Glucose and Its Metabolites Have Distinct Effects on the Calcium-Induced Mitochondrial Permeability Transition

Mitochondrial production of reactive oxy- gen species (ROS) due to up-regulated glucose oxida- tion is thought to play a crucial, unifying role in the pathogenesis of chronic complications associated with diabetes mellitus. Mitochondrial permeability transition (MPT) is an interesting phenomenon in- volved in calcium signalling and cell death. We inves- tigated the effects of glucose and several of its me- tabolites on calcium-induced MPT (measured as mitochondrial swelling) in isolated rat liver mito- chondria. The presence of glucose, glucose 1-phos- phate (both at 30 mM) or methylglyoxal (6 mM) sig- nificantly slowed calcium-induced mitochondrial swelling. Thirty mM glucose also resulted in a signifi- cant delay of MPT onset. In contrast, 30 mM fruc- tose 6-phosphate accelerated swelling, whereas glu- cose 6-phosphate did not influence the MPT. The calcium binding potentials of the three hexose phos- phates were tested and found similar. In vitro hydro- gen peroxide production by mitochondria respiring on succinate in the presence of rotenone was inde- pendent of mitochondrial membrane potential and increased transiently during calcium-induced MPT. Inhibition of MPT with cyclosporine A resulted in decreased mitochondrial ROS production in re- sponse to calcium. In contrast, inhibition of MPT by methylglyoxal was accompanied by increased ROS production in response to calcium. In conclusion, we confirm that methylglyoxal is a potent inhibitor of MPT. In addition, high levels of glucose, glucose 1-phosphate and fructose 6-phosphate can also affect MPT. Methylglyoxal simultaneously inhibits MPT and increases mitochondrial ROS production in re- sponse to calcium. Our findings provide a novel con- text for the role of MPT in glucose sensing and the cellular toxicity caused by methylglyoxal.