Mitochondrial dysfunction in neurons in Friedreich's ataxia.

Friedreich's ataxia is a multisystemic genetic disorder within the family of mitochondrial diseases that is characterized by reduced levels of the essential mitochondrial protein frataxin. Based on clinical evidence, the peripheral nervous system is affected early, neuronal dysfunction progresses towards the central nervous system, and other organs (such as heart and pancreas) are affected later. However, little attention has been given to the specific aspects of mitochondria function altered by frataxin depletion in the nervous system. For years, commonly accepted views on mitochondria dysfunction in Friedreich's ataxia stemmed from studies using non-neuronal systems and may not apply to neurons, which have their own bioenergetic needs and present a unique, extensive neurite network. Moreover, the basis of the selective neuronal vulnerability, which primarily affects large sensory neurons in the dorsal root ganglia, large principal neurons in the dentate nuclei of the cerebellum, and pyramidal neurons in the cerebral cortex, remains elusive. In order to identify potential misbeliefs in the field and highlight controversies, we reviewed current knowledge on frataxin expression in different tissues, discussed the molecular function of frataxin, and the consequences of its deficiency for mitochondria structural and functional properties, with a focus on the nervous system.