Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid
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1
Department of Medical Biochemistry, Semmelweis University, Hungary
Dihydrolipoamide dehydrogenase (LADH) is a flavo-enzyme that serves as a subunit of -ketoglutarate dehydrogenase (-KGDHC). Reactive oxygen species (ROS) generation by -KGDHC has been assigned to LADH (E3-subunit) and explained by the analogous diaphorase activity of E3. Dysfunctions of -KGDHC and concurrent ROS-production have been implicated in neurodegeneration, ischemia-reperfusion and other pathological conditions. In this work we investigated the intimate details of ROS-generation by isolated LADH and -KGDHC. We found a parallel generation of superoxide and hydrogen peroxide by the E3-subunit of -KGDHC which could be blocked by lipoic acid at a site that does not reside on the E3-subunit. The pathologically relevant ROS-generation (at high NADH/NAD+ ratios and low pH) in the reverse mode of -KGDHC could also be inhibited by lipoic acid. Our results contradict the previously proposed mechanism for pH-dependent ROS-generation by LADH, showing no disassembling of the E3 functional homodimer at acidic pH using a physiologically relevant method for the examination. Lipoic acid can potentially be used as a clinical intervention strategy in lessening the detrimental effects of ROS by preconditioning patients and by local administration in acute cases.
Conference:
12th Meeting of the Hungarian Neuroscience Society, Budapest, Hungary, 22 Jan - 24 Jan, 2009.
Presentation Type:
Poster Presentation
Topic:
Pathophysiology and neurology - degenerative disorders
Citation:
Adam-Vizi
V,
Ambrus
A and
Tretter
L
(2009). Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid.
Front. Syst. Neurosci.
Conference Abstract:
12th Meeting of the Hungarian Neuroscience Society.
doi: 10.3389/conf.neuro.01.2009.04.136
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Received:
04 Mar 2009;
Published Online:
04 Mar 2009.
*
Correspondence:
Vera Adam-Vizi, Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary, Veronika.Adam@eok.sote.hu