Scientists have identified a genetic modifier that helps cells cope with the loss of frataxin, the protein at the core of Friedreich’s ataxia. By lowering activity of the FDX2 gene, experiments in worms, human cells, and mice showed that key energy‑producing processes can be restored, pointing to a potential new treatment strategy.
Friedreich’s ataxia (FA) is a serious inherited neurodegenerative disorder that usually appears in childhood or early adolescence, often between ages 5 and 15. Many affected individuals live only into their 30s or 40s. There is currently no broadly approved therapy that reliably slows or alters the course of the disease, and existing treatments do not work for everyone.
Researchers from Mass General Brigham and the Broad Institute have now uncovered a genetic approach that may help address this unmet need. In a study published in Nature in December 2025, the team reports that specific mutations affecting the mitochondrial ferredoxin gene FDX2 and the cysteine desulfurase gene NFS1 allow cells to function despite the loss of frataxin, a mitochondrial protein required for the production of iron–sulfur clusters. These clusters are essential cofactors for many metabolic enzymes and are critical for cellular energy production.
To find these genetic modifiers, the investigators used Caenorhabditis elegans worms engineered to lack frataxin. Building on earlier work from the Mootha laboratory showing that low‑oxygen (hypoxic) conditions can partially rescue frataxin deficiency, they maintained these worms at permissive low oxygen levels so they could survive. The team then performed a genome‑scale forward genetic screen: mutagenized worms were shifted to higher, non‑permissive oxygen levels, and rare survivors were isolated and analyzed by whole‑genome sequencing. This approach pinpointed dominant missense mutations in FDX2/fdx‑2 and NFS1/nfs‑1 as suppressors that bypass the need for frataxin by boosting iron–sulfur cluster production.
Follow‑up experiments in mammalian systems supported these findings. In human cell models, the researchers showed that excess FDX2 interferes with frataxin‑stimulated NFS1 activity and blocks iron–sulfur cluster formation, whereas reducing FDX2—either through specific point mutations or by removing one copy of the normal gene—restores cluster synthesis and improves cell health. In a mouse model of Friedreich’s ataxia, lowering levels of wild‑type FDX2 under normal oxygen conditions ameliorated the animals’ ataxia‑like neurological phenotype, suggesting that carefully dialing down FDX2 activity can compensate for reduced frataxin.
“The balance between frataxin and FDX2 is key,” said senior and co‑corresponding author Vamsi Mootha, MD, of Massachusetts General Hospital and the Broad Institute, in a statement released by Mass General Brigham. “When you are born with too little frataxin, bringing down FDX2 a bit helps. So, it’s a delicate balancing act to ensure proper biochemical homeostasis.”
Lead and co‑corresponding author Joshua Meisel, PhD, who conducted the work as a postdoctoral fellow at Massachusetts General Hospital and is listed as first author on the Nature paper, underscored the therapeutic potential of the target. In the Mass General Brigham release, Meisel noted that lowering FDX2 levels through partial knockdown could form the basis of a more targeted treatment strategy for Friedreich’s ataxia, because the modifier acts on a pathway directly tied to the disease mechanism.
The authors caution, however, that the optimal balance between frataxin and FDX2 likely varies by tissue and physiological context. Further preclinical work will be needed to understand how this balance is controlled in people and to determine whether modulating FDX2 is safe and effective enough to justify human trials.
According to Mass General Brigham, the study was supported by the Friedreich’s Ataxia Research Alliance, the U.S. National Institutes of Health, the Robert A. Welch Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, and the Deutsche Forschungsgemeinschaft, among others. Several authors, including Meisel and Mootha, are listed as inventors on patents related to the technology and hold equity in Falcon Bio, a company developing this approach.
