Frataxin depletion leads to decreased soma size and activation of AMPK metabolic pathway in dorsal root ganglia sensory neurons

Friedreichs ataxia (FA) is an inherited neurodegenerative disorder caused by frataxin deficiency, leading to mitochondrial dysfunction and impaired iron-sulfur (Fe-S) cluster biogenesis. Proprioceptive dorsal root ganglia (DRG) neurons are among the most vulnerable cell types in FA, yet the mechanisms underlying their selective susceptibility remain unclear. Here, we developed a primary culture model of embryonic mouse DRG neurons with complete frataxin depletion, which faithfully reproduces key biochemical hallmarks of FA, including Fe-S enzyme deficiency, mitochondrial iron dysregulation, and oxidative stress. Despite long-term survival, frataxin-deficient neurons exhibited a marked reduction in soma size, identifying a previously unrecognized growth phenotype. Mechanistically, this defect was mediated by AMP-activated protein kinase (AMPK) hyperactivation and suppression of mTOR signaling in response to mitochondrial dysfunction and redox imbalance. Restoration of frataxin expression, genetic inhibition of AMPK, or treatment with -lipoic acid (ALA) rescued soma growth, normalize ATP levels and reduce AMPK activation. Our findings uncover AMPK-mTOR dysregulation as a key driver of neuronal growth impairment in FA. This robust neuronal model provides new insights into proprioceptive neuron vulnerability and offers a platform for therapeutic discovery.