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

Research output: Contribution to journalArticle

84 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3787-3799
Number of pages13
JournalHuman Molecular Genetics
Volume14
Issue number24
DOIs
StatePublished - Dec 15 2005

Fingerprint

Heme
Coproporphyrinogen Oxidase
Ferrochelatase
Metallochaperones
Down-Regulation
Friedreich Ataxia
Deficiency Diseases
Electron Transport Complex IV
Transcriptome
frataxin
Up-Regulation
Yeasts
Metals
Cell Proliferation
T-Lymphocytes
Polymerase Chain Reaction
Messenger RNA
Liver

ASJC Scopus subject areas

  • Genetics

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 journalArticle

Schoenfeld, RA, Napoli, E, Wong, A, Zhan, S, Reutenauer, L, Morin, D, Buckpitt, AR, Taroni, F, Lonnerdal, B, Ristow, M, Puccio, H & Cortopassi, GA 2005, 'Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells', Human Molecular Genetics, vol. 14, no. 24, pp. 3787-3799. https://doi.org/10.1093/hmg/ddi393
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. / Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. In: Human Molecular Genetics. 2005 ; Vol. 14, No. 24. pp. 3787-3799.
@article{2abff03cc7e44b279eedee435cac64f5,
title = "Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells",
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.",
author = "Schoenfeld, {Robert A.} and Eleonora Napoli and Alice Wong and Shan Zhan and Laurence Reutenauer and Dexter Morin and Buckpitt, {Alan R} and Franco Taroni and Bo Lonnerdal and Michael Ristow and H{\'e}l{\`e}ne Puccio and Cortopassi, {Gino A}",
year = "2005",
month = "12",
day = "15",
doi = "10.1093/hmg/ddi393",
language = "English (US)",
volume = "14",
pages = "3787--3799",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",

}

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 -