Fig. 6
a Two distinct iron-binding sites are present in the human NM pigment with different affinity. The multinuclear iron cluster, similarly to ferritin, contains iron(III) ions (blue colored) that are coupled by oxy-hydroxy bridges and bound through catechol groups to melanic portion of NM pigment. At this site, iron is likely stored with high affinity and maintained in a redox inactive state, and is principally detected by Mössbauer spectroscopy. In the mononuclear iron center, iron ions (red) are six-coordinated by oxygen atoms of catechols moieties in octahedral arrangement, and possibly by hydroxo groups. This could be a low-affinity binding site occupied in cases of iron overload, when the high-affinity centers are saturated, as occurs in iron overload conditions of PD. In this case, the mononuclear iron could be redox reactive and catalyze the production of toxic species causing iron-mediated toxicity. Iron in this site is principally detected by EPR spectroscopy. The structural differences between high and low-affinity sites, their accessibility, and reactivity toward small binding ligands and biological substrates, with reliable quantification of iron, still need further investigation. Figure reproduced from ref. 21 by permission of Elsevier. b Concentration of total iron in LC (empty circles) and in SN (black circles) from human normal subjects during aging (mean ± SEM; n = 2). The concentration of iron in LC is constant during aging and much lower than that measured in SN tissues. Conversely, the concentration of iron in SN has a smooth increase throughout life according to a linear model. b Reproduced from ref. 41, copyright (2004) National Academy of Sciences, USA. c EPR spectra of NM–iron complex in SN and in LC tissues. The signal at g = 4.3 corresponds to iron(III) high spin complex in octahedral configuration, while signal at g = 2.0 corresponds to the stable organic radical typically present in both NM pigments and all melanic pigments. From the ratio between two signals intensities and previous EPR calibrations,40 it appears that iron content of NM pigment in LC neurons is about 7.9% of that in SN neurons. The same signals were present in NM pigments chemically isolated from LC and SN areas, but with different signal ratios. c Modified from ref. 41, copyright (2004) National Academy of Sciences, USA
