Molecular bases of cellular iron toxicity.

Patients with hereditary or secondary hemochromatosis are liable to cardiac and hepatic failure, and type II diabetes. Despite the highly likely conjecture that iron-mediated tissue damage involves the conspiracy of cellular oxidizing and reducing equivalents, the pathophysiologic events have not been fully elucidated. These latter likely involve toxic effects of iron on intracellular organelles, in particular, mitochondria and lysosomes. The tissues at risk-heart, liver, and pancreatic beta cells-all have highly active mitochondria, which incidentally generate activated oxygen species capable of causing synergistic toxicity with intracellular iron. This suggests the general concept that iron may be preferentially toxic to cells with high mitochondrial activity. At least part of the long-term toxicity may involve iron-mediated oxidative damage to the mitochondrial genome with an accumulation of mutational events leading to progressive mitochondrial dysfunction. An alternative-and not mutually exclusive-mechanism for cellular iron toxicity involves iron-catalyzed oxidative destabilization of lysosomes, leading to leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death.