title: Iron-sulfur cluster damage by the superoxide radical in neural tissues of the SOD1(G93A) ALS rat model.
abstract: Extensive clinical investigations, in hand with biochemical and biophysical research, have associated brain iron accumulation with the pathogenesis of the amyotrophic lateral sclerosis (ALS) disease. The origin of iron is still not identified, but it is proposed that it forms redox active complexes that can participate in the Fenton reaction generating the toxic hydroxyl radical. In this paper, the state of iron in the neural tissues isolated from SOD1(G93A) transgenic rats was investigated using low temperature EPR spectroscopy and is compared with that of nontransgenic (NTg) littermates. The results showed that iron in neural tissues is present as high- and low-spin, heme and non-heme iron. It appears that the SOD1(G93A) rat neural tissues were most likely exposed in vivo to higher amounts of reactive oxygen species when compared to the corresponding NTg tissues, as they showed increased oxidized [3Fe-4S](1+) cluster content relative to [4Fe-4S](1+). Also, the activity of cytochrome c oxidase (CcO) was found to be reduced in these tissues, which may be associated with the observed uncoupling of heme a3 Fe and CuB in the O2-reduction site of the enzyme. Furthermore, the SOD1(G93A) rat spinal cords and brainstems contained more manganese, presumably from MnSOD, than those of NTg rats. The addition of potassium superoxide to all neural tissues ex vivo, led to the [4Fe-4S]→[3Fe-4S] cluster conversion and concurrent release of Fe. These results suggest that the superoxide anion may be the cause of the observed oxidative damage to SOD1(G93A) rat neural tissues and that the iron-sulfur clusters may be the source of poorly liganded redox active iron implicated in ALS pathogenesis. Low temperature EPR spectroscopy appears to be a valuable tool in assessing the role of metals in neurodegenerative diseases.
authors.affiliation: University of Belgrade - Faculty of Physical Chemistry, EPR Laboratory, Studentski trg 12-16, 11158 Belgrade, Serbia. Electronic address: ana@ffh.bg.ac.rs.
authors.forename: Ana
authors.initials: A
authors.lastname: Popović-Bijelić
authors.affiliation: University of Belgrade - Faculty of Physical Chemistry, EPR Laboratory, Studentski trg 12-16, 11158 Belgrade, Serbia.
authors.forename: Miloš
authors.initials: M
authors.lastname: Mojović
authors.affiliation: University of Belgrade - Faculty of Biology, Center for Laser Microscopy, Studentski trg 3, 11158 Belgrade, Serbia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stamenković
authors.affiliation: University of Belgrade - Faculty of Biology, Center for Laser Microscopy, Studentski trg 3, 11158 Belgrade, Serbia.
authors.forename: Miloš
authors.initials: M
authors.lastname: Jovanović
authors.affiliation: Institute for Medical Research, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Selaković
authors.affiliation: University of Belgrade - Faculty of Biology, Center for Laser Microscopy, Studentski trg 3, 11158 Belgrade, Serbia.
authors.forename: Pavle
authors.initials: P
authors.lastname: Andjus
authors.affiliation: University of Belgrade - Faculty of Physical Chemistry, EPR Laboratory, Studentski trg 12-16, 11158 Belgrade, Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Bačić
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D003576:Electron Transport Complex IV / Q000378:metabolism; D006418:Heme / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D051381:Rats; D055647:Rats, Transgenic; D013455:Sulfur / Q000737:chemistry; D000072105:Superoxide Dismutase-1 / Q000235:genetics* / Q000378:metabolism; D013481:Superoxides / Q000633:toxicity
chemical_list: D013481:Superoxides; D006418:Heme; D013455:Sulfur; D007501:Iron; C000606292:Sod1 protein, rat; D000072105:Superoxide Dismutase-1; D003576:Electron Transport Complex IV
keywords: ALS; EPR; Fe-S cluster; SOD1(G93A); Superoxide radical