Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis.
Previous phenotyping of glucose homeostasis and insulin secretion in a mouse model of hereditary hemochromatosis (Hfe(-/-)) and iron overload suggested mitochondrial dysfunction. Mitochondria from Hfe(-/-) mouse liver exhibited decreased respiratory capacity and increased lipid peroxidation. Although the cytosol contained excess iron, Hfe(-/-) mitochondria contained normal iron but decreased copper, manganese, and zinc, associated with reduced activities of copper-dependent cytochrome c oxidase and manganese-dependent superoxide dismutase (MnSOD). The attenuation in MnSOD activity was due to substantial levels of unmetallated apoprotein. The oxidative damage in Hfe(-/-) mitochondria is due to diminished MnSOD activity, as manganese supplementation of Hfe(-/-) mice led to enhancement of MnSOD activity and suppressed lipid peroxidation. Manganese supplementation also resulted in improved insulin secretion and glucose tolerance associated with increased MnSOD activity and decreased lipid peroxidation in islets. These data suggest a novel mechanism of iron-induced cellular dysfunction, namely altered mitochondrial uptake of other metal ions.
Jouihan
Hani A
HA
Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Cobine
Paul A
PA
Cooksey
Robert C
RC
Hoagland
Emily A
EA
Boudina
Sihem
S
Abel
E Dale
ED
Winge
Dennis R
DR
McClain
Donald A
DA
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D019587:Dietary Supplements; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006432:Hemochromatosis / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage / Q000378:metabolism*; D015227:Lipid Peroxidation; D008345:Manganese / Q000008:administration & dosage / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism*; D010101:Oxygen Consumption; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D007328:Insulin; D008565:Membrane Proteins; D017392:Thiobarbituric Acid Reactive Substances; D008345:Manganese; D007501:Iron; D013482:Superoxide Dismutase; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D000154:Aconitate Hydratase; D005947:Glucose