Iron-sulfur cluster damage by the superoxide radical in neural tissues of the SOD1G93A ALS rat model

Publication date: July 2016
Source:Free Radical Biology and Medicine, Volume 96
Author(s): Ana Popović-Bijelić, Miloš Mojović, Stefan Stamenković, Miloš Jovanović, Vesna Selaković, Pavle Andjus, Goran Bačić
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.

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