Frataxin

Frataxin is a protein that in humans is encoded by the FXN gene. Frataxin plays a crucial role in cellular energy metabolism, particularly in the mitochondria, where it is involved in the assembly of iron-sulfur clusters. These clusters are essential for the function of various mitochondrial enzymes involved in energy production. Deficiency or reduced levels of frataxin are associated with the development of Friedreich's ataxia, a hereditary neurodegenerative disease.

Function

Frataxin is primarily located in the mitochondria and is involved in the biosynthesis of iron-sulfur (Fe-S) clusters. These clusters are critical components of several key enzymes in the mitochondrial electron transport chain, which is responsible for ATP production through oxidative phosphorylation. Additionally, iron-sulfur clusters are necessary for the function of aconitase and various other enzymes involved in the TCA cycle and DNA repair processes. By facilitating the assembly of these clusters, frataxin plays a vital role in cellular energy metabolism and the maintenance of iron homeostasis within the mitochondria.

Genetic and Molecular Basis

The FXN gene, located on chromosome 9q21.11, encodes the frataxin protein. Mutations in the FXN gene, particularly GAA triplet repeat expansions within the first intron, lead to decreased expression of frataxin. This reduction in frataxin levels is the primary cause of Friedreich's ataxia, a condition characterized by progressive damage to the nervous system and impaired muscle coordination. The exact mechanism by which frataxin deficiency leads to neurodegeneration is not fully understood, but it is believed to involve mitochondrial dysfunction and oxidative stress due to impaired iron-sulfur cluster assembly.

Clinical Significance

1. 1. 1. Friedreich's Ataxia ###

Friedreich's ataxia is the most common inherited ataxia, with symptoms typically beginning in childhood or adolescence. Clinical manifestations include progressive gait and limb ataxia, dysarthria, loss of deep tendon reflexes, and a reduction in proprioception and vibratory sensation. Cardiomyopathy and diabetes mellitus are also common. The disease progresses gradually, leading to significant disability.

1. 1. 1. Therapeutic Approaches ###

Current research efforts are focused on developing therapies that can increase frataxin levels or ameliorate the consequences of its deficiency. Strategies include gene therapy to deliver functional copies of the FXN gene, small molecules that can increase frataxin expression, and antioxidants to reduce oxidative stress in affected cells. While there is no cure for Friedreich's ataxia, these therapeutic approaches hold promise for slowing disease progression and improving quality of life for affected individuals.

See Also

• Mitochondrial disease
• Neurodegeneration
• Genetic disorder
• Iron metabolism

References

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