Cardioprotective effect of alpha-tocopherol, ascorbate, deferoxamine, and deferiprone: Mitochondrial function in cultured, iron-loaded heart cells

Because mitochondrial inner membrane respiratory complexes are important ta rgets of iron toxicity we used iron-loaded rat heart cells in culture to st udy the beneficial effect on mitochondrial enzymes of the iron chelators de feroxamine (DFO) and deferiprone (L1) and of antioxidants and reducing agen ts (ascorbate and alpha-tocopherol). Reduced nicotinamide adenine dinucleot ide-cytochrome c oxidoreductase (complex I-III) and succinate dehydrogenase were the most-sensitive indicators of iron toxicity and cardioprotective e ffect, Although at concentrations below 0.3 mmol/L the iron-mobilizing effe ct of L1 was less than that of DFO, both were equally effective in protecti ng or restoring mitochondrial respiratory enzyme activity. At 1.0 mmol/L, L 1 toxicity was manifested in respiratory enzyme inhibition, whereas DFO had no such effect. Ascorbate (0.057 to 5.7 mmol/L) had a mild cardioprotectiv e effect at the highest concentration only, in association with decreased c ellular iron uptake. By contrast, alpha-tocopherol (0.023 mmol/L) completel y inhibited mitochondrial iron toxicity without affecting iron uptake or re lease, and irrespective of whether it was used before, during, or after in vitro iron loading, These observations illustrate the usefulness and limita tions of iron chelators and other agents used for preventing iron toxicity to the heart and other vital organs, and they underline the need for explor ing in more detail the effects of these agents in the clinical setting.