Age Modulates Fe3O4 Nanoparticles Liver Toxicity: Dose-Dependent Decrease in Mitochondrial Respiratory Chain Complexes Activities and Coupling in Middle-Aged as Compared to Young Rats

We examined the effects of iron oxide nanoparticles (IONPs) on mitochondrial respiratory chain complexes activities and mitochondrial coupling in young (3 months) and middle-aged (18 months) rat liver, organ largely involved in body iron detoxification. Isolated liver mitochondria were extracted using differential centrifugations. Maximal oxidative capacities (V-max, complexes I, III, and IV activities), V-succ (complexes II, III, and IV activities), and V-tmpd, (complex IV activity), together with mitochondrial coupling (V-max/V-0) were determined in controls conditions and after exposure to 250, 300, and 350 mu g/ml Fe3O4 in young and middle-aged rats. In young liver mitochondria, exposure to IONPs did not alter mitochondrial function. In contrast, IONPs dose-dependently impaired all complexes of the mitochondrial respiratory chain in middle-aged rat liver: V-max (from 30 +/- 1.6 to 17.9 +/- 1.5; P < 0.001), V-succ (from 33.9 +/- 1.7 to 24.3 +/- 1.0; P < 0.01), V-tmpd (from 43.0 +/- 1.6 to 26.3 +/- 2.2 mu mol O-2/min/g protein; P < 0.001) using Fe3O4 350 mu g/ml. Mitochondrial coupling also decreased. Interestingly, 350 mu g/ml Fe3O4 in the form of Fe3+ solution did not impair liver mitochondrial function in middle-aged rats. Thus, IONPs showed a specific toxicity in middle-aged rats suggesting caution when using it in old age.