International Journal of Cell Biology / 2012 / Article / Fig 5

Review Article

Pathological Significance of Mitochondrial Glycation

Figure 5

Intra- versus extracellular glycation—involvement in diabetes and ageing. Glycation can take place in the extracellular environment or within cells in the cytosol and in organelles like mitochondria. Extracellular AGEs may arise from oxidative and nonoxidative modifications of the Amadori product or from direct reaction of α,β-dicarbonyls with proteins. Extracellular AGEs may bind to cell surface receptors such as RAGE, thereby activating cell signalling pathways. The formation of lipid-AGEs on the cell surface membrane can further generate reactive α,β-dicarbonyls such as glyoxal. These reactive carbonyl species can diffuse through lipid membranes and enter cells where they react with cellular biomolecules to form intracellular AGEs. They can also diffuse further into mitochondria and similarly cause glycation damage within these organelles. Intracellular glycation may also arise from α,β-dicarbonyls produced during the breakdown of triose phosphates generated during glycolysis. Normally, glycation damage is kept under control by defences such as the glyoxalase enzyme system and aldehyde dehydrogenases. However, in diabetes, glycation damage increases due to elevated formation of α,β-dicarbonyls, arising from high glucose levels and consequent inhibition of the glycolytic enzyme, G3P dehydrogenase, both of which lead to a rise in triose phosphate levels. These in turn break down nonenzymatically to form methylglyoxal, a major precursor of glycation. In addition, activation of RAGE is associated with decreased glyoxalase I expression, which is expected to further raise methylglyoxal levels by preventing its removal. During ageing, glycation damage also increases, but mainly as a result of a loss of glyoxalase activity with age.

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