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 (0.3 mM), 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.

Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells

“…However, an important role for Glo2 in counteracting MGO toxicity has also been proposed [6,7], including after loading HT22 cells with purified Glo2 or in vivo after an ischemic episode [8]. Our recent study showed that MGO treatment of mouse HT22 nerve cells leads to a marked decrease in Glo2 after 8 h of treatment with either a subtoxic (0.3 mM) or toxic (0.75 mM) concentration of MGO [9], but the mechanisms underlying this effect are not known.…”

“…Decreased levels of Trx in the neural tissue and increased levels in plasma and cerebrospinal fluid were found in Alzheimer disease patients, and such changes were correlated to clinical scores and were of prognostic value [14]. There is some in vitro evidence showing that components of the Trx/TrxR system are molecular targets of MGO toxicity [9,15,16]. Endothelial cells exposed to MGO downregulate Trx1 protein and mRNA copy number [17].…”

“…Endothelial cells exposed to MGO downregulate Trx1 protein and mRNA copy number [17]. In HT22 nerve cells, MGO induced a marked decrease in Trx activity and Trx1 protein, as well as a decrease in TrxR activity [9]. Furthermore, it was shown that TrxR1 was heavily modified with MGO-adducts, possibly explaining the loss of function [9].…”

“…In HT22 nerve cells, MGO induced a marked decrease in Trx activity and Trx1 protein, as well as a decrease in TrxR activity [9]. Furthermore, it was shown that TrxR1 was heavily modified with MGO-adducts, possibly explaining the loss of function [9]. Nevertheless, much remains to be determined about the mechanisms involved in the effects of MGO on the Trx/TrxR system.…”

Evolving Evidence of Methylglyoxal and Dicarbonyl Stress Related Diseases from Diabetic to Non-Diabetic Models

“…When MGO concentration is within a tolerable range, the cell upregulates GLO1 to hasten detoxification. However, extreme increases in MGO abundance may cause allosteric binding to GLO1 and inhibit this enzyme's function [22]. Different tissues and organs have different quantities of glutathione and GLO1 [23].…”