Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia

Pilotto F, Dall'Agnol L, Reutenauer L, Paschaki M, Puccio H. Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia. Hum Gene Ther. 2026 Aug 9:10430342261474315. doi: 10.1177/10430342261474315. Epub ahead of print. PMID: 42572232. 

Although gene therapy strategies aimed at restoring FXN have shown promise, excessive expression can lead to mitochondrial dysfunction, emphasizing the importance of maintaining FXN within a physiological range. Here, we evaluated a gene therapy approach based on a human mini-frataxin construct (miniFXN7) incorporating an endogenous regulatory element to enable controlled FXN expression. The construct was delivered systemically using an AAV-PHP.eB vector in the Pvalb-cKO mouse model of FA. MiniFXN7 treatment resulted in widespread neuronal transduction and restoration of FXN expression toward a near-physiological range in the neuronal populations examined. Treated mice exhibited sustained improvements in motor coordination and proprioceptive function, including normalization of H-reflex responses. At the cellular level, miniFXN7 restored succinate dehydrogenase activity, a mitochondrial Fe-S enzyme, and was associated with partial normalization of mitochondrial morphology. In parallel, neuronal integrity was preserved and astrogliosis reduced across the cerebellum. These findings demonstrate that physiologically regulated FXN replacement is sufficient to achieve substantial functional rescue in FA, supporting a gene therapy strategy based on a transgene expression driven by endogenous regulatory elements.

Directional information flow in human frataxin defines allosteric pathways connecting the hydrophobic core to the iron-binding ridge

Kırboğa KK, Küçüksille EU. Directional information flow in human frataxin defines allosteric pathways connecting the hydrophobic core to the iron-binding ridge. FEBS J. 2026 Aug 13. doi: 10.1111/febs.70687. Epub ahead of print. PMID: 42593048. 

We identify LEU47 (LEU136 in UniProt Q16595 numbering) and LEU51 (LEU140) as primary signal sources with net transfer entropy values of 0.415 and 0.249, respectively, connecting the hydrophobic core to the iron-binding acidic ridge. NMR relaxation at 600 and 800 MHz reveals elevated R2/R1 ratios (9.90-10.00) and significant exchange contributions (Rex = 3-5 s-1) specifically at these primary signal source residues, indicating μs-ms dynamics. Hydrogen-deuterium exchange mass spectrometry demonstrates that hub residues possess intermediate protection factors (ln(PF) = 5.97-6.07) optimal for conformational signaling, while iron binding induces bidirectional protection changes propagating through the identified pathway. Systematic mutagenesis confirms that disruption of hub residues reduces iron-binding affinity 1.9-4.2-fold and decreases thermal stability by 4.3-11.2 °C, despite occupying buried-core positions distant from the iron-coordinating acidic-ridge residues (LEU136/LEU140 Cα to ASP122, ASP124, and GLU189 = 6.7 to 11.8 Å in PDB 1EKG). The strong prediction-experiment correlation establishes transfer entropy as a reliable predictor of functionally important allosteric residues and provides a methodological framework applicable to other proteins of biomedical significance.

Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease

Cho, H., Sayana, R., Koladiya, A. et al. Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease. Nat Commun (2026). doi:10.1038/s41467-026-76775-y 

 Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.

Allosteric rewiring of mitochondrial stress signaling through Miro1

Drwesh L, Fitzgerald J; Allosteric rewiring of mitochondrial stress signaling through Miro1: Cell Chemical Biology, 33, 1071-1073. doi:10.1016/j.chembiol.2026.07.011 

 Mitochondrial dysfunction is a common feature of both inherited mitochondrial disorders and neurodegenerative diseases. Although these disorders differ clinically, many converge on shared underlying pathobiology, including oxidative damage, impaired mitochondrial homeostasis, and defective mitochondrial quality control. Chandra and colleagues investigate these shared stress pathways in the context of Friedreich’s ataxia.

Unlocking Sulforaphane’s Potential in Friedreich Ataxia: Further Evidence from Preclinical Investigations Using Induced Pluripotent Stem Cell-Derived Sensory Neurons

Yang W, Thompson B, Miellet S, et al. Unlocking Sulforaphane’s Potential in Friedreich Ataxia: Further Evidence from Preclinical Investigations Using Induced Pluripotent Stem Cell-Derived Sensory Neurons. Antioxidants & Redox Signaling. 2026;0(0). doi:10.1177/15230864261470377 

 In FA1, SF treatment improved cell viability and reduced oxidative stress and inflammation. In FA3, SF increased cell viability, FXN protein levels, and gene and protein expression of redox markers, while targeting dysregulated epigenetic mechanisms and inflammation. All three lines showed SF’s consistent anti-oxidant and anti-inflammatory effects. Responses to Omav and DMF varied across the FA lines with less pronounced effects than when treated with SF. Overall, SF was more effective than Omav and DMF in improving cell viability and regulating FXN expression and epigenetic, redox, and inflammatory pathways.