Metformin promotes isolated rat liver mitochondria impairment.
Metformin, a drug widely used in the treatment of type 2 diabetes, has recently received attention due to the new and contrasting findings regarding its effects on mitochondrial function. In the present study, we evaluated the effect of metformin in isolated rat liver mitochondria status. We observed that metformin concentrations > or =8 mM induce an impairment of the respiratory chain characterized by a decrease in RCR and state 3 respiration. However, only metformin concentrations > or =10 mM affect the oxidative phosphorylation system by decreasing the mitochondrial transmembrane potential and increasing the repolarization lag phase. Moreover, our results show that metformin does not prevent H(2)O(2) production, neither protects against lipid peroxidation induced by the pro-oxidant pair ADP/Fe(2+). In addition, we observed that metformin exacerbates Ca(2+)-induced permeability transition pore opening by decreasing the capacity of mitochondria to accumulate Ca(2+ )and increasing the oxidation of thiol groups. Taken together, our results show that metformin can promote liver mitochondria injury predisposing to cell death.
Carvalho
Cristina
C
Department of Zoology - Faculty of Sciences and Technology, University of Coimbra, Coimbra 3000-354, Portugal.
Correia
Sónia
S
Santos
Maria S
MS
Seiça
Raquel
R
Oliveira
Catarina R
CR
Moreira
Paula I
PI
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013438:Sulfhydryl Compounds; D017392:Thiobarbituric Acid Reactive Substances; D008687:Metformin; D006861:Hydrogen Peroxide