Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study.
Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.
Guigas
Bruno
B
INSERM E-0221 Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, BP 53X, 38041 Grenoble Cedex, Grenoble, France.
Detaille
Dominique
D
Chauvin
Christiane
C
Batandier
Cécile
C
De Oliveira
Frédéric
F
Fontaine
Eric
E
Leverve
Xavier
X
D016923:Cell Death / Q000187:drug effects*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects* / Q000378:metabolism; D007624:KB Cells; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010101:Oxygen Consumption / Q000187:drug effects; D010539:Permeability
D007004:Hypoglycemic Agents; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D045304:Cytochromes c; D008687:Metformin; D002950:Citrate (si)-Synthase; D042967:Electron Transport Complex I