Factors that may increase mitochondrial ROS production include respiratory activity, iron uptake, iron storage, and production of signaling molecules with free radical properties, such as carbon monoxide and nitric oxide. Current data do not single out any of these factors as acting in particular in the target cells for FRDA. Respiratory activity is high in many neurons, including many untouched by FRDA. In this regard, in primates, the amount of cytochrome oxidase, an indicator of respiratory activity, is as high in some ventral horn motor neurons as in some DRG sensory neurons.68
Furthermore, among cat DRG neurons, those with the highest complex II activity, another marker of oxidative capacity, are small neurons,69
a size not affected by FRDA. The neurons affected by FRDA are not known to have high production of nitric oxide or carbon monoxide. In the spinal cord and DRG of most species, nitric oxide is generated by intermediolateral column neurons (visceral effectors), by small neurons in the DRG, and by some neurons in the posterior horns,70all spared by FRDA. Iron uptake in the brain is reported to be highest in the cerebellum, followed by the brainstem; the frontal, parietal, and occipital cortexes; the hippocampus; and the caudate nucleus, in decreasing order.71
Therefore, brain iron uptake seems to be higher in certain regions that show some involvement in FRDA, but these data need much further refinement for our purposes. The most important pathway for brain iron uptake seems to involve the binding of transferrin iron to transferrin receptors on endothelial cells, transport of iron to the interstitial space, binding to transferrin synthesized in the CNS, diffusion through the interstitial space and the cerebrospinal fluid, and, finally, internalization into cells carrying transferrin receptors,72but transferrin-independent pathways are also operating.71More than 30 years ago, a report suggested that brain iron uptake was increased in FRDA,73but it was not followed by any similar study, and the study's method, including the diagnostic criteria for FRDA, would not be considered adequate by today's standards. As for iron storage, stainable iron is normally present particularly but not exclusively in the globus pallidus, caudate nucleus, substantia nigra, and dentate nucleus.72,74The amount of iron in some of these areas may be as high as in the liver, a very iron-rich organ. With the exception of the dentate nucleus, these areas (as well as the liver) are marginally affected or not affected in FRDA. Interestingly, however, the regional differences in iron storage in the brain not only do not match the distribution of FRDA pathology, they also do not match the rates of iron uptake.