Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease

Abstract

Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. Enzymes metabolising dicarbonyls, glyoxalase 1 and aldoketo reductases, provide an efficient and stress-response enzyme defence against dicarbonyl stress. Dicarbonyl stress is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites, and by exposure to exogenous dicarbonyls. It contributes to ageing, disease and activity of cytototoxic chemotherapeutic agents.

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

“…We studied renal failure as an example of severe dicarbonyl stress: plasma MG concentration in healthy subjects is ca. 100 nM and increases 5 -7 fold in renal failure [1,63]. The prevalence of increased GLO1 copy number was higher than spontaneous GLO1 duplication in the human population of ca.…”

“…To explore the possibility that Glo1 may suffer dicarbonyl stress-induced copy number alteration, we studied prolonged exposure of mESCs in vitro to severe dicarbonyl stress imposed by high concentrations of exogenous MG [1]. For physiological relevance we studied Glo1 activity and copy number changes also under an atmosphere of 3% oxygenequivalent to ambient oxygen concentration for embryonic stem cells in vivo [41].…”

“…Glyoxalase 1 (Glo1) is part of the glyoxalase metabolic pathway in all mammalian cells and tissues [1] (Figure 1a). The glyoxalase pathway consists of two enzymes, Glo1 and glyoxalase 2 (Glo2), and a catalytic amount of reduced glutathione (GSH).…”

“…Increased MG-H1 and related protein inactivation and dysfunction contributes to ageing [7], insulin resistance [8,9], cardiovascular disease [10], vascular complications of diabetes [4,11] and renal failure [12]. Increased MG concentration, a metabolic state called dicarbonyl stress, is driven by increased formation of MG and/or decreased activity of Glo1 [1]. To counter periods of increased MG formation, expression of Glo1 is under stress-responsive transcriptional control through transcription factor Nrf2 which binds to a functional regulatory antioxidant response element and increases Glo1 expression [13].…”

Correlations between Photodegradation of Bisretinoid Constituents of Retina and Dicarbonyl Adduct Deposition

“…The dicarbonyl molecules methylglyoxal (MG) 2 and glyoxal (GO) are highly reactive clinically relevant molecules that are implicated in the molecular damage that accompanies aging changes (1) and chronic disease states such as diabetes and uremia (2). In diabetes, MG and GO are best known for being major precursors of carbonyl adducts (advanced glycation end products, AGEs) that form non-enzymatically from the degradation of sugar-phosphate intermediates such as glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (3).…”