Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells

Robert A. Schoenfeld, Eleonora Napoli, Alice Wong, Shan Zhan, Laurence Reutenauer, Dexter Morin, Alan R Buckpitt, Franco Taroni, Bo Lonnerdal, Michael Ristow, Hélène Puccio, Gino A Cortopassi

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93 Scopus citations


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. Quantitative RT-PCR studies confirmed the significant down-regulation 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 was 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, whereas 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. As ataxic symptoms occur in other diseases of heme deficiency, the heme defect we observe in frataxin-deficient cells could be primary to the pathophysiological process.

Original languageEnglish (US)
Pages (from-to)3787-3799
Number of pages13
JournalHuman Molecular Genetics
Issue number24
StatePublished - Dec 15 2005

ASJC Scopus subject areas

  • Genetics


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