期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 49, 期 3, 页码 401-407出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2010.04.033
关键词
Mitochondrial DNA; Iron overload; Cardiomyopathy
资金
- NIH [RO1 DK073586, RO1AA018016]
- Commonwealth of Kentucky Research Challenge Trust
In patients with hemochromatosis, cardiac dysfunction may appear years after they have reached a state of iron overload. We hypothesized that cumulative iron-catalyzed oxidant damage to mitochondrial DNA (mtDNA) might explain the cardiomyopathy of chronic iron overload. Mice were given repetitive injections of iron dextran for a total of 4 weeks after which the iron-loaded mice had elevated cardiac iron, modest cardiac hypertrophy, and cardiac dysfunction. OCR amplification of near-full-length (similar to 16 kb) mtDNA revealed >50% loss of full-length product, whereas amounts of a OCR product of a nuclear gene (13 kb region of beta globin) were unaffected. Quantitative rtPCR analyses revealed 60-70% loss of mRNA for proteins encoded by mtDNA with no change in mRNA abundance for nuclear-encoded respiratory subunits. These changes coincided with proportionate reductions in complex I and IV activities and decreased respiration of isolated cardiac mitochondria. We conclude that chronic iron overload leads to cumulative iron-mediated damage to mtDNA and impaired synthesis of mitochondrial respiratory chain subunits. The resulting respiratory dysfunction may explain the slow development of cardiomyopathy in chronic iron overload and similar accumulation of damage to mtDNA may also explain the mitochondrial dysfunction observed in slowly progressing diseases such as neurodegenerative disorders. (C) 2010 Elsevier Inc. All rights reserved.
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