Iron-induced peroxidative injury to isolated rat hepatic mitochondria.
Peroxidative injury to the mitochondrial inner membrane with resultant defects in oxidative metabolism may be partially responsible for hepatocellular injury in iron overload. We examined the effects of iron-induced lipid peroxidation in vitro on hepatic mitochondrial morphology and function and determined if various inhibitors of free-radical-mediated injury could be protective. Normal rat liver mitochondria were prepared by differential centrifugation and were incubated with 1, 2, and 3 microM Fe2+, NADPH, and with and without oxygen radical scavengers, iron chelators, and antioxidants. There was a direct linear relationship between the concentration of added iron and the degree of lipid peroxidation as measured by malondialdehyde (MDA) production (r = .85). With 3 microM Fe2+ there was a decrease in the respiratory control ratio (RCR) for all four substrates tested; this decrease in RCR was due to a decrease in the state 3 respiratory rate for all substrates, with no changes in the state 4 respiratory rate for glutamate, beta-hydroxybutyrate, or succinate. Oxygen radical scavengers failed to prevent iron-induced lipid peroxidation or to protect against associated mitochondrial dysfunction. Iron chelators and antioxidants prevented MDA formation and mitochondrial function was maintained. Iron-induced lipid peroxidation in vitro produces an irreversible inhibitory defect in mitochondrial electron transport that may be specific at complex IV (cytochrome oxidase).
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D005296:Ferrous Compounds / Q000633:toxicity*; D005609:Free Radicals; D007425:Intracellular Membranes / Q000187:drug effects / Q000648:ultrastructure; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D002614:Chelating Agents; D005296:Ferrous Compounds; D005609:Free Radicals; D008054:Lipid Peroxides; D008563:Membrane Lipids; C020748:ferrous sulfate; D010100:Oxygen