Glial-specific mitochondrial failure and redox imbalance contribute to regional vulnerability in Friedreich's ataxia

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 FXN^I151F 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.