Iron-mediated mitochondrial dysfunction in a mouse model of hemochromatosis

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Title Iron-mediated mitochondrial dysfunction in a mouse model of hemochromatosis
Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Jouihan, Hani Abdelrahim
Date 2007-05
Description 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 ? cell failure. Our data demonstrate that iron overload in Hfe-/- mice results in diminished insulin secretory capacity secondary to ? cell apoptosis, loss of ? 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.
Type Text
Publisher University of Utah
Subject Etiology; Mitochondrial Pathology; Iron in the Body; Mice; Physiology
Subject MESH Hemochromatosis; Mitochondrial Diseases; Iron
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Iron-mediated mitochondrial dysfunction in a mouse model of hemochromatosis." Spencer S. Eccles Health Sciences Library. Print version of "Iron-mediated mitochondrial dysfunction in a mouse model of hemochromatosis." available at J. Willard Marriott Library Special Collection. RC39.5 2007 .J68
Rights Management © Hani Abdelrahim Jouihan.
Format application/pdf
Format Medium application/pdf
Format Extent 1,987,115 bytes
Identifier undthes,4764
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 1,987,161 bytes
ARK ark:/87278/s6xs5x37
Setname ir_etd
ID 190320
Reference URL https://collections.lib.utah.edu/ark:/87278/s6xs5x37
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