title: Modular kinetic analysis reveals differences in Cd2+ and Cu2+ ion-induced impairment of oxidative phosphorylation in liver.
abstract: Impaired mitochondrial function contributes to copper- and cadmium-induced cellular dysfunction. In this study, we used modular kinetic analysis and metabolic control analysis to assess how Cd(2+) and Cu(2+) ions affect the kinetics and control of oxidative phosphorylation in isolated rat liver mitochondria. For the analysis, the system was modularized in two ways: (a) respiratory chain, phosphorylation and proton leak; and (b) coenzyme Q reduction and oxidation, with the membrane potential (Delta psi) and fraction of reduced coenzyme Q as the connecting intermediate, respectively. Modular kinetic analysis results indicate that both Cd(2+) and Cu(2+) ions inhibited the respiratory chain downstream of coenzyme Q. Moreover, Cu(2+), but not Cd(2+) ions stimulated proton leak kinetics at high Delta psi values. Further analysis showed that this difference can be explained by Cu(2+) ion-induced production of reactive oxygen species and membrane lipid peroxidation. In agreement with modular kinetic analysis data, metabolic control analysis showed that Cd(2+) and Cu(2+) ions increased control of the respiratory and phosphorylation flux by the respiratory chain module (mainly because of an increase in the control exerted by cytochrome bc(1) and cytochrome c oxidase), decreased control by the phosphorylation module and increased negative control of the phosphorylation flux by the proton leak module. In summary, we showed that there is a subtle difference in the mode of action of Cd(2+) and Cu(2+) ions on the mitochondrial function, which is related to the ability of Cu(2+) ions to induce reactive oxygen species production and lipid peroxidation.
authors.affiliation: Centre of Environmental Research, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas, Lithuania. jolita.ciapaite@falw.vu.nl
authors.forename: Jolita
authors.initials: J
authors.lastname: Ciapaite
authors.forename: Zita
authors.initials: Z
authors.lastname: Nauciene
authors.forename: Rasa
authors.initials: R
authors.lastname: Baniene
authors.forename: Marijke J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Klaas
authors.initials: K
authors.lastname: Krab
authors.forename: Vida
authors.initials: V
authors.lastname: Mildaziene
mesh_terms: D000818:Animals; D002104:Cadmium / Q000737:chemistry / Q000378:metabolism*; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D004579:Electron Transport / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007477:Ions / Q000737:chemistry / Q000378:metabolism*; D015227:Lipid Peroxidation; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D007477:Ions; D016877:Oxidants; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D002104:Cadmium; D014451:Ubiquinone; D003300:Copper; D006861:Hydrogen Peroxide; D013385:Succinate Dehydrogenase