Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells

Gabriela Link, Ann Saada, Arie Pinson, Abraham M. Konijn, Chaim Hershko*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


Our previous studies in iron-loaded rat heart cells showed that in vitro iron loading results in peroxidative injury, manifested in a marked decrease in rate and amplitude of heart cell contractility and rhythmicity, which is correctable by treatment with deferoxamine (DF). In the present studies we explored the role of mitochondrial damage in myocardial iron toxicity. Iron loading by 24-hour incubation with 0.36 mmol/L ferric ammonium citrate resulted in a decrease in the activity of nicotinamide adenine dinucleotide (NADH)-cytochrome c oxidoreductase (complex I+III) to 35.3% ± 11.2% of the value in untreated controls; of succinate-cytochrome c oxidoreductase (complex II+III) to 57.4% ± 3.1%; and of succinate dehydrogenase to 63.5% ± 12.6% (p < 0.001 in all cases). The decrease in activity of other mitochondrial enzymes, including NADH-ferricyanide reductase, succinate ubiquinone oxidoreductase (complex II), cytochrome c oxidase (complex IV), and ubiquinol cytochrome c oxidoreductase (complex III), was less impressive and ranged from 71.5% ± 15.8% to 91.5% ± 14.6% of controls. That the observed loss of respiratory enzyme activity was a specific effect of iron toxicity was clearly demonstrated by the complete restoration of enzyme activities by in vitro iron chelation therapy. Sequential treatment with iron and doxorubicin caused a loss of complex I+III and complex II+III activity that was greater than that seen with either agent alone but was only partially correctable by DF treatment. Alterations in cellular adenosine triphosphate measurements paralleled very closely the changes observed in respiratory complex activity. These findings demonstrate for the first time the impairment of cardiac mitochondrial respiratory enzyme activity caused by iron loading at conditions formerly shown to produce severe abnormalities in contractility and rhythmicity.

Original languageAmerican English
Pages (from-to)466-474
Number of pages9
JournalJournal of Laboratory and Clinical Medicine
Issue number5
StatePublished - May 1998

Bibliographical note

Funding Information:
From the Laboratory of Myocardial Research, Hebrew University, Hadassah Medical School, and the Metabolic Disease Unit and Department of Medicine, Shaare Zedek Medical Center, Jerusalem. Supported by the Israel Science Foundation, administered by the Israel Academy of Sciences and Humanities, and by the Vidal-Mad-jar, Rebecca Arief, and Jossef Dabbah Foundations. Submitted for publication Oct. 31, 1997; revision submitted Jan. 8, 1998; accepted Jan. 12, 1998. Reprint requests: C. Hershko, Department of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel. Copyright © 1998 by Mosby, Inc. 0022-2143/98 $5.00 + 0 511188936


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