Histone H3 Enzyme Activity as a Regulator of Iron-Sulfur Cluster Stability in Friedreich’s Ataxia

In FA, the shortage of frataxin makes it difficult for cells to produce enough Iron-Sulfur Clusters (ISCs), which are specialized factors cells need to function properly and to generate energy. This research introduces a new idea for treating FA: instead of focusing on making more ISCs, Dr. Kurdistani and his team propose slowing down ISCs degradation. They have discovered that histone H3, a protein usually involved in organizing DNA, also acts as an enzyme that produces reduced copper (Cu1+). They hypothesize that Cu1+ is a key driver of ISC degradation in FA. Reduced copper or Cu1+ in cells is thought to affect the assembly and stability of ISCs, and because ISC production is already compromised in FA, even normal levels of Cu1+ could be harmful. Preliminary findings show that reducing the enzyme activity of histone H3 (therefore producing less Cu1+) can rescue cellular defects associated with frataxin deficiency in a yeast model of FA. By lowering Cu1+ levels, the existing ISCs last longer and can function more effectively, even if their overall production remains low in FA cells. This research offers a novel perspective into the pathology of FA, potentially leading to new therapeutic approaches aimed at protecting, rather than replacing, the essential ISCs.