Frataxin knockdown causes loss of cytoplasmic iron-sulfur cluster functions, redox alterations and induction of heme transcripts

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Abstract

Frataxin protein deficiency causes the neurodegenerative disease Friedreich ataxia. We used inducible siRNA to order the consequences of frataxin deficiency that we and others have previously observed. The earliest consequence of frataxin deficiency was a defect in cytoplasmic iron-sulfur proteins. In the second phase, protein oxidative damage increased, and CuZnSOD was induced, as was the unfolded protein response (UPR), long before any decline in mitochondrial aconitase activity. In the third phase, mitochondrial aconitase activity declined. And in the fourth phase, coincident with the decrease in heme-containing cytochrome c protein, a transcriptional induction of the heme-dependent transcripts ALAS1 and MAOA occurred. These observations suggest that the earliest consequences of frataxin deficiency occur in ISC proteins of the cytoplasm, resulting in oxidative damage and stress and activation of the unfolded protein response which has been associated with neurological disease, and that later consequences involve mitochondrial iron-sulfur cluster deficiency, heme deficiency, and then increased heme biosynthesis.

Original languageEnglish (US)
Pages (from-to)111-122
Number of pages12
JournalArchives of Biochemistry and Biophysics
Volume457
Issue number1
DOIs
StatePublished - Jan 1 2007

Fingerprint

Heme
Sulfur
Oxidation-Reduction
Iron
Aconitate Hydratase
Unfolded Protein Response
Proteins
Iron-Sulfur Proteins
Friedreich Ataxia
Protein Deficiency
Cytochromes c
Neurodegenerative Diseases
Neurodegenerative diseases
Small Interfering RNA
Cytoplasm
Oxidative Stress
Biosynthesis
frataxin
Chemical activation
Defects

Keywords

  • Frataxin
  • Heme pathway
  • Iron-sulfur cluster
  • Redox alterations
  • RNAi
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

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title = "Frataxin knockdown causes loss of cytoplasmic iron-sulfur cluster functions, redox alterations and induction of heme transcripts",
abstract = "Frataxin protein deficiency causes the neurodegenerative disease Friedreich ataxia. We used inducible siRNA to order the consequences of frataxin deficiency that we and others have previously observed. The earliest consequence of frataxin deficiency was a defect in cytoplasmic iron-sulfur proteins. In the second phase, protein oxidative damage increased, and CuZnSOD was induced, as was the unfolded protein response (UPR), long before any decline in mitochondrial aconitase activity. In the third phase, mitochondrial aconitase activity declined. And in the fourth phase, coincident with the decrease in heme-containing cytochrome c protein, a transcriptional induction of the heme-dependent transcripts ALAS1 and MAOA occurred. These observations suggest that the earliest consequences of frataxin deficiency occur in ISC proteins of the cytoplasm, resulting in oxidative damage and stress and activation of the unfolded protein response which has been associated with neurological disease, and that later consequences involve mitochondrial iron-sulfur cluster deficiency, heme deficiency, and then increased heme biosynthesis.",
keywords = "Frataxin, Heme pathway, Iron-sulfur cluster, Redox alterations, RNAi, Unfolded protein response",
author = "Chunye Lu and Cortopassi, {Gino A}",
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T1 - Frataxin knockdown causes loss of cytoplasmic iron-sulfur cluster functions, redox alterations and induction of heme transcripts

AU - Lu, Chunye

AU - Cortopassi, Gino A

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Frataxin protein deficiency causes the neurodegenerative disease Friedreich ataxia. We used inducible siRNA to order the consequences of frataxin deficiency that we and others have previously observed. The earliest consequence of frataxin deficiency was a defect in cytoplasmic iron-sulfur proteins. In the second phase, protein oxidative damage increased, and CuZnSOD was induced, as was the unfolded protein response (UPR), long before any decline in mitochondrial aconitase activity. In the third phase, mitochondrial aconitase activity declined. And in the fourth phase, coincident with the decrease in heme-containing cytochrome c protein, a transcriptional induction of the heme-dependent transcripts ALAS1 and MAOA occurred. These observations suggest that the earliest consequences of frataxin deficiency occur in ISC proteins of the cytoplasm, resulting in oxidative damage and stress and activation of the unfolded protein response which has been associated with neurological disease, and that later consequences involve mitochondrial iron-sulfur cluster deficiency, heme deficiency, and then increased heme biosynthesis.

AB - Frataxin protein deficiency causes the neurodegenerative disease Friedreich ataxia. We used inducible siRNA to order the consequences of frataxin deficiency that we and others have previously observed. The earliest consequence of frataxin deficiency was a defect in cytoplasmic iron-sulfur proteins. In the second phase, protein oxidative damage increased, and CuZnSOD was induced, as was the unfolded protein response (UPR), long before any decline in mitochondrial aconitase activity. In the third phase, mitochondrial aconitase activity declined. And in the fourth phase, coincident with the decrease in heme-containing cytochrome c protein, a transcriptional induction of the heme-dependent transcripts ALAS1 and MAOA occurred. These observations suggest that the earliest consequences of frataxin deficiency occur in ISC proteins of the cytoplasm, resulting in oxidative damage and stress and activation of the unfolded protein response which has been associated with neurological disease, and that later consequences involve mitochondrial iron-sulfur cluster deficiency, heme deficiency, and then increased heme biosynthesis.

KW - Frataxin

KW - Heme pathway

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KW - Redox alterations

KW - RNAi

KW - Unfolded protein response

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