| Hereditary hemochromatosis (HH) is a common iron loading disorder characterized by increased intestinal iron absorption and tissue iron overload. Although diabetes is part of the classical presentation of HH, there is still controversy about its pathogenesis. Utilizing a mouse model of hemochromatosis with target deletion of hemochromatosis gene (Hfe-/-), we assessed potential iron-mediated damages that could lead to pancreatic beta cell failure. Our data demonstrate that iron overload in Hfe -/- mice results in diminished insulin secretory capacity secondary to beta cell apoptosis, loss of beta cell mass, and desensitization of glucose-stimulated insulin secretion. These findings are suggestive of potential mitochondrial dysfunction. We, therefore, examined the function of mitochondria isolated from Hfe-/- mouse liver. These mitochondria exhibited decreased respiration and a significant increase in lipid peroxidation, a marker of oxidative damage. To determine if the mitochondrial dysfunction and oxidant stress were consequences of abnormal metal homeostasis in the Hfe-/- mice, the levels of four transition metals relevant to mitochondrial function were assessed. We demonstrate that iron accumulation in Hfe-/- mice is confined to liver cytosol while mitochondrial iron content is maintained at normal levels. However, Hfe-/- mutant mice are significantly deficient in mitochondrial manganese, copper, and zinc. This is associated with decreased activity of copper- and manganese-dependent mitochondrial enzymes and an overall decrease in mitochondrial respiration. This mitochondrial dysfunction is reversible. Manganese supplementation restores mitochondrial dysfunction leading to enhance insulin secretory capacity and glucose tolerance in Hfe-/- mice. Iron has previously been though to cause oxidative damage mainly by catalyzing the production of free radicals (Fenton chemistry). However, our present findings suggest a new component to iron toxicity, namely altering mitochondrial metal uptake resulting in attenuated mitochondrial antioxidant defenses and overall function. The deficiencies of manganese, copper, and zinc in mitochondria from Hfe -/- mice are new factors in understanding the pathogenesis of hemochromatosis and possibly other diseases characterized by mitochondrial dysfunction and oxidative stress. The further consequences of and potential ability to correct these abnormalities in mitochondrial metal content are under investigation and present a potential for therapeutic intervention. |
