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 language | English (US) |
|---|---|
| Pages (from-to) | 111-122 |
| Number of pages | 12 |
| Journal | Archives of Biochemistry and Biophysics |
| Volume | 457 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2007 |
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Keywords
- Frataxin
- Heme pathway
- Iron-sulfur cluster
- Redox alterations
- RNAi
- Unfolded protein response
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Molecular Biology
Cite this
Frataxin knockdown causes loss of cytoplasmic iron-sulfur cluster functions, redox alterations and induction of heme transcripts. / Lu, Chunye; Cortopassi, Gino A.
In: Archives of Biochemistry and Biophysics, Vol. 457, No. 1, 01.01.2007, p. 111-122.Research output: Contribution to journal › Article
}
TY - JOUR
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
KW - Iron-sulfur cluster
KW - Redox alterations
KW - RNAi
KW - Unfolded protein response
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UR - http://www.scopus.com/inward/citedby.url?scp=33845693952&partnerID=8YFLogxK
U2 - 10.1016/j.abb.2006.09.010
DO - 10.1016/j.abb.2006.09.010
M3 - Article
C2 - 17098208
AN - SCOPUS:33845693952
VL - 457
SP - 111
EP - 122
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
SN - 0003-9861
IS - 1
ER -