Human Molecular Genetics Advance Access first published online on October 20, 2005
This version published online on November 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi393
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1 Department of Molecular Biosciences, University of California, Davis
* To whom correspondence should be addressed. Deficiency of the frataxin mRNA alters the transcriptome, triggering neuro- and cardiodegeneration in Friedreich's ataxia. We microarrayed murine frataxin-deficient heart tissue, liver tissue and cardiocytes, and observed a transcript down-regulation to up-regulation ratio of nearly 2:1 with a mitochondrial localization of transcriptional changes. Combining all mouse and human microarray data for frataxin-deficient cells and tissues, the most consistently decreased transcripts were mitochondrial coproporphyrinogen oxidase (CPOX) of the heme pathway, and mature T-cell proliferation 1, a homolog of yeast COX23, which is thought to function as a mitochondrial metallochaperone. QRTPCR studies confirmed the significant downregulation of Isu1, CPOX, and ferrochelatase at 10 weeks in mouse hearts. We observed that mutant cells were resistant to aminolevulinate-dependent toxicity, as expected if the heme pathway were inhibited. Consistent with this, we observed increased cellular protoporphyrin IX levels, reduced mitochondrial heme a and heme c levels, and reduced activity of cytochrome oxidase, suggesting a defect between protoporphyrin IX and heme a. Fe-chelatase activities were similar in mutants and controls, while Zn-chelatase activities were slightly elevated in mutants, supporting the idea of an altered metal-specificity of ferrochelatase. These results suggest that frataxin deficiency causes defects late in the heme pathway. Since ataxic symptoms occur in other diseases of heme deficiency, the heme defect we observe in frataxin-deficient cells could be primary to the pathophysiologic process.
Received August 18, 2005
Revised October 13, 2005
Accepted October 13, 2005
Article
Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells
2 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, Strasbourg, France
3 Division of Bichemistry and Genetics, Instituto Nazionale Neurologico, Carlo Besta, Via Celoria 11, Milan, Italy
4 Department of Nutrition, University of California, Davis
5 Department of Human Nutrition, Institute of Nutrition, University of Jena, Germany
6 Department of Molecular Biosciences, University of California, 1 Shields Ave., Davis, CA 95616
Gino A. Cortopassi, E-mail: gcortopassi{at}ucdavis.edu
Abstract
The Advanced Access version of this article has been updated to correct the spelling of Eleonora Napoli's forename, and add Laurence Reutenauer to the list of authors.
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