Abstract
Reactive oxygen species (ROS) are produced constantly inside the cells as a consequence of nutrient catabolism. The balance between ROS production and elimination allows to maintain cell redox homeostasis and biological functions, avoiding the occurrence of oxidative distress causing irreversible oxidative damages. A fundamental player in this fine balance is reduced glutathione (GSH), required for the scavenging of ROS as well as of the reactive 2-oxoaldehydes methylglyoxal (MGO). MGO is a cytotoxic compound formed constitutively as byproduct of nutrient catabolism, and in particular of glycolysis, detoxified in a GSH-dependent manner by the glyoxalase pathway consisting in glyoxalase I and glyoxalase II reactions. A physiological increase in ROS production (oxidative eustress, OxeS) is promptly signaled by the decrease of cellular GSH/GSSG ratio which can induce the reversible S-glutathionylation of key proteins aimed at restoring the redox balance. An increase in MGO level also occurs under oxidative stress (OxS) conditions probably due to several events among which the decrease in GSH level and/or the bottleneck of glycolysis caused by the reversible S-glutathionylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase. In the present review, it is shown how MGO can play a role as a stress signaling molecule in response to OxeS, contributing to the coordination of cell metabolism with gene expression by the glycation of specific proteins. Moreover, it is highlighted how the products of MGO metabolism, S-D-lactoylglutathione (SLG) and D-lactate, which can be taken up and metabolized by mitochondria, could play important roles in cell response to OxS, contributing to cytosol-mitochondria crosstalk, cytosolic and mitochondrial GSH pools, energy production, and the restoration of the GSH/GSSG ratio. The role for SLG and glyoxalase II in the regulation of protein function through S-glutathionylation under OxS conditions is also discussed. Overall, the data reported here stress the need for further studies aimed at understanding what role the evolutionary-conserved MGO formation and metabolism can play in cell signaling and response to OxS conditions, the aberration of which may importantly contribute to the pathogenesis of diseases associated to elevated OxS.
Highlights
To maintain its function and structure, a cell requires energy
The most important enzyme complexes in the Krebs cycle that respond to redox changes occurring in the matrix are pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH), representing entry points for carbohydrate and amino acid derivatives into the Krebs cycle, respectively
As proposed in [11], if the decrease in total GLO2 activity of highly proliferating tissues reflects a decrease in the activity of the cytosolic isoform only, which is the most abundant isoform in the cell [50], this would determine an increase in the cytosolic level of SLG favoring its import and metabolism by mitochondria, feeding the mitochondrial GSH pool (mGSH) pool and D-LAC formation in the matrix
Summary
To maintain its function and structure, a cell requires energy. In cellular metabolism, energy-producing reactions from biomolecules are controlled by oxido-reductases, a group of enzymes that transfer electrons from donors to electron acceptors. Under OxdS conditions, which can lead to significant GSH decrease, GLO1 activity might decrease causing MGO concentration increase and cytotoxic effects mainly due to the glycation of proteins and DNA [26] Another factor that could limit MGO elimination is the accumulation of GLO1 reaction product, namely SLG, due to reduced. D-LAC transport and metabolism inside mitochondria might favor MGO elimination and sustain NADPH production in the cytosol, both events having important implications for the control of GSH/GSSG ratio and cell redox state [31] (Figure 1) Multifactorial pathologic states, such as neurodegenerative diseases, are commonly characterized by elevated OxS and high levels of AGEs formed mainly by the nonenzymatic glycation of proteins, lipids, or nucleic acids by MGO [23,32], and refs therein]. Increased oxidative stress and inflammation and metabolic impairment such as those occurring in neurodegenerative diseases, as well as in aging, can be the consequence of abnormal MGO formation and metabolism, (see references in [11,32])
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