Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease

Hisey JA, Masnovo C, Mirkin SM. Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease. NAR Mol Med. 2024 Dec 5;1(4):ugae024. doi: 10.1093/narmme/ugae024. PMID: 39723156; PMCID: PMC11667243. 

H-DNA-forming repeats have been implicated in four REDs: Friedreich's ataxia, GAA-FGF14-related ataxia, X-linked Dystonia Parkinsonism, and cerebellar ataxia, neuropathy and vestibular areflexia syndrome. In this review, we summarize H-DNA's discovery and characterization, evidence for its existence and function in vivo, and the field's current knowledge on its role in physiology and pathology.

Harshly Oxidized Activated Charcoal Enhances Protein Persulfidation with Implications for Neurodegeneration as Exemplified by Friedreich's Ataxia

Vo ATT, Khan U, Liopo AV, Mouli K, Olson KR, McHugh EA, Tour JM, Pooparayil Manoj M, Derry PJ, Kent TA. Harshly Oxidized Activated Charcoal Enhances Protein Persulfidation with Implications for Neurodegeneration as Exemplified by Friedreich's Ataxia. Nanomaterials (Basel). 2024 Dec 13;14(24):2007. doi: 10.3390/nano14242007. PMID: 39728543. 

We demonstrate that pleozymes increased overall protein persulfidation in cells from apparently healthy individuals and from individuals with the mitochondrial protein mutation responsible for Friedreich's ataxia. We further find that pleozymes specifically enhanced Keap1 persulfidation, with subsequent increased accumulation of Nrf2 and Nrf2's antioxidant targets.

Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review

Umrao, A., Pahuja, M. & Chatterjee, N.S. Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review. Orphanet J Rare Dis 19, 495 (2024). doi:10.1186/s13023-024-03474-6 

The results of the Omav treatment indicated a persistent benefit to FA patients who received Omav for an extended period. The greater effect on longer GAA lengths than shorter repeats and the lower degree of improvement in pes cavus patients suggest that Omav aims for the most severe or progressive abnormalities in FA patients in a time-dependent manner.

Therefore, based on the available literature and the quality of the studies, further randomized controlled trials may include patients with progressive disease with the consideration of pes cavus, foot deformity. Considering the progressive nature of the disease, long-term follow-up beyond three years to constantly evaluate the effect of Omav on FA patients shall be considered.

Health-Related Quality of Life in Patients with Friedreich Ataxia Using Mobility Assistive Technologies: Limited Fit of the EQ-5D-3L Mobility Dimension

Health-Related Quality of Life in Patients with Friedreich Ataxia Using Mobility Assistive Technologies: Limited Fit of the EQ-5D-3L Mobility Dimension. Maresa Buchholz, Michelle Pfaff, Audrey Iskandar, Kathrin Reetz, Jörg B. Schulz, Marcus Grobe-Einsler, Thomas Klockgether, Bernhard Michalowsky, EFACTS Study Group, Neurology and Therapy, Print ISSN: 2193-8253, Elektronische ISSN: 2193-6536, DOI: 10.1007/s40120-024-00694-7 

There are concerns about using HRQoL measures, such as the EQ-5D, in mobility-impaired individuals who had difficulties finding appropriate response options for mobility-related items. Our findings demonstrated limitations of the EQ-5D-3L mobility item in patients with FA using MAT, detecting a noticeable amount of non-responses in the mobility item in wheelchair users and a tendency to the mid-response level “some problems” in individuals using walking aids.

Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies

Thomas Lilley, Donny M. Camera, Faith A.A. Kwa, Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies, Drug Discovery Today, n2024, 104283, ISSN 1359-6446, doi:10.1016/j.drudis.2024.104283. 

Nrf2 upregulates mitochondrial gene expression pathways associated with improved mitochondrial substrate metabolism [peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) and frataxin (FXN)], mitochondrial biogenesis, and mitochondrial adenosine triphosphate (ATP) production via oxidative phosphorylation (OXPHOS).

Sulforaphane-induced Nrf2 expression has been linked to several reparative pathways key to the pathogenesis of mitochondrial dysfunction and pertinent to mitochondrial myopathies such as sarcopenia, proximal myopathy, CPEO, and Friedreich ataxia, including antioxidant system upregulation, inflammatory downregulation, upregulated expression of mitochondrial-related genes such as FXN, and increased muscle mass and function.

Plasma miRNAs Correlate with Structural Brain and Cardiac Damage in Friedreich’s Ataxia

Peluzzo, T.M., Vieira, A.S., Matos, A.H.B. et al. Plasma miRNAs Correlate with Structural Brain and Cardiac Damage in Friedreich’s Ataxia. Cerebellum 24, 15 (2025). https://doi.org/10.1007/s12311-024-01766-y 

Our results showed that miR-26a-5p is upregulated and miR-15a-5p is downregulated. The first was correlated with age at onset, cerebellum volume, spinal cord cross-sectional area (C2-CSA) and the left ventricle mass (LV_Mass). For the miR-15a-5p, significant correlations were found with cerebellum volume, spinal cord eccentricity and LV_Mass. It has been previously hypothesized that these miRs target BDNF, modulating its expression and, when this gene is downregulated, it leads to neuronal loss, explaining the ataxic phenotype and our results reinforce this hypothesis. The miR-26a-5p was already associated with cardiomyocyte hypertrophy through the increased NLRP3 inflammasome activity, which is indirectly linked with cardiac hypertrophy. Considering that, we propose these miRNAs as possible prognostic biomarkers for FRDA. However, longitudinal studies are still needed to validate their clinical use.

Management of Friedreich Ataxia–Associated Cardiomyopathy in Pregnancy: A Review of the Literature

Management of Friedreich Ataxia–Associated Cardiomyopathy in Pregnancy: A Review of the Literature, Peterson, Ashleigh N. et al., American Journal of Cardiology, Volume 210, 118 - 129, DOI: 10.1016/j.amjcard.2023.10.019 

A major manifestation of Friedreich ataxia (FRDA) is cardiomyopathy, caused by mitochondrial proliferation in myocytes. Because the lifespan for patients with FRDA improves with better treatment modalities, more patients are becoming pregnant, meaning that more medical providers must know how to care for this population. This report provides a review of the literature on multidisciplinary management of pregnant patients with FRDA and cardiomyopathy from preconception through lactation.

Low expression of Frataxin might contribute to diabetic peripheral neuropathy in a mouse model

Siyu Xia, Lin Wu, Jing Chen, Kuanyu Li, Dezhi Bian, Low expression of Frataxin might contribute to diabetic peripheral neuropathy in a mouse model, Biochemical and Biophysical Research Communications, Volume 744, 2025, 151228, ISSN 0006-291X, doi:10.1016/j.bbrc.2024.151228.  

Diabetes is one of the most prevalent metabolic disorders, and its incidence has been experiencing a steady annual rise in recent years. Diabetic peripheral neuropathy (DPN) represents the most frequent adverse complication, exerting a profound impact on the quality of life for those suffering from diabetes. The etiology of DPN is complex, including impaired mitochondrial function. Iron-sulfur clusters (Fe–S) are essential cofactors for numerous essential enzymes crucial for mitochondrial function. Our previous study showed that expression of Frataxin, encoded by the Fxn gene, is downregulated in leptin receptor knockout (so-called db/db) mice, a commonly used DPN mouse model. Fxn is one of the core components of Fe–S biogenesis machinery. Here, we found that the mitochondria-targeted antioxidant SS-31 markedly improved the behavioral indices and significantly mitigated the damage to the sciatic nerve. SS-31 treatment effectively elevated Fxn expression, meliorated mitochondrial function, and inflammation in the sciatic nerve (SCN). We also found that SS-31 effectively mitigated high glucose-induced disruption of iron and redox homeostasis in RSC96 cells, a typical cell model of DPN, thereby improving mitochondrial function. These findings suggest enhancing Fe–S biogenesis could be an effective therapeutic strategy for treating DPN.

Characterization of Arabidopsis thaliana FRATAXIN HOMOLOG in heme catabolism

Jing Zhang, Yingying Zhou, Qianyi Duan, Xinhe Xu, Xiao Wang, Jia Wang, Lin Liu, Characterization of Arabidopsis thaliana FRATAXIN HOMOLOG in heme catabolism, Biochimie, 2024, doi:10.1016/j.biochi.2024.12.010. 

Frataxin plays vital roles in various iron related processes. Arabidopsis thaliana FRATAXIN HOMOLOG (AtFH) is the first identified plant frataxin and has been found to regulate the last step of heme biosynthesis. Here, we report of the involvement of AtFH in heme catabolism by regulating the activity of heme oxygenase. AtFH forms a homodimer, and its crystal structure shows the dimeric interactions. A structural comparison with known frataxin structures suggests the iron binding sites, and the site for heme oxygenase activity is possibly located in a region containing Glu78. The results indicate a previously uncharacterized role of plant frataxin in heme catabolism.

Tachycardiomyopathy Treated With Ablation by Using 3D Mapping System in a Patient With Friedreich Ataxia

Hayıroğlu Mİ, Kalenderoğlu K, Gürkan K. Tachycardiomyopathy Treated With Ablation by Using 3D Mapping System in a Patient With Friedreich Ataxia. Pacing Clin Electrophysiol. 2024 Dec 24. doi: 10.1111/pace.15125. Epub ahead of print. PMID: 39717928. 

This report highlights the importance of a multidisciplinary approach in diagnosing and treating cardiac manifestations in patients with Friedreich ataxia, as well as the efficacy of 3D mapping technology in guiding successful ablation therapies.