Premium
Inhibition of the alpha‐ketoglutarate dehydrogenase‐mediated reactive oxygen species generation by lipoic acid
Author(s) -
Ambrus Attila,
Tretter László,
AdamVizi Vera
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.05942.x
Subject(s) - reactive oxygen species , biochemistry , dihydrolipoamide dehydrogenase , nad+ kinase , alpha lipoic acid , chemistry , g alpha subunit , dehydrogenase , protein subunit , biology , enzyme , oxidative stress , gene
Dihydrolipoamide dehydrogenase (LADH) is a flavo‐enzyme that serves as a subunit of α‐ketoglutarate dehydrogenase complex (α‐KGDHC). Reactive oxygen species (ROS) generation by α‐KGDHC has been assigned to LADH (E3 subunit) and explained by the diaphorase activity of E3. Dysfunctions of α‐KGDHC and concurrent ROS production have been implicated in neurodegeneration, ischemia‐reperfusion, and other pathological conditions. In this work we investigated the in‐depth details of ROS generation by isolated LADH and α‐KGDHC. We found a parallel generation of superoxide and hydrogen peroxide by the E3 subunit of α‐KGDHC which could be blocked by lipoic acid (LA) acting on a site upstream of the E3 subunit. The pathologically relevant ROS generation (at high NADH/NAD + ratio and low pH) in the reverse mode of α‐KGDHC could also be inhibited by LA. 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. It is also suggested that LA could be beneficial in reducing the cell damage related to excessive ROS generation under pathological conditions.