Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)222-229
Number of pages8
JournalJournal of neurochemistry
Volume109
Issue numberSUPPL. 1
DOIs
Publication statusPublished - May 1 2009

Keywords

  • Lipoic acid
  • ROS
  • α-ketoglutarate dehydrogenase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid'. Together they form a unique fingerprint.

  • Cite this