Metformin selectively targets redox control of complex I energy transduction

Abstract

Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.

MKP1 reduces neuroinflammation via inhibiting endoplasmic reticulum stress and mitochondrial dysfunction

“…Immunofluorescence assay analysis was carried out as previously described (Biernacki et al, ; Cameron et al, ). The primary antibodies used in the present study were p‐JNK (1:1000; #9251; Cell Signaling Technology), CHOP (1:1000; #ab11419; Abcam), and PERK (1:1000; #ab65142; Abcam; Kazakov et al, ; Y. Zhang et al, ).…”

Mitochondrial targets of metformin—Are they physiologically relevant?

“…To avoid the limitation of drug redistribution across mitochondrial membranes, researchers tested inhibitory effect of metformin in submitochondrial particles (SMPs), where matrix side of complex I is accessible to the tested drugs, or directly on isolated complex I. The inhibition of NADH‐dependent respiration in SMPs was minor and even the prolonged treatment had no effect . The reported IC 50 for metformin on complex I activity are extremely high and range from 20 to 80 mmol/L .…”

“…The inhibition of NADHdependent respiration in SMPs was minor and even the prolonged treatment had no effect. 16,35 The reported IC 50 for metformin on complex I activity are extremely high and range from 20 to 80 mmol/L. 33,38,40 Moreover, the specific site of metformin binding to the complex I remains elusive as it was shown to influence both flavin and ubiquinone-F I G U R E 1 Suggested molecular targets of metformin.…”

Role of mitochondria and mitochondria‐targeted agents in non‐alcoholic fatty liver disease

“…However, its role in NAFLD has not yet been evaluated. Metformin has an effect on the energy transduction by selectively inducing a state in complex I . However, the FDA have so far not recommended any effective therapy other than physical exercise, and dietary modification for NAFLD.…”