On the other side, the observed decrease in catalase activity after LEE011 molecular weight cisplatin administration could account for the disability of kidney to eliminate and scavenge toxic H2O2 and lipid peroxides. The inhibition of mitochondrial and postmitochondrial antioxidant enzyme activities may occur due to direct binding of cisplatin to essential sulfhydryl groups at the active sites of these enzymes and depletion of copper and manganese which are essential for SOD activity. Meanwhile, the oxidative stress demonstrated in the current study may target multiple molecules in the cells and damage cell structural components such as lipids, proteins and other organelles where mitochondria are among the most affected ones. Cisplatin exposure induces a mitochondria-dependent ROS generation that significantly contributes to cisplatin-induced nephrotoxicity. Mitochondrial dysfunction has been reported to occur in rats following the depletion of cytosolic GSH with subsequent increase in lipid peroxidation in cisplatin-treated renal cortical slices. Disturbances of the respiratory electron flow or the antioxidant defense mechanisms, can lead to an overproduction of superoxide anions in the respiratory chain of mitochondria by reaction of oxygen with iron-sulfur centers in complex I and by partially reduced ubiquinone and cytochrome b in complex III. A previous study using cultured mouse proximal tubular cells demonstrated cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation and a reduction of complex IV protein. In the present study, cisplatin-induced mitochondrial dysfunction was demonstrated by inhibition of complexes I and III of the respiratory chain. This result is in agreement with previous studies describing the inhibition of the mitochondrial respiratory chain complexes in vitro and the decline in mitochondrial respiratory activity in vivo by cisplatin. The inhibition of complexes I and III activities demonstrated in the current study was accompanied by deterioration of mitochondrial oxidative phosphorylation capacity, resulting in disruption of renal cellular energy production. The decrease in oxidative phosphorylation might be explained by the observed induction of mNOS in the present study which would increase NO production. Increased mitochondrial NO production possibly inhibits cytochrome c oxidase activity by competing with oxygen and also inhibits the electron transport chain at complexes I and III favoring superoxide formation. This in turn would increase peroxynitrite level, alter energy production by increased oxidation of mitochondrial proteins and induce macromolecular damage and cell death. Partial ATP depletion as observed in the present study may constitute a common biochemical pathway that initiates a cascade of events leading to further cellular dysfunctions and activation of programmed cell death. This in turn may accelerate ROS formation by the damaged cells, which may contribute to an amplification of ROS-mediated cell death of the same cell or even the neighboring cells.