Mitochondrial dysfunction may explain the cardiomyopathy of chronic iron overload.
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 4weeks after which the iron-loaded mice had elevated cardiac iron, modest cardiac hypertrophy, and cardiac dysfunction. qPCR amplification of near-full-length ( approximately 16kb) mtDNA revealed >50% loss of full-length product, whereas amounts of a qPCR product of a nuclear gene (13kb 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.
Gao
Xueshan
X
Department of Oncology, University of Linköping, Linköping, Sweden.
Qian
Mingwei
M
Campian
Jian Li
JL
Marshall
James
J
Zhou
Zhanxiang
Z
Roberts
Andrew M
AM
Kang
Y James
YJ
Prabhu
Sumanth D
SD
Sun
Xiao-Feng
XF
Eaton
John W
JW
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology*; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D019190:Iron Overload / Q000150:complications*; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I
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