholar 

  34. Smith MG, Snyder M (2006) Yeast as a model for human disease. Curr Protoc Hum Genet. https://doi.org/10.1002/0471142905.hg1506s48

    PubMed  Google Scholar 

  35. Sousa M, Duarte AM, Fernandes TR, Chaves SR, Pacheco A, Leao C, Corte-Real M, Sousa MJ (2013) Genome-wide identification of genes involved in the positive and negative regulation of acetic acid-induced programmed cell death in Saccharomyces cerevisiae. BMC Genom 14:838

    Article  Google Scholar 

  36. Teichert U, Mechler B, Müller H, Wolf DH (1989) Lysosomal (vacuolar) proteinases of yeast are essential catalysts for protein degradation, differentiation, and cell survival. J Biol Chem 264(27):16037–16045

    CAS  PubMed  Google Scholar 

  37. Toyama BH, Hetzer MW (2013) Protein homeostasis: live long, won’t prosper. Nat Rev Mol Cell Biol 14(1):55–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vilaça R, Mendes V, Mendes MV, Carreto L, Amorim MA, de Freitas V, Moradas-Ferreira P, Mateus N, Costa V (2012) Quercetin protects Saccharomyces cerevisiae against oxidative stress by inducing trehalose biosynthesis and the cell wall integrity pathway. PLoS ONE 7(9):e45494

    Article  PubMed  PubMed Central  Google Scholar 

  39. Woolford CA, Daniels LB, Park FJ, Jones EW, Van Arsdell JN, Innis MA (1986) The PEP4 gene encodes an aspartyl protease implicated in the posttranslational regulation of Saccharomyces cerevisiae vacuolar hydrolases. Mol Cell Biol 6(7):2500–2510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yamaki M, Umehara T, Chimura T, Horikoshi M (2001) Cell death with predominant apoptotic features in Saccharomyces cerevisiae mediated by deletion of the histone chaperone ASF1/CIA1. Genes Cells 6(12):1043–1054

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Phaniendra alugoju thanks Pondicherry University and UGC-BSR F-7-370/2012(BSR) for providing fellowship. The authors are very thankful to UGC-BSR (F NO 42–665/2013 (SR dated 25-03-2013)) for providing financial assistance to buy reagents, DBT-IPLS, and DST-FIST for infrastructure.

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Correspondence to Madhu Dyavaiah.

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Alugoju, P., Janardhanshetty, S.S., Subaramanian, S. et al. Quercetin Protects Yeast Saccharomyces cerevisiae pep4 Mutant from Oxidative and Apoptotic Stress and Extends Chronological Lifespan. Curr Microbiol 75, 519–530 (2018). https://doi.org/10.1007/s00284-017-1412-x

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  • DOI: https://doi.org/10.1007/s00284-017-1412-x

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