Aminoacetone induces iron-mediated oxidative damage to isolated rat liver mitochondria.
Aminoacetone (AA) is a threonine metabolite accumulated in threoninemia, cri-du-chat, and diabetes, where it contributes toward the formation of cytotoxic and genotoxic methylglyoxal (MG). Oxyradicals yielded from iron-catalyzed AA aerobic oxidation to MG are shown here to promote Ca2+ -mediated mitochondrial membrane permeabilization in an AA dose-dependent way. The inhibitory effect of added EGTA, cyclosporin A, Mg2+, and DTT observed in this study suggests the formation of transition pores in the inner mitochondrial membrane by AA, associated with thiol protein aggregation. That the mitochondrial iron pool plays a coadjutant role in the transition of mitochondrial permeability is indicated by the dramatic inhibitory effect of added o-phenanthroline. Iron released from ferritin by AA oxidation products--superoxide anion and AA enolyl radicals--is shown to act as an alternative source of ferrous iron, intensifying the mitochondrial damage. These findings may contribute to clarify the role of accumulated AA and iron overload in the mitochondrial oxidative damage reportedly occurring in diabetes mellitus.
Dutra
Fernando
F
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, SP, CEP 05508-900, Brazil.
Bechara
Etelvino J H
EJ
D000096:Acetone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D005293:Ferritins / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010539:Permeability / Q000187:drug effects; D010618:Phenanthrolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D007502:Iron Chelating Agents; D010618:Phenanthrolines; D017382:Reactive Oxygen Species; D000096:Acetone; D004533:Egtazic Acid; D016572:Cyclosporine; D005293:Ferritins; D007501:Iron; D008274:Magnesium; D004229:Dithiothreitol; C006495:aminoacetone