Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia
4 affiliations
- 1Dept. Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Av. Alcalde Rovira Roure 80, Lleida, 25198, Spain; Institut de Recerca Biomèdica de Lleida - Fundació Dr. Pifarré, IRBLleida (ROR: 03mfyme49), Av. Alcalde Rovira Roure 80, Lleida, 25198, Spain. Electronic address: [email protected].
- 2Dept. Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Av. Alcalde Rovira Roure 80, Lleida, 25198, Spain; Institut de Recerca Biomèdica de Lleida - Fundació Dr. Pifarré, IRBLleida (ROR: 03mfyme49), Av. Alcalde Rovira Roure 80, Lleida, 25198, Spain.
- 3Instituto de Biología Funcional y Genómica (IBFG), Universidad de Salamanca, CSIC, Zacarías González 2, Salamanca, 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Plaza de San Vicente 58, 182, Salamanca, 37007, Spain.
- 4Dept. Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Av. Alcalde Rovira Roure 80, Lleida, 25198, Spain; Institut de Recerca Biomèdica de Lleida - Fundació Dr. Pifarré, IRBLleida (ROR: 03mfyme49), Av. Alcalde Rovira Roure 80, Lleida, 25198, Spain. Electronic address: [email protected].
Abstract
Friedreich's ataxia (FA) is a rare autosomal recessive neurodegenerative disorder caused by reduced expression of frataxin, a mitochondrial protein important for iron–sulfur cluster assembly and mitochondrial homeostasis. Although FA has traditionally been attributed to neuronal dysfunction, increasing evidence suggests that glial cells play a critical role in disease progression, although their contribution remains poorly defined. Using the FXNI151F mouse model, we investigated cell-type–specific metabolic and redox alterations in neurons and glial populations from the cerebrum, cerebellum, and dorsal root ganglia (DRG). Neuronal and glial-enriched fractions were isolated by immunomagnetic separation and analyzed for mitochondrial function, iron metabolism and reactive oxygen species (ROS). The analyses identified the DRG as the most severely affected region, exhibiting early and progressive mitochondrial respiratory deficits, increased ROS, mitochondrial iron accumulation, lipid peroxidation, and reduced levels of glutathione peroxidase 4 and nuclear factor erythroid 2–related factor 2 in both neuronal and non-neuronal cells, ultimately resulting in significant neuronal loss. These results highlight the vulnerability of sensory neurons and their supporting satellite glial cells. In contrast, in the cerebrum and cerebellum, astrocytes displayed earlier and more severe alterations than neurons, including impaired respiratory chain efficiency, disrupted complex I-III supercomplex interaction, elevated ROS, and hallmarks consistent with ferroptosis. Neuronal abnormalities emerged later, suggesting that glial dysfunction precedes and may contribute to neuronal pathology. Overall, these findings reveal pronounced region and cell-type-specific vulnerabilities in FA and support the importance of targeting glial mechanisms—particularly iron dysregulation, oxidative stress, and ferroptosis-associated alterations— as targets for potential therapeutic strategies.
Related
- The MAPK phosphatase VHP-1 buffers pharynx-to-body proportions against tissue-specific growth imbalance in C. elegans
- Identifying human-specific transcription factor binding site gains and losses that contribute to human-specific phenotypes
- Single-nucleus transcriptomics uncovers region-specific molecular features underlying selective aging vulnerability of cholinergic neurons
- A DNM1L GTPase Effector Domain Deletion Causes Intermediate Defects in Peroxisomal and Mitochondrial Dynamics and Reveals a Targetable Metabolic Vulnerability
- Long-Term Experience in the Molecular Genetic Diagnosis of Friedreich Ataxia in the Russian Federation
BibTeX
@article{sanzalcazar2026glialspecific,
title = {{Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia}},
author = {Arabela Sanz-Alcázar and Marta Portillo-Carrasquer and Israel Manjarres-Raza and Maria Pazos-Gil and Fabien Delaspre and Jordi Tamarit and Juan P Bolaños and Joaquim Ros and Elisa Cabiscol},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104437},
url = {https://doi.org/10.1016/j.redox.2026.104437},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia
AU - Arabela Sanz-Alcázar
AU - Marta Portillo-Carrasquer
AU - Israel Manjarres-Raza
AU - Maria Pazos-Gil
AU - Fabien Delaspre
AU - Jordi Tamarit
AU - Juan P Bolaños
AU - Joaquim Ros
AU - Elisa Cabiscol
PY - 2026
DA - 2026/10/13
JO - Redox Biology
DO - 10.1016/j.redox.2026.104437
UR - https://doi.org/10.1016/j.redox.2026.104437
AB - Friedreich's ataxia (FA) is a rare autosomal recessive neurodegenerative disorder caused by reduced expression of frataxin, a mitochondrial protein important for iron–sulfur cluster assembly and mitochondrial homeostasis. Although FA has traditionally been attributed to neuronal dysfunction, increasing evidence suggests that glial cells play a critical role in disease progression, although their contribution remains poorly defined. Using the FXNI151F mouse model, we investigated cell-type–specific metabolic and redox alterations in neurons and glial populations from the cerebrum, cerebellum, and dorsal root ganglia (DRG). Neuronal and glial-enriched fractions were isolated by immunomagnetic separation and analyzed for mitochondrial function, iron metabolism and reactive oxygen species (ROS). The analyses identified the DRG as the most severely affected region, exhibiting early and progressive mitochondrial respiratory deficits, increased ROS, mitochondrial iron accumulation, lipid peroxidation, and reduced levels of glutathione peroxidase 4 and nuclear factor erythroid 2–related factor 2 in both neuronal and non-neuronal cells, ultimately resulting in significant neuronal loss. These results highlight the vulnerability of sensory neurons and their supporting satellite glial cells. In contrast, in the cerebrum and cerebellum, astrocytes displayed earlier and more severe alterations than neurons, including impaired respiratory chain efficiency, disrupted complex I-III supercomplex interaction, elevated ROS, and hallmarks consistent with ferroptosis. Neuronal abnormalities emerged later, suggesting that glial dysfunction precedes and may contribute to neuronal pathology. Overall, these findings reveal pronounced region and cell-type-specific vulnerabilities in FA and support the importance of targeting glial mechanisms—particularly iron dysregulation, oxidative stress, and ferroptosis-associated alterations— as targets for potential therapeutic strategies.
SN - 2213-2317
ER -