Frataxin knockdown causes loss of cytoplasmic iron–sulfur cluster functions, redox alterations and induction of heme transcripts
Open accessAbstract
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.
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Ferritin mRNA induction was observed during DMSO- or hemin-induced differentiation of mouse Friend leukemia cells and hemin-mediated differentiation of K562 human chronic myelogenous leukemia cells.
“Ferritin mRNA induction was observed during DMSO-or hemin-induced differentiation of mouse Friend leukemia cells (FLC) and hemin-mediated differentiation of K562 human chronic myelogenous leukemia cells (17, 143, 194).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [194]
The proximal region of the human ferritin H gene was activated by NF-Y and p300 during hemin-induced FLC differentiation, and this proximal region was also responsible for cAMP.
“The proximal region of the human ferritin H gene was activated by NF-Y and p300 during hemin-induced FLC differentiation, and this proximal region was also responsible for cAMP (80, 194, 248).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [194]
The NF-Y transcription factor was bound to a 100-bp region upstream from the transcription start site of the human ferritin H gene.
“The NF-Y transcription factor was bound to a 100-bp region upstream from the transcription start site of the human ferritin H gene (194).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [194]
All NF-Y subunits A, B, and C were required for binding to DNA; at least the NF-YA subunit was required to activate the ferritin H gene in response to hemin treatment during differentiation of monocytes to macrophages.
“All NF-Y subunits, A, B, and C, were required for binding to DNA; then at least the NF-YA subunit was required to activate the ferritin H gene in response to hemin treatment during differentiation of monocytes to macrophages (194).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [194]
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References 57 · Cited by 94
Research works printed but not linked: 1
- [10]Lamarche DSJB, Cote M, Lemieux B. Cardiac iron deposits in Friedreich’s ataxia. In: Lechtenberg R, editor. Handbook of Cerebellar Diseases. Marcel Dekker; 1993. pp. 453–458. [Google Scholar]
- Authors
- Lu, C., & Cortopassi, G.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Cortopassi, Gino
- ORCID
- Cortopassi, Gino
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 2007-01
- Volume
- 457
- Issue
- 1
- Pages
- 111-122
- ISSN
- 0003-9861 (ISSN-L)
- PMC
- PMC1847786
- OpenAlex
- W2006402127
- Cited by
- 94
- References
- 57
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 3 · 2015: 6 · 2014: 3 · 2013: 7 · 2012: 1
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service
- National Institute on Aging (AG-11967, AG16719, AG23311, R01AG016719, R03AG023311, R01AG011967)
- National Eye Institute (R01EY012245, EY 12245)
- National Cancer Institute (R01CA042742)
- National Institute of Neurological Disorders and Stroke (R01NS077777)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- frataxin, Friedreich's ataxia, iron-sulfur clusters, mitochondrial iron-sulfur proteins, oxidative stress, unfolded protein response, copper-zinc superoxide dismutase, mitochondrial aconitase, heme biosynthesis, ALAS1, monoamine oxidase A, cytochrome c
- MeSH terms
- Frataxin, Cell Line, Cytoplasm, Heme, Humans, Iron-Sulfur Proteins, Superoxide Dismutase, Signal Transduction, Gene Expression, Protein Folding, Oxidative Stress, Mitochondrial Proteins, Iron-Binding Proteins, RNA, Small Interfering, Cytochromes c
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