Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I

Abstract

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 μmol/l rosiglitazone, −54 ± 7; and 100 μmol/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 μmol/l rosiglitazone, −24 ± 4; and 100 μmol/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 μmol/l metformin, −30 ± 9%; 9 μmol/l rosiglitazone, −25 ± 8; and 9 μmol/l pioglitazone, −45 ± 3; lactate release: 270 μmol/l metformin, +84 ± 12; 9 μmol/l rosiglitazone, +38 ± 6; and 9 μmol/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.