A naturally occurring variant of ISCU2 protein can have the same molecular role as frataxin, an experimental study has found. This discovery may pave the way for the development of new strategies to bypass the effects of frataxin deficiency, which is known to cause Friedreich’s ataxia.
The study, “Mechanism of frataxin ‘bypass’ in human iron-sulfur cluster biosynthesis with implications for Friedreich’s ataxia,” was published in the Journal of Biological Chemistry.
Friedreich’s ataxia is caused by a large expansion of a small DNA sequence — the GAA trinucleotide repeat — within the FXN gene, which gives instructions for the production of frataxin protein. The GAA segment is abnormally repeated 66 to more than 1,000 times, which disrupts the gene coding sequence and greatly reduces the levels of functional frataxin in cells.
Although it’s not fully clear how this leads to Friedreich’s ataxia, a shortage in active frataxin seems to impair the activity of proteins that contain iron-sulfur (Fe-S) clusters. Such proteins are particularly important in the energy production process in mitochondria, or the cells’ ‘power plants.’
In humans, the addition of iron-sulfur clusters to proteins depends on the activity of frataxin, which binds to and activates the cell machinery responsible for the production of such clusters.
ISCU2 codes for an iron-sulfur cluster assembly protein and directly takes part in the formation of iron-sulfur clusters. This protein is known to work together with frataxin to stimulate that chemical process.
When normal ISCU2 protein in yeast was replaced by a mutated version carrying the M140I variant (which is naturally found in humans), the Fe-S cluster assembly process occurred much faster, the team found. The variant accelerated the rate of Fe-S load to proteins, adding up to the same effect as produced by frataxin.
This suggested that ISCU2 was speeding up the clusters’ production at a different step of the pathway compared to frataxin. Further analysis revealed that, contrary to frataxin, ISCU2 variant was accelerating not the production of Fe-S clusters but rather their transfer to proteins.
“Together, these results reveal an unexpected mechanism,” the researchers wrote, adding that “the human ISCU2-M140I variant can overcome the loss of FXN function.”
This study provides insights on potential “strategies to overcome the loss of cellular FXN that may be relevant to the development of therapeutics for Friedreich’s ataxia,” they stated.