Abstract
A broad range of health benefits have been attributed to resveratrol (RSV) supplementation in mammalian systems, including the increases in longevity. Nonetheless, despite the growing number of studies performed with RSV, the molecular mechanism by which it acts still remains unknown. Recently, it has been proposed that inhibition of the oxidative phosphorylation activity is the principal mechanism of RSV action. This mechanism suggests that RSV might induce mitochondrial dysfunction resulting in oxidative damage to cells with a concomitant decrease of cell viability and cellular life span. To prove this hypothesis, the chronological life span (CLS) of Saccharomyces cerevisiae was studied as it is accepted as an important model of oxidative damage and aging. In addition, oxygen consumption, mitochondrial membrane potential, and hydrogen peroxide (H2O2) release were measured in order to determine the extent of mitochondrial dysfunction. The results demonstrated that the supplementation of S. cerevisiae cultures with 100 μM RSV decreased CLS in a glucose-dependent manner. At high-level glucose, RSV supplementation increased oxygen consumption during the exponential phase yeast cultures, but inhibited it in chronologically aged yeast cultures. However, at low-level glucose, oxygen consumption was inhibited in yeast cultures in the exponential phase as well as in chronologically aged cultures. Furthermore, RSV supplementation promoted the polarization of the mitochondrial membrane in both cultures. Finally, RSV decreased the release of H2O2 with high-level glucose and increased it at low-level glucose. Altogether, this data supports the hypothesis that RSV supplementation decreases CLS as a result of mitochondrial dysfunction and this phenotype occurs in a glucose-dependent manner.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L (2007) Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 128:546–552. doi:10.1016/j.mad.2007.07.007
Baur JA et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342. doi:10.1038/nature05354
Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. The Biochemical journal 435:297–312. doi:10.1042/BJ20110162
Cai H et al. (2015) Cancer chemoprevention: evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. Science translational medicine 7:298ra117. doi:10.1126/scitranslmed.aaa7619
Choi KM, Lee HL, Kwon YY, Kang MS, Lee SK, Lee CK (2013) Enhancement of mitochondrial function correlates with the extension of lifespan by caloric restriction and caloric restriction mimetics in yeast. Biochem Biophys Res Commun 441:236–242. doi:10.1016/j.bbrc.2013.10.049
Desquiret-Dumas V et al (2013) Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells. J Biol Chem 288:36662–36675. doi:10.1074/jbc.M113.466490
Gledhill JR, Montgomery MG, Leslie AG, Walker JE (2007) Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci U S A 104:13632–13637. doi:10.1073/pnas.0706290104
Gueguen N et al (2015) Resveratrol directly binds to mitochondrial complex I and increases oxidative stress in brain mitochondria of aged mice. PLoS One 10:e0144290. doi:10.1371/journal.pone.0144290
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300
Hawley SA et al (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11:554–565. doi:10.1016/j.cmet.2010.04.001
Howitz KT et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196. doi:10.1038/nature01960
Hussain AR, Uddin S, Bu R, Khan OS, Ahmed SO, Ahmed M, Al-Kuraya KS (2011) Resveratrol suppresses constitutive activation of AKT via generation of ROS and induces apoptosis in diffuse large B cell lymphoma cell lines. PLoS One 6:e24703. doi:10.1371/journal.pone.0024703
Jeandet P, Hebrard C, Deville MA, Cordelier S, Dorey S, Aziz A, Crouzet J (2014) Deciphering the role of phytoalexins in plant-microorganism interactions and human health. Molecules 19:18033–18056. doi:10.3390/molecules191118033
Johnson AA, Riehle MA (2015) Resveratrol fails to extend life span in the mosquito Anopheles Stephensi. Rejuvenation Res 18:473–478. doi:10.1089/rej.2015.1670
Kaeberlein M (2010) Lessons on longevity from budding yeast. Nature 464:513–519. doi:10.1038/nature08981
Kaeberlein M et al (2005) Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 280:17038–17045. doi:10.1074/jbc.M500655200
Madreiter-Sokolowski CT et al (2016) Resveratrol specifically kills cancer cells by a devastating increase in the Ca2+ coupling between the greatly tethered endoplasmic reticulum and mitochondria. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 39:1404–1420. doi:10.1159/000447844
Madrigal-Perez LA, Ramos-Gomez M (2016) Resveratrol inhibition of cellular respiration: new paradigm for an old mechanism. Int J Mol Sci 17:368. doi:10.3390/ijms17030368
Madrigal-Perez LA, Nava GM, Gonzalez-Hernandez JC, Ramos-Gomez M (2015) Resveratrol increases glycolytic flux in Saccharomyces cerevisiae via a SNF1-dependet mechanism. J Bioenerg Biomembr 47:331–336. doi:10.1007/s10863-015-9615-y
Madrigal-Perez LA, Canizal-Garcia M, Gonzalez-Hernandez JC, Reynoso-Camacho R, Nava GM, Ramos-Gomez M (2016) Energy-dependent effects of resveratrol in Saccharomyces cerevisiae. Yeast 33:227–234. doi:10.1002/yea.3158
Moreira AC, Silva AM, Santos MS, Sardao VA (2013) Resveratrol affects differently rat liver and brain mitochondrial bioenergetics and oxidative stress in vitro: investigation of the role of gender. Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 53:18–26. doi:10.1016/j.fct.2012.11.031
Murphy MP (2009) How mitochondria produce reactive oxygen species. The Biochemical journal 417:1–13. doi:10.1042/BJ20081386
Murakami CJ, Burtner CR, Kennedy BK, Kaeberlein M (2008) A method for high-throughput quantitative analysis of yeast chronological life span. J Gerontol A Biol Sci Med Sci 63(2):113–121
Orozco H, Matallana E, Aranda A (2012) Two-carbon metabolites, polyphenols and vitamins influence yeast chronological life span in winemarking conditions. Microb Cell Factories 11:104
Pearson KJ et al (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168. doi:10.1016/j.cmet.2008.06.011
Plauth A et al (2016) Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress. Free Radic Biol Med. doi:10.1016/j.freeradbiomed.2016.08.006
Pozniakovsky AI, Knorre DA, Markova OV, Hyman AA, Skulachev VP, Severin FF (2005) Role of mitochondria in the pheromone- and amiodarone-induced programmed death of yeast. J Cell Biol 168:257–269. doi:10.1083/jcb.200408145
Price NL et al (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690. doi:10.1016/j.cmet.2012.04.003
Ristow M (2014) Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med 20:709–711. doi:10.1038/nm.3624
Sassi N, Mattarei A, Azzolini M, Szabo I, Paradisi C, Zoratti M, Biasutto L (2014) Cytotoxicity of mitochondria-targeted resveratrol derivatives: interactions with respiratory chain complexes and ATP synthase. Biochim Biophys Acta 1837:1781–1789. doi:10.1016/j.bbabio.2014.06.010
Whitlock NC, Baek SJ (2012) The anticancer effects of resveratrol: modulation of transcription factors. Nutr Cancer 64:493–502. doi:10.1080/01635581.2012.667862
Yoshino J et al (2012) Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab 16:658–664. doi:10.1016/j.cmet.2012.09.015
Zheng J, Ramirez VD (2000) Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br J Pharmacol 130:1115–1123. doi:10.1038/sj.bjp.0703397
Zini R, Morin C, Bertelli A, Aa B, Tillement J (1998) Effects of resveratrol on the rat brain respiratory chain. Drugs Exp Clin Res 25:87–97
Acknowledgements
This study was funded by grants from Instituto Tecnológico Superior de Ciudad Hidalgo (3308.100310), Tecnológico Nacional de México (165.14.2-PD and 166.14.2-PD) and Programa para el Desarrollo Profesional Docente (PRODEP program; ITESCH-002). The authors would like to thank M.C Adriana González-Gallardo and Dra. Anaid Antaramian (Unidad de Proteogenómica del INB-UNAM) for their technical support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing financial interest.
Rights and permissions
About this article
Cite this article
Ramos-Gomez, M., Olivares-Marin, I.K., Canizal-García, M. et al. Resveratrol induces mitochondrial dysfunction and decreases chronological life span of Saccharomyces cerevisiae in a glucose-dependent manner. J Bioenerg Biomembr 49, 241–251 (2017). https://doi.org/10.1007/s10863-017-9709-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10863-017-9709-9