Metformin and thiazolidinediones (TZDs) are believed to exert their antidiabetic effects via different mechanisms. As evidence suggests that both impair cell respiration in vitro, this study compared their effects on mitochondrial functions. The activity of complex I of the respiratory chain, which is known to be affected by metformin, was measured in tissue homogenates that contained disrupted mitochondria. In homogenates of skeletal muscle, metformin and TZDs reduced the activity of complex I (30 mmol/l metformin, ؊15 ؎ 2%; 100 mol/l rosiglitazone, ؊54 ؎ 7; and 100 mol/l pioglitazone, ؊12 ؎ 4; P < 0.05 each). Inhibition of complex I was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate ؉ malate as substrates for complex I (30 mmol/l metformin, ؊77 ؎ 1%; 100 mol/l rosiglitazone, ؊24 ؎ 4; and 100 mol/l pioglitazone, ؊18 ؎ 5; P < 0.05 each), whereas respiration with succinate feeding into complex II was unaffected. In line with inhibition of complex I, 24-h exposure of isolated rat soleus muscle to metformin or TZDs reduced cell respiration and increased anaerobic glycolysis (glucose oxidation: 270 mol/l metformin, ؊30 ؎ 9%; 9 mol/l rosiglitazone, ؊25 ؎ 8; and 9 mol/l pioglitazone, ؊45 ؎ 3; lactate release: 270 mol/l metformin, ؉84 ؎ 12; 9 mol/l rosiglitazone, ؉38 ؎ 6; and 9 mol/l pioglitazone, ؉64 ؎ 11; P < 0.05 each). As both metformin and TZDs inhibit complex I activity and cell respiration in vitro, similar mitochondrial actions could contribute to their antidiabetic effects. Diabetes

In this review we consider the physiological effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and non-enzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.

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Nitrite, which is the major stable degradation product of nitric oxide, exists in all tissues capable of nitric oxide synthesis from L-arginine. The present study provides experimental evidence that nitrite in contact with respiring mitochondria accepts reducing equivalents from the ubiquinone cycle of the respiratory chain. Univalent reduction of nitrite was totally inhibited by myxothiazol. We therefore conclude on the involvement of redox cycling that ubisemiquinone is associated with the bc 1 complex. Recycling of nitric oxide degradation products via these electron carriers may become a threat to energy-linked respiration since nitric oxide in direct contact with mitochondria was shown to slow the energy-linked respiration down and to trigger a mitochondrial source for superoxide radicals. Until now, the existence of nitrite reductase activity was only demonstrated in plants and bacteria. In addition, the present observation elucidates the existence of a nitric oxide synthaseindependent nitric oxide source.z 1999 Federation of European Biochemical Societies.