Enhanced frataxin expression in Arabidopsis thaliana modulates iron metabolism and improves growth under iron stress

A. Terenzi, M.A. Pagani, M.V. Busi, D.F. Gomez-Casati, Enhanced frataxin expression in Arabidopsis thaliana modulates iron metabolism and improves growth under iron stress, Plant Physiology and Biochemistry, Volume 238, 2026, 111687, ISSN 0981-9428, doi: 10.1016/j.plaphy.2026.111687.

Frataxin plays a crucial role in iron homeostasis, Fe-S cluster, and heme biogenesis. This study investigated the impact of constitutive AtFH overexpression in Arabidopsis thaliana. The results demonstrated significant alterations in Fe-S protein activity, iron distribution, and the expression of genes associated with iron transport, Fe-S cluster assembly, and iron storage. Notably, AtFH-overexpressing plants displayed enhanced growth, with increased rosette area and improved root development, under both iron-deficient and iron-excess conditions. While these findings provide valuable insights into the regulatory potential of frataxin in optimizing plant iron homeostasis, they also highlight the need for tissue-specific and stress-inducible approaches to fully evaluate its application in crop resilience.

Serial assessment of echocardiographic measures in Friedreich ataxia

David R. Lynch, Medina Keita, Katherine Gunther, Courtney Park, Kimberly Schadt, Laura Mercer Rosa, Kimberly Y. Lin, Serial assessment of echocardiographic measures in Friedreich ataxia, American Heart Journal Plus: Cardiology Research and Practice, 2026, 100869, ISSN 2666-6022, doi:10.1016/j.ahjo.2026.100869. 

Overall, FRDA hearts initially showed mild hypertrophy with normal systolic function, and a decrease in systolic function up to 30 years later in the disease course. Markers of maximal hypertrophy, in particular septal wall thickness (IVSTd), moderately correlated with genetic severity (GAA1). GAA1 values predicted later stage cardiac disease manifestations in FRDA (presence of arrhythmias, decreases in ejection fraction to less than 50%). Among echocardiographic parameters, early elevations in septal and posterior wall thickness and a hyperdynamic ejection fraction predicted later adverse outcomes including arrhythmias, decreases in ejection fraction, and death.

Hearing Aid Benefit in Auditory Neuropathy Due to Friedreich Ataxia: A Case Report

Melville IZ, Smith AH, Coad GB, Thorne PR, Roxburgh RH, Taylor RL. Hearing Aid Benefit in Auditory Neuropathy Due to Friedreich Ataxia: A Case Report. J Speech Lang Hear Res. 2026 Aug 26:1-11. doi: 10.1044/2026_JSLHR-25-00671. Epub ahead of print. PMID: 42647417. 

Behavioral and electrophysiological testing confirmed ANSD. Aided testing showed improved speech detection and discrimination for low-intensity sounds in quiet, although benefit in noise was limited. The patient experienced reduced fatigue and reported additional unique hearing benefits that extended beyond speech discrimination. 

Hearing aids have the potential to improve hearing, hearing-related quality of life, and fatigue in patients with Friedreich ataxia and auditory neuropathy, with benefits extending beyond speech discrimination. A trial with an amplification device should be considered for all adults with Friedreich ataxia and hearing loss due to ANSD, verified using subjective and behavioral assessments. Use of open-ended, patient-centered validation tools is recommended to capture the full scope of benefit.

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.

Graviton BioScience Announces Clearance of Investigational New Drug (IND) for GV101 for the Treatment of Friedreich's Ataxia

NEW YORK, Aug. 11, 2026 /PRNewswire/ -- Graviton BioScience Corporation, a privately held, clinical-stage biotechnology company developing a diverse pipeline of therapeutics, including selective ROCK2 inhibitors for metabolic, inflammatory, fibrotic, and central nervous system disorders, announced that the U.S. Food and Drug Administration (FDA) has cleared an Investigational New Drug (IND) application for a novel capsule formulation of GV101, a proprietary oral ROCK2 inhibitor being developed for Friedreich's ataxia (FA). This new formulation of GV101 was specifically optimized for development in FA and other potential orphan indications. Preclinical and clinical studies have demonstrated that GV101 increases frataxin protein levels, which is a potentially disease modifying therapeutic approach that addresses the root cause of Friedreich's ataxia (FA). Following the FDA's 30-day review period, Graviton received IND clearance on August 7, 2026, enabling the initiation of a Phase 2 clinical study in individuals living with FA. 

 Graviton now plans to initiate a 12-week, randomized, placebo-controlled, dose-finding Phase 2 trial enrolling up to 48 participants at multiple sites in the United States and internationally. The study is designed to evaluate the efficacy, safety, and tolerability of a range of GV101 capsule doses in individuals living with Friedreich's ataxia. The primary endpoint is an increase from baseline in frataxin levels measured in patients' cells.

Assessing airway clearance dysfunction in Friedreich's ataxia: A focus on peak cough flow

Smith BK, Coker MA, Liberati C, Meyer BP, Norman S, Ehrbar J, Leon-Astudillo C, Subramony S, Corti M. Assessing airway clearance dysfunction in Friedreich's ataxia: A focus on peak cough flow. J Neuromuscul Dis. 2026 Jun 8:22143602261452334. doi: 10.1177/22143602261452334. Epub ahead of print. PMID: 42253100; PMCID: PMC13437907. 

The study demonstrates respiratory dysfunction in patients with FRDA, and shows that disease severity and muscle weakness affect airway clearance. PCF is a more direct and clinically meaningful indicator of cough effectiveness than FVCpp. Comprehensive respiratory evaluations, including muscle-strength testing, can identify individuals who may benefit from targeted interventions to prevent complications.

Impaired Glur2 palmitoylation in cerebellar Purkinje cells of a Friedreich ataxia mouse model

Elizabeth Mercado-Ayón, Jennifer Coulman, Jia-Ying Lee, Eunjoo Lancaster, Elliot Goga, Mohammad Asad, Eric Witze, David R. Lynch, Impaired Glur2 palmitoylation in cerebellar Purkinje cells of a Friedreich ataxia mouse model, Experimental Neurology, 2026, 115955, ISSN 0014-4886, doi:10.1016/j.expneurol.2026.115955.

Mechanistically, reduced GluR2 palmitoylation associates with decreased expression and palmitoylation of the palmitoyl acyltransferase DHHC3, while levels of depalmitoylating enzymes remain unchanged. In vitro, DHHC3 enhances GluR2 palmitoylation, supporting a direct enzymatic relationship. Partial restoration of frataxin expression rescues GluR2 and DHHC3 protein levels and partially restores GluR2 palmitoylation. These findings identify impaired GluR2 palmitoylation as an early, selective synaptic alteration in FRDA and implicate dysregulated lipid-dependent post-translational modification as a mechanism linking frataxin deficiency to cerebellar synaptic vulnerability.

Partial bypass of frataxin deficiency by ISCU M141I restores cytosolic and nuclear Fe–S cluster assembly

Mosbach, V., Maio, N., Hermet, L. et al. Partial bypass of frataxin deficiency by ISCU M141I restores cytosolic and nuclear Fe–S cluster assembly. Cell Death Differ (2026). doi:10.1038/s41418-026-01832-4  

Results reveal a previously unrecognized compartment-specific rescue of Fe-S cluster dependent processes by the ISCU M141I variant in mammalian cells, raising for the first time the possibility of compartmental regulation of Fe-S cluster biogenesis.

Autophagy activation by urolithin-a derivative UA-36 mitigates Friedreich's ataxia pathologies induced by frataxin deficiency

Gong Q, Liu T, Han X, Zhang R, Liu X, Xiong B, Ali T, Huang J, Xie Y, Li S, Yang X. Autophagy activation by urolithin-a derivative UA-36 mitigates Friedreich's ataxia pathologies induced by frataxin deficiency. Mol Biomed. 2026 Jun 4;7(1):82. doi: 10.1186/s43556-026-00457-w. PMID: 42240896; PMCID: PMC13237351. 

 Here, we investigate the therapeutic efficacy and underlying mechanisms of UA-36, a novel water-soluble and bioavailable derivative of urolithin A, in cellular and animal models of FA. In Fxn-knockdown N2a cells, UA-36 significantly restored FXN protein levels, enhanced autophagic flux, improved mitochondrial function, and attenuated oxidative stress–induced damage. In vivo, oral administration of UA-36 for eight weeks in YG8R transgenic mice, a well-established FA model, markedly improved motor coordination, gait performance, and skeletal muscle strength. Histological and ultrastructural analyses revealed substantial protection against cerebellar Purkinje cell loss and iron deposition, cardiac hypertrophy, and the degree of skeletal muscle atrophy and fibrosis. Proteomic analysis of cerebellar tissue demonstrated that UA-36 robustly reprograms the FA-associated molecular landscape by upregulating pathways related to autophagy, mitochondrial biogenesis, oxidative phosphorylation, and redox homeostasis, while suppressing apoptosis and neuroinflammatory signaling. Together, these findings identify UA-36 as a promising lead compound and provide compelling evidence that therapeutic enhancement of autophagy and mitochondrial quality control represents a viable, mechanism-based strategy for the treatment of FA.

Visual Pathways Involvement in Friedreich’s Ataxia Patients Without Macular Impairment

Parisi, V.; Barbano, L.; Di Renzo, A.; Dell’Aquila, C.; D’Andrea, M.; Castelluzzo, A.M.; Colacino, G.; Gioiosa, V.; Coppola, G.; Casali, C.; et al. Visual Pathways Involvement in Friedreich’s Ataxia Patients Without Macular Impairment. J. Clin. Med. 2026, 15, 6097. doi:10.3390/jcm15156097 

 Fourteen FA patients (14 eyes; mean age 38.64 ± 8.21 years) without functional or structural macular abnormalities, confirmed by multifocal electroretinogram (mfERG) and spectral domain–optical coherence tomography (SD-OCT), and 20 age-matched healthy controls were enrolled. Patients were classified as late-onset (FA1, disease onset > 25 years) or early-onset (FA2, disease onset < 25 years). All participants underwent comprehensive ophthalmological and neurological evaluations. RGC function and visual pathway conduction were assessed through simultaneous pattern electroretinogram (PERG) and VEP recordings using 60′ and 15′ checkerboard stimuli. Retino-cortical time (RCT) was calculated as the difference between VEP P100 and PERG P50 implicit times. Statistical analyses included a general linear model. Results: 60′ PERG amplitude (A) was significantly (p < 0.01) reduced in the FA group compared to the Control group. FA patients showed significantly delayed 60′ and 15′ VEP ITs and significantly increased 60′ and 15′ RCT values, particularly in the FA1 group. In late-onset patients, no significant relationships were found between age at onset of disease and all electrophysiological parameters (60′ and 15′ VEP and PERG ITs and As and RCTs). Conclusions: In our selected FA, RCG function and neural conduction along the post-retinal visual pathways are impaired. The abnormal neuronal conduction is greater in late-onset FA patients and is not related to patients’ age and the age at the onset of the disease. The duration of the disease has a slight effect on the post-retinal neural conduction on small optic nerve fibers.

BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin

Brandon, C.J., Robinson-Thiewes, S., Kaulage, M. et al. BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin. Nat Cell Biol (2026). doi:10.1038/s41556-026-02044-1 

 How genes are desilenced without erasure of repressive chromatin is a poorly understood phenomenon. A dominant mode of repression occurs through methylation of lysine 9 of histone H3 (H3K9me3), a mark that engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure and replacement of this repressive mark with acetyl/acyl groups recruits positive factors such as BRD4/BET to elicit gene transcription. Here we report that, in Friedreich’s ataxia, a synthetic gene regulator (SynGR1/SynTEF1) licenses transcription across repressive chromatin without removal or replacement of H3K9me3 or HP1. By recruiting BRD4/BET into repressive GAA repeats in frataxin (FXN), SynGR1 creates a paradoxical state wherein gene transcription and repressive chromatin coexist. Contrary to convention, we find that BRD4 partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus offering a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. More broadly, our study highlights the dynamic nature of repressive chromatin and the context dependence of epigenetic marks in regulating gene expression

Larimar Therapeutics Reports Second Quarter 2026 Financial and Business Update

BALA CYNWYD, Pa., Aug. 04, 2026 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar). “Open label (OL) study data announced in June further reinforce the disease-modifying potential of nomlabofusp, demonstrating continued directional improvements in key clinical endpoints over time alongside a well-characterized safety profile. Following receipt of minutes from a successful Type B multidisciplinary pre-BLA meeting with the Food and Drug Administration (FDA), the first module of our rolling Biologics License Application (BLA) has been submitted, with completion expected in the second half of 2026. We continue to see strong enthusiasm from patients and investigators as we advance the OL study with additional participants dosed in July and several adults and adolescents in screening. We are also on track to initiate dosing in our global confirmatory study this quarter. Looking ahead, we are focused on execution as we work to bring forward nomlabofusp as the first potential therapy to address the underlying cause of disease for pediatric and adult patients living with Friedreich’s ataxia (FA).”

Stem Cell Transplantation in Friedreich Ataxia: Cure for Leukemia but No Effect on Neurological Progression

A. Gitman, N. Bhandari, M. Castellaro, K. Schadt, M. Cancio, and D. R. Lynch, “ Stem Cell Transplantation in Friedreich Ataxia: Cure for Leukemia but No Effect on Neurological Progression,” Annals of Clinical and Translational Neurology (2026): 1–3, doi:10.1002/acn3.70455. 

After the transplant, her neurologic disease progressed similarly to other patients, but her blood frataxin levels returned to normal and cardiac hypertrophy decreased. This shows that FRDA patients can be treated with bone marrow transplantation, but such treatment alone has no direct effect on progression of neurologic disease.

Adjuvia Therapeutics Closes $8 Million Series Seed Financing to Advance Novel Mitochondrial Disease Therapy into the Clinic

Jul 29, 2026. SAN FRANCISCO--(BUSINESS WIRE)--Adjuvia Therapeutics, a biotechnology company developing therapeutics to treat mitochondrial dysfunction and disease, today announced the closing of an $8 million Series Seed financing. The financing will support the submission of an Investigational New Drug (IND) application for Adjuvia's lead candidate, ATI-105, later this summer, followed by the initiation of the Phase 1 clinical trial in healthy volunteers in Fall 2026. Adjuvia also plans to begin a Phase 1/2 study in patients with Friedreich's ataxia in early 2027.

Goldenrod Therapeuticsare committed to developing a next-generation phosphodiesterase 4 (PDE4) inhibitor designed to address serious neurological conditions, including Friedreich’s ataxia

Goldenrod Therapeutics is a portfolio company of Fannin based in Houston, Texas. We are committed to developing a next-generation phosphodiesterase 4 (PDE4) inhibitor designed to address serious neurological conditions, including Friedreich’s ataxia, other neurodegenerative diseases, substance use disorders (SUDs), and pain. 

Neurophysiological assessment of disease severity in Friedreich’s Ataxia: a study of brainstem auditory and visual evoked potentials

Maccora S, Quartetti U, Lima SM, Rini N, Cucchiara M, Agnello L, Gambino CM, Brighina F, Ciaccio M, Di Stefano V. Neurophysiological assessment of disease severity in Friedreich's Ataxia: a study of brainstem auditory and visual evoked potentials. Clin Neurophysiol. 2026 Aug;188:2111933. doi: 10.1016/j.clinph.2026.2111933. Epub 2026 May 14. PMID: 42143837. 

 BAEPs and p-VEPs are highly prevalent and closely associated with clinical severity in chronic FRDA, outperforming tested serum biomarkers. Evoked potentials provide accessible, non-invasive, quantitative candidate biomarkers for severity assessment and longitudinal monitoring in FRDA, supporting their use in clinical practice and trial design when fluid markers are inconclusive.