Frataxin Human
Description
Functional Roles of Frataxin
Frataxin is essential for mitochondrial iron metabolism and Fe-S cluster assembly, critical for respiratory complexes (I, II, III) and enzymes like aconitase. Key functions include:
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Fe-S cluster biogenesis: Acts as a sulfide donor or accelerates sulfur transfer from cysteine residues .
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Iron storage: Binds iron in a non-toxic form, preventing oxidative damage .
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Interaction with respiratory complexes: Co-localizes with complexes I, II, and III near mitochondrial cristae, influencing their Fe-S content .
Table 2: Frataxin’s Interaction with Mitochondrial Complexes
Clinical Relevance: Friedreich’s Ataxia
FRDA arises from FXN gene mutations, primarily GAA triplet repeat expansions in intron 1, leading to transcriptional silencing and frataxin deficiency:
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Genetic Mechanism:
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Pathophysiology:
Table 3: GAA Repeat Effects on Frataxin and Disease
| Repeat Length | Frataxin Level | Age of Onset | Disease Severity |
|---|---|---|---|
| 6–36 | Normal | N/A | N/A |
| 70–1200 | <30% | Adolescence | Moderate to severe |
| >1200 | <10% | Early childhood | Severe |
Isoforms and Extra-Mitochondrial Roles
Recent studies identify novel frataxin isoforms with distinct functions:
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hFXN-E: Found in erythrocytes, lacks an MTS, and may contribute to cytosolic iron regulation. Its role in FRDA pathogenesis remains unclear .
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Tissue-specific splicing: Exon 1B-containing isoforms (e.g., FXN II) are enriched in cerebellum and heart, suggesting specialized roles in high-energy-demand tissues .
Diagnostic Tools
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HTRF-based immunoassays: Detect frataxin levels in cell lysates using Europium Cryptate and d2-labeled antibodies .
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Mass spectrometry: Quantifies mature hFXN (81–210) and hFXN-E (76–210) in blood samples .
Therapeutic Strategies
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Gene therapy: AAV-mediated FXN gene delivery to restore frataxin expression .
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Iron chelators: Reduce mitochondrial iron overload, though efficacy remains debated .
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Nqo15 protein: A bacterial frataxin-like protein shown to rescue respiratory complex I defects in FRDA models .
Research Gaps and Future Directions
Product Specs
The Frataxin solution is supplied at a concentration of 1mg/ml and contains 20mM Tris-HCl buffer (pH 8.5), 1mM DTT, 0.1M NaCl, and 20% glycerol.
Adding a carrier protein like 0.1% HSA or BSA is recommended for long-term storage.
Repeated freezing and thawing should be avoided.
Product Science Overview
Frataxin, also known as FXN, is a mitochondrial protein that plays a crucial role in iron metabolism. It is encoded by the FXN gene and is involved in the biosynthesis of iron-sulfur (Fe-S) clusters and heme, which are essential for various cellular processes . Deficiency in frataxin leads to Friedreich’s ataxia (FRDA), a progressive neurodegenerative disorder characterized by gait and limb ataxia, cardiomyopathy, and diabetes .
Frataxin is synthesized as a precursor polypeptide consisting of 210 amino acids. It is directed to the mitochondrial matrix, where it undergoes proteolytic cleavage to form the mature protein . The mature form of frataxin is involved in iron storage and acts as an iron chaperone, preventing mitochondrial damage and reactive oxygen species production . It is essential for the formation of Fe-S clusters, which are critical for mitochondrial function and cellular viability .
Friedreich’s ataxia is caused by mutations in the FXN gene, leading to a significant reduction in frataxin levels. The most common mutation is a GAA trinucleotide repeat expansion within the first intron of the FXN gene . This mutation interferes with transcriptional elongation and leads to heterochromatin formation, resulting in decreased frataxin expression . The deficiency in frataxin disrupts iron metabolism, leading to iron accumulation in mitochondria, impaired Fe-S cluster biosynthesis, and increased oxidative stress .
Recombinant human frataxin is produced using genetic engineering techniques to express the human FXN gene in various host systems, such as bacteria or yeast . This recombinant protein is used in research to study the biochemical function of frataxin and to develop potential therapeutic approaches for FRDA . The availability of recombinant human frataxin has facilitated the investigation of its role in iron metabolism and its potential as a therapeutic target .
