Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

Hani A Jouihan; Paul A Cobine; Robert C Cooksey; Emily A Hoagland; Sihem Boudina; E Dale Abel; Dennis R Winge; Donald A McClain

doi:10.2119/2007-00114.Jouihan

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Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

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Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis

Hani A Jouihan, Paul A Cobine, Robert C Cooksey, Emily A Hoagland, Sihem Boudina, E Dale Abel, Dennis R Winge and Donald A McClain

Molecular medicine (Cambridge, Mass.), Vol.14(3-4), pp.98-108

2008

DOI: 10.2119/2007-00114.Jouihan

PMCID: PMC2258172

PMID: 18317567

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Abstract

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.

Details

Title: Subtitle: Iron-Mediated Inhibition of Mitochondrial Manganese Uptake Mediates Mitochondrial Dysfunction in a Mouse Model of Hemochromatosis
Creators: Hani A Jouihan - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
Paul A Cobine - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
Robert C Cooksey - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
Emily A Hoagland - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
Sihem Boudina - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
E Dale Abel - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
Dennis R Winge - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
Donald A McClain - Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, USA and
Resource Type: Journal article
Publication Details: Molecular medicine (Cambridge, Mass.), Vol.14(3-4), pp.98-108
DOI: 10.2119/2007-00114.Jouihan
PMID: 18317567
PMCID: PMC2258172
NLM abbreviation: Mol Med
ISSN: 1076-1551
eISSN: 1528-3658
Publisher: ScholarOne
Language: English
Date published: 2008
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025300002771

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