title: Methylglyoxal, the foe and friend of glyoxalase and Trx/TrxR systems in HT22 nerve cells.
abstract: Methylglyoxal (MGO) is a major glycating agent that reacts with basic residues of proteins and promotes the formation of advanced glycation end products (AGEs) which are believed to play key roles in a number of pathologies, such as diabetes, Alzheimer's disease, and inflammation. Here, we examined the effects of MGO on immortalized mouse hippocampal HT22 nerve cells. The endpoints analyzed were MGO and thiol status, the glyoxalase system, comprising glyoxalase 1 and 2 (GLO1/2), and the cytosolic and mitochondrial Trx/TrxR systems, as well as nuclear Nrf2 and its target genes. We found that nuclear Nrf2 is induced by MGO treatment in HT22 cells, as corroborated by induction of the Nrf2-controlled target genes and proteins glutamate cysteine ligase and heme oxygenase 1. Nrf2 knockdown prevented MGO-dependent induction of glutamate cysteine ligase and heme oxygenase 1. The cystine/glutamate antiporter, system xc(-), which is also controlled by Nrf2, was also induced. The increased cystine import (system xc(-)) activity and GCL expression promoted GSH synthesis, leading to increased levels of GSH. The data indicate that MGO can act as both a foe and a friend of the glyoxalase and the Trx/TrxR systems. At low concentrations of MGO (0.3mM), GLO2 is strongly induced, but at high MGO (0.75 mM) concentrations, GLO1 is inhibited and GLO2 is downregulated. The cytosolic Trx/TrxR system is impaired by MGO, where Trx is downregulated yet TrxR is induced, but strong MGO-dependent glycation may explain the loss in TrxR activity. We propose that Nrf2 can be the unifying element to explain the observed upregulation of GSH, GCL, HO1, TrxR1, Trx2, TrxR2, and system xc(-) system activity.
authors.affiliation: Biochemistry Department, Federal University of Santa Catarina, Florianópolis, SC, Brazil. Electronic address: alcir.dafre@ufsc.br.
authors.forename: A L
authors.initials: AL
authors.lastname: Dafre
authors.affiliation: Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: J
authors.initials: J
authors.lastname: Goldberg
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Spiegel
authors.affiliation: Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: P
authors.initials: P
authors.lastname: Maher
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011765:Pyruvaldehyde / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: C471550:Gcl protein, mouse; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; C515559:Txn1 protein, mouse; D013879:Thioredoxins; D011765:Pyruvaldehyde; D000429:Alcohol Oxidoreductases; C493348:gluconolactone oxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D005978:Glutathione
keywords: Glutathione; Glyoxalase; HT22 cells; Methylglyoxal; Nrf2; Thioredoxin reductase