Scientists discovered that reducing a gene called FDX2 can help cells survive the damage caused by Friedreich’s ataxia. This finding opens the door to a fresh and potentially powerful treatment strategy.
Friedreich’s ataxia (FA) is an uncommon but deeply life-altering inherited condition. Most people with FA begin showing symptoms between ages 5 and 15 and often live only into early or mid-adulthood. There is no widely accepted therapy that slows or reverses the disease, and current treatments do not work well for everyone.
Researchers at Mass General Brigham and the Broad Institute are working to change this. They have identified a genetic factor that influences the severity of FA, a discovery that highlights a promising direction for future therapies. Their results were published today (December 10) in Nature.
Studying FA Through Simple Model Organisms
To better understand how FA develops, scientists are turning to small but scientifically powerful organisms. FA arises when the body loses frataxin, a critical mitochondrial protein involved in forming iron sulfur clusters, which are key components that help cells generate energy. An earlier study from the Mootha lab found that exposing human cells, worms, and mice to low oxygen (hypoxia) can partially counteract the impact of frataxin loss.
“In this paper, instead of trying to pursue hypoxia to slow or postpone the disease as a therapy, we simply used it as a trick. We used it as a laboratory tool with which to discover genetic suppressors,” said lead and co-corresponding author Joshua Meisel, a former postdoctoral fellow at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system. Meisel is now an assistant professor at Brandeis University. “The reason this is exciting is because the suppressor that we’ve identified, FDX2, is now a protein that can be targeted using more conventional medicines.”
Worm Experiments Reveal Surprising Genetic Clues
To explore how cells might cope without frataxin, the team, which included Nobel laureate Gary Ruvkun, PhD, turned to the roundworm C. elegans. They created worms completely lacking frataxin and kept them alive in low-oxygen environments. This setup allowed the researchers to search for rare genetic changes that might help the worms survive even when oxygen levels increased (a typically fatal situation for worms missing frataxin).
After sequencing the genomes of the surviving worms, the team uncovered mutations in two mitochondrial genes known as FDX2 and NFS1. They then confirmed the importance of these mutations using advanced genetic tools, laboratory biochemistry, and additional experiments in human cells and mice to test whether the same strategy might work in more complex organisms.
How FDX2 and NFS1 Help Cells Compensate
The research showed that particular mutations in FDX2 and NFS1 can help cells work around the absence of frataxin. With these mutations, cells were better able to create iron-sulfur clusters, which are essential for energy production and normal cell activity. The team found that excessive FDX2 disrupts this process, but reducing FDX2 — either by altering the gene or removing one of the two gene copies — restores cluster formation and improves cell function.
“The balance between frataxin and FDX2 is key,” said senior and co-corresponding author Vamsi Mootha, MD, of the Department of Molecular Biology and Center for Genome Medicine at MGH. Mootha is also an institute member and co-director of the Metabolism Program at Broad. “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.”
Therapeutic Potential and Future Directions
Lowering FDX2 levels in a mouse model of FA led to meaningful improvements in neurological symptoms, offering early evidence that this approach could form the basis of a new treatment. Overall, the study suggests that adjusting the levels of proteins that interact genetically with frataxin may help offset the damage caused by frataxin loss.
Although these results are encouraging, the researchers emphasize that the ideal balance between frataxin and FDX2 is likely different from one situation to another. More work is needed to understand how this balance is controlled in humans. Additional pre-clinical research will also be essential to determine whether reducing FDX2 is safe and effective as a potential therapy for FA before moving toward any future human trials.
Reference: “Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency” by Joshua D. Meisel, Pallavi R. Joshi, Amy N. Spelbring, Hong Wang, Sandra M. Wellner, Presli P. Wiesenthal, Maria Miranda, Jason G. McCoy, David P. Barondeau, Gary Ruvkun and Vamsi K. Mootha, 10 December 2025, Nature.
DOI: 10.1038/s41586-025-09821-2
In addition to Meisel, Mootha and Ruvkun, authors include Pallavi R. Joshi, Amy N. Spelbring, Hong Wang, Sandra M. Wellner, Presli P. Wiesenthal, Maria Miranda, Jason G. McCoy, and David P. Barondeau.
Mootha is listed as an inventor on patents filed by MGH on therapeutic uses of hypoxia. Meisel, Ruvkun, and Mootha are listed as inventors on a patent filed by MGH on technology reported in this paper; Meisel, Ruvkun, and Mootha own equity in and are paid advisors to Falcon Bio, a company focusing on this technology. Mootha is a paid advisor to 5am Ventures.
This work was supported in part by the Friedreich’s Ataxia Research Alliance, the National Institutes of Health (R00GM140217, R01NS124679, R01AG016636, and R01GM096100), and the Robert A. Welch Foundation (A-1647). Meisel was supported by The Jane Coffin Childs Memorial Fund for Medical Research. Miranda was supported by the Deutsche Forschungsgemeinschaft (431313887). Mootha is an Investigator of the Howard Hughes Medical Institute.
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