Frataxin expression rescues mitochondrial dysfunctions in FRDA cells
Abstract
Friedreich's ataxia (FRDA) is the result of mutations in the nuclear-encoded frataxin gene, which is expressed in mitochondria. Several lines of evidence have suggested that frataxin is involved in mitochondrial iron homeostasis. We have transfected the frataxin gene into lymphoblasts of FRDA compound heterozygotes (FRDA-CH) with deficient frataxin expression to produce FRDA-CH-t cells in which message and protein are rescued to near-physiological levels. FRDA-CH cells were more sensitive to oxidative stress by challenge with free iron, hydrogen peroxide and the combination, consistent with a Fenton chemical mechanism of pathophysiology, and this sensitivity was rescued to control levels in FRDA-CH-t cells. Iron challenge caused increased mitochondrial iron levels in FRDA-CH cells, and a decreased mitochondrial membrane potential (MMP), both of which were rescued in FRDA-CH-t cells. The rescue of the low MMP, and high mitochondrial iron concentration by frataxin overexpression suggests that these cellular phenotypes are relevant to the central pathophysiological process in FRDA which is aggravated by exposure to free iron. However, even at physiological iron concentrations, FRDA-CH cells had decreased MMP as well as lower activities of aconitase and ICDH (two enzymes supporting MMP), and twice the level of filtrable mitochondrial iron (but no increase in total mitochondrial iron), and the observed phenotypes were either fully or partially rescued in FRDA-CH-t cells. Free iron is known to be toxic. The observation that frataxin deficiency (either directly or indirectly) causes an increase in filtrable mitochondrial iron provides a new hypothesis for the mechanism of cell death in this disease, and could be a target for therapy.
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Ferritin H translocation into the nucleus does not require ferroxidase activity.
“ferritin H translocation into the nucleus does not require ferroxidase activity (292).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [292]
Ferritin translocated into the nucleus and bound to DNA without the requirement of a particular DNA-binding sequence.
“ferritin translocated into the nucleus and bound to DNA without the requirement of a particular DNA-binding sequence (292).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [292]
Binding of mutant ferritin H to DNA was lower and less effective for protection of DNA from UV damage.
“the binding of this mutant ferritin H to DNA was lower and less effective for the protection of DNA from UV damage”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [292]
Ferric ammonium citrate, cytokines, and H2O2 exposure resulted in a change in ferritin localization from the cytosol to the nucleus in SW1088 human astrocytoma cells.
“Ferric ammonium citrate, cytokines, and H2O2 exposure resulted in a change in ferritin localization from the cytosol to the nucleus (292).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [292]
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- Authors
- Tan, G.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Tan, G.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-09-01
- Volume
- 10
- Issue
- 19
- Pages
- 2099-2107
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2121157958
- Cited by
- 82
- References
- 33
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2019: 4 · 2018: 5 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 5 · 2013: 3
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30es005707-15)
- U.S. Public Health Service
- National Institute on Aging (AG-11967, AG16719, R01AG016719, R01AG011967)
- National Eye Institute (R01EY012245, EY 12245)
- National Institute of Environmental Health Sciences (P 30 ES05707)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Friedreich's ataxia, frataxin, mitochondrial iron homeostasis, mitochondrial dysfunction, oxidative stress, Fenton reaction, mitochondrial membrane potential, aconitase, isocitrate dehydrogenase, gene rescue, lymphoblasts, cell death mechanisms, therapeutic target
- MeSH terms
- Frataxin, Aconitate Hydratase, Cells, Cultured, Friedreich Ataxia, Humans, Iron, Isocitrate Dehydrogenase, Lymphocytes, Mitochondria, Plasmids, RNA, Messenger, Transfection, Blotting, Western, Gene Expression, Phosphotransferases (Alcohol Group Acceptor), DNA Primers, Oxidative Stress, Reverse Transcriptase Polymerase Chain Reaction, Iron-Binding Proteins
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