A Breakthrough in Understanding Friedreich Ataxia: Overexpression of a Mitochondrial Factor Offers Hope.
- Ray Sullivan
- Jul 24
- 3 min read
Friedreich ataxia is a devastating inherited neurodegenerative disease affecting approximately 1 in 50,000 worldwide. The disease not only affects the nervous system but also causes severe heart problems, significantly impacting patients' quality of life and longevity. The root cause of Friedreich ataxia lies in a deficiency of frataxin, a highly conserved protein primarily located in the mitochondrial matrix. In the yeast Saccharomyces cerevisiae, the human frataxin homolog is called Yfh1.
Frataxin is a vital component of the iron–sulfur (Fe-S) cluster assembly complex in mitochondria. Fe-S clusters are essential inorganic cofactors that play critical roles in numerous cellular processes, including cellular respiration, protein translation, iron sensing, and DNA synthesis and repair. Frataxin's function is to facilitate the transfer of sulfur during the early stages of Fe-S cluster assembly, optimally positioning key residues for rapid sulfur transfer.
When frataxin (or Yfh1 in yeast) is depleted, the consequences are severe: Fe-S clusters are significantly and globally depleted across mitochondrial, cytoplasmic, and nuclear locations. This leads to a cascade of cellular problems, including impaired respiration, deficient metabolic pathways (like the TCA cycle), altered DNA synthesis and repair, and even iron accumulation in mitochondria.
Given frataxin's central role, scientists are interested in "frataxin bypass scenarios"—situations where the effects of frataxin deficiency can be mitigated. Such bypass mechanisms could pave the way for new treatment strategies for Friedreich ataxia. Debkumar Pain’s lab at Rutgers New Jersey Medical School reports a significant frataxin/Yfh1 bypass achieved through the overexpression of Rsm22, a protein that functions as an assembly factor for the mitochondrial ribosome. Rsm22 is homologous to the human protein METTL17.
Pain’s lab found that overexpressing Rsm22 in Yfh1-depleted yeast cells led to a remarkable reversal of many of the deleterious effects. The suppression was "quite global":
Yfh1-depleted yeast, which normally struggles to grow on non-fermentable carbon sources, showed significantly improved growth when Rsm22 was overexpressed, almost reaching wild-type levels.
Crucial mitochondrial processes were restored, including the formation and activity of [4Fe-4S] clusters for aconitase, a key TCA cycle enzyme. The biosynthesis of mitochondrial [2Fe-2S] cluster proteins, such as ferredoxin (Yah1), was also rescued.
Proteins containing lipoic acid, which are dependent on Fe-S cluster formation for their stability, were restored. This, in turn, appeared to restore heme synthesis and increase levels of cytochrome c, a non-Fe-S heme protein crucial for electron transport.
The characteristic mitochondrial iron accumulation seen in frataxin deficiency was reversed, returning iron levels to normal.
The impaired mitochondrial membrane potential in Yfh1-depleted cells was completely recovered with Rsm22 overexpression, indicating restored respiratory complex function.
Importantly, the suppression extended beyond the mitochondria. The ability of mitochondria to promote cytoplasmic Fe-S cluster assembly, crucial for proteins like Leu1 (involved in leucine biosynthesis), was almost completely restored. This finding is particularly notable as it differs from previous studies in human cells, which observed a dissociation of mitochondrial and cytoplasmic Fe-S cluster restoration.
The lab’s study explored how Rsm22 overexpression achieves such widespread rescue. A key insight came from observing the levels of ferredoxin (Yah1), an essential component of the mitochondrial ISC machinery. Yah1 protein levels were significantly reduced in Yfh1-depleted mitochondria but were restored by Rsm22 overexpression.
Strikingly, direct overexpression of Yah1 in Yfh1-depleted cells mimicked many of the salutary effects of Rsm22 overexpression, including the restoration of aconitase protein and activity, and significantly promoting cytoplasmic Fe-S cluster assembly. This suggests a hypothesis: Rsm22 overexpression might enhance the stability and/or activity of Yah1, which then allows for Fe-S cluster biosynthesis to proceed even in the absence of frataxin/Yfh1. Yah1 is known to compete with Yfh1 for binding sites on the Nfs1 core complex, potentially compensating for frataxin's absence.
These findings provide new insights into alternative pathways for Fe-S cluster assembly when frataxin is deficient. While further molecular investigations are needed to fully establish this hypothetical mechanism, the discovery of Rsm22's ability to globally bypass Yfh1 depletion phenotypes in yeast offers significant insight. Exploring whether similar compensatory mechanisms exist and can be leveraged in human cells for proteins like FDX2 (the human homolog of Yah1) could open up potentially new therapeutic targets for Friedreich’s ataxia.
Pandey AK, Singh P, Pain J, Dancis A, Pain D. Salutary Effects of Overexpression of Rsm22, an Assembly Factor for the Mitochondrial Ribosome, on Frataxin/Yfh1 Depletion Phenotypes in Saccharomyces cerevisiae. Biomolecules. 2025 May 28;15(6):785. doi: 10.3390/biom15060785. PMID: 40563426; PMCID: PMC12191369.
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