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dc.creatorVučićević, Ljubica
dc.creatorMisirkić Marjanović, Maja
dc.creatorĆirić, Darko
dc.creatorMartinović, Tamara
dc.creatorJovanović, Maja
dc.creatorIsaković, Aleksandra
dc.creatorMarković, Ivanka
dc.creatorŠaponjić, Jasna
dc.creatorForetz, Marc
dc.creatorRabanal-Ruiz, Yoana
dc.creatorKorolchuk, Viktor I.
dc.creatorTrajković, Vladimir
dc.date.accessioned2019-12-03T14:07:23Z
dc.date.available2900-01-01
dc.date.issued2019
dc.identifier.urihttp://link.springer.com/10.1007/s00018-019-03356-2
dc.identifier.urihttps://ibiss-r.rcub.bg.ac.rs/handle/123456789/3528
dc.description.abstractWe investigated the role of autophagy, a controlled lysosomal degradation of cellular macromolecules and organelles, in glutamate excitotoxicity during nutrient deprivation in vitro. The incubation in low-glucose serum/amino acid-free cell culture medium synergized with glutamate in increasing AMP/ATP ratio and causing excitotoxic necrosis in SH-SY5Y human neuroblastoma cells. Glutamate suppressed starvation-triggered autophagy, as confirmed by diminished intracellular acidification, lower LC3 punctuation and LC3-I conversion to autophagosome-associated LC3-II, reduced expression of proautophagic beclin-1 and ATG5, increase of the selective autophagic target NBR1, and decreased number of autophagic vesicles. Similar results were observed in PC12 rat pheochromocytoma cells. Both glutamate-mediated excitotoxicity and autophagy inhibition in starved SH-SY5Y cells were reverted by NMDA antagonist memantine and mimicked by NMDA agonists D-aspartate and ibotenate. Glutamate reduced starvation-triggered phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) without affecting the activity of mammalian target of rapamycin complex 1, a major negative regulator of autophagy. This was associated with reduced mRNA levels of autophagy transcriptional activators (FOXO3, ATF4) and molecules involved in autophagy initiation (ULK1, ATG13, FIP200), autophagosome nucleation/elongation (ATG14, beclin-1, ATG5), and autophagic cargo delivery to autophagosomes (SQSTM1). Glutamate-mediated transcriptional repression of autophagy was alleviated by overexpression of constitutively active AMPK. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, reduced the sensitivity of nutrient-deprived SH-SY5Y cells to glutamate excitotoxicity. These data indicate that transcriptional inhibition of AMPK-dependent cytoprotective autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173053/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41025/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173022/RS//
dc.relationCost Action TRANSAUTOPHAGY CA15138
dc.rightsrestrictedAccess
dc.sourceCellular and Molecular Life Sciences
dc.subjectBrain
dc.subjectEnergy stress
dc.subjectIschemia
dc.subjectNeurodegeneration
dc.subjectNeurotoxicity
dc.titleTranscriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.
dc.typearticleen
dc.rights.licenseARR
dcterms.abstractВучићевић, Љубица; Ћирић, Дарко; Шапоњић, Јасна; Трајковић, Владимир; Мисиркић Марјановић, Маја; Мартиновић, Тамара; Форетз, Марц; Јовановић, Маја; Исаковић, Aлександра; Марковић, Иванка; Рабанал-Руиз, Yоана; Королцхук, Виктор И.;
dc.rights.holder© 2019, Springer Nature Switzerland AG.
dc.identifier.doi10.1007/s00018-019-03356-2
dc.identifier.pmid31720741
dc.identifier.scopus2-s2.0-85075142282
dc.identifier.wos000495944900001
dc.citation.apaVucicevic, L., Misirkic, M., Ciric, D., Martinovic, T., Jovanovic, M., Isakovic, A., et al. (2019). Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells. Cellular and Molecular Life Sciences, DOI_10.1007/s00018-019-03356-2.
dc.citation.vancouverVucicevic L, Misirkic M, Ciric D, Martinovic T, Jovanovic M, Isakovic A, Markovic I, Saponjic J, Foretz M, Rabanal-Ruiz Y, Korolchuk VI, Trajkovic V. Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells. Cell Mol Life Sci. 2019;DOI_10.1007/s00018-019-03356-2.
dc.type.versionacceptedVersion
dc.citation.rankM21


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