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Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by GAA expansions in the FXN gene, which codes for the protein frataxin (FXN). These mutations reduce FXN expression, leading to mitochondrial dysfunction and multisystemic disease. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, may drive the neurological phenotypes of FRDA, but the mechanisms underlying such neurological phenotypes remain unclear. To investigate the neural circuit basis of this dysfunction, we employed field recordings to measure Purkinje cell (PC) function and synaptic properties along with western blotting and immunohistochemistry to determine their density and structure in two established FRDA mouse models, the shRNA-frataxin (FRDAkd) and the frataxin knock in-knockout (KIKO) mice. Western blotting demonstrated subtle changes in mitochondrial proteins and only a modest reduction in the density of calbindin positive cells PCs in the cerebellar cortex of the FRDAkd mice, with no change in the density of PCs in the KIKO mice. Though PC density differed slightly in the two models, field recordings of parallel fiber-PC synapses in the molecular layer demonstrated concordant hypo-excitability of basal synaptic transmission and impairments of long-term plasticity using induction protocols associated with both potentiation and depression of synaptic strength. These results indicate that synaptic instability might be a common feature in FRDA mouse models., Competing Interests: Declarations. Generative AI in Scientific Writing: The authors declare that generative artificial intelligence (AI) and AI-assisted technologies were not used in the writing process of this manuscript. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s).)

Friedreich's ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide-positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not "fail" per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.

In addition to ATP synthesis, mitochondria are highly dynamic organelles that modulate apoptosis, ferroptosis, and inflammasome activation. Through executing these varied functions, the mitochondria play critical roles in the development and progression of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich ataxia, among others. Impaired mitochondrial biogenesis and abnormal mitochondrial dynamics contribute to mitochondrial dysfunction in these diseases. Additionally, dysfunctional mitochondria play critical roles in signaling for both inflammasome activation and ferroptosis. Therapeutics are being developed to circumvent inflammasome activation and ferroptosis in dysfunctional mitochondria. Targeting these aspects of mitochondrial dysfunction may present viable therapeutic strategies for combatting the neurodegenerative diseases. This review aims to summarize the role of the mitochondria in the development and progression of neurodegenerative diseases and to present current therapeutic approaches that target mitochondrial dysfunction in these diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease with developmental features caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently, ATP production abnormalities. Based on the involvement of such processes in FRDA, initial pathophysiological hypotheses focused on reactive oxygen species (ROS) production as a key component of the mechanism. With further study, a variety of other events appear to be involved, including abnormalities of mitochondrially related metabolism and dysfunction in mitochondrial biogenesis. Consequently, present therapies focus not only on free radical damage, but also on control of metabolic abnormalities and correction of mitochondrial biogenesis. Understanding the multitude of abnormalities in FRDA thus offers possibilities for treatment of this disorder., Competing Interests: The authors declare that there are no competing interests associated with the manuscript., (© 2018 The Author(s).)