Abstract
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 language | English |
|---|---|
| Pages (from-to) | 3787-3799 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 14 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - Dec 15 2005 |
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Cite this
Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. / Schoenfeld, Robert A.; Napoli, Eleonora; Wong, Alice; Zhan, Shan; Reutenauer, Laurence; Morin, Dexter; Buckpitt, Alan R.; Taroni, Franco; Lonnerdal, Bo; Ristow, Michael; Puccio, Hélène; Cortopassi, Gino A.
In: Human Molecular Genetics, Vol. 14, No. 24, 15.12.2005, p. 3787-3799.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells
AU - Schoenfeld, Robert A.
AU - Napoli, Eleonora
AU - Wong, Alice
AU - Zhan, Shan
AU - Reutenauer, Laurence
AU - Morin, Dexter
AU - Buckpitt, Alan R.
AU - Taroni, Franco
AU - Lonnerdal, Bo
AU - Ristow, Michael
AU - Puccio, Hélène
AU - Cortopassi, Gino A.
PY - 2005/12/15
Y1 - 2005/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=29644442275&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=29644442275&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddi393
DO - 10.1093/hmg/ddi393
M3 - Article
C2 - 16239244
AN - SCOPUS:29644442275
VL - 14
SP - 3787
EP - 3799
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 24
ER -