PMID- 19393031
OWN - NLM
STAT- MEDLINE
DCOM- 20090521
LR  - 20141120
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 109 Suppl 1
DP  - 2009 May
TI  - Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen 
      species generation by lipoic acid.
PG  - 222-9
LID - 10.1111/j.1471-4159.2009.05942.x [doi]
AB  - Dihydrolipoamide dehydrogenase (LADH) is a flavo-enzyme that serves as a subunit 
      of alpha-ketoglutarate dehydrogenase complex (alpha-KGDHC). Reactive oxygen 
      species (ROS) generation by alpha-KGDHC has been assigned to LADH (E3 subunit) 
      and explained by the diaphorase activity of E3. Dysfunctions of alpha-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 
      alpha-KGDHC. We found a parallel generation of superoxide and hydrogen peroxide 
      by the E3 subunit of alpha-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 
      alpha-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.
FAU - Ambrus, Attila
AU  - Ambrus A
AD  - Department of Medical Biochemistry, Neurobiochemical Research Group, Hungarian 
      Academy of Sciences and Szentagothai Janos Knowledge Center, Semmelweis 
      University, Budapest, Hungary.
FAU - Tretter, Laszlo
AU  - Tretter L
FAU - Adam-Vizi, Vera
AU  - Adam-Vizi V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Antioxidants)
RN  - 0 (Reactive Oxygen Species)
RN  - 11062-77-4 (Superoxides)
RN  - 73Y7P0K73Y (Thioctic Acid)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 1.2.4.2 (Ketoglutarate Dehydrogenase Complex)
RN  - EC 1.8.1.4 (Dihydrolipoamide Dehydrogenase)
SB  - IM
MH  - Animals
MH  - Antioxidants/*pharmacology
MH  - Dihydrolipoamide Dehydrogenase/metabolism
MH  - Hydrogen Peroxide/metabolism
MH  - Hydrogen-Ion Concentration
MH  - In Vitro Techniques
MH  - Ketoglutarate Dehydrogenase Complex/*antagonists & inhibitors/*metabolism
MH  - Male
MH  - Membrane Potentials/drug effects
MH  - Mice
MH  - Mitochondria/drug effects/enzymology/metabolism
MH  - Mitochondrial Membranes/drug effects
MH  - Oxygen Consumption/drug effects
MH  - Photometry
MH  - Reactive Oxygen Species/*metabolism
MH  - Spectrophotometry, Ultraviolet
MH  - Superoxides/metabolism
MH  - Thioctic Acid/*pharmacology
EDAT- 2009/05/07 09:00
MHDA- 2009/05/22 09:00
CRDT- 2009/04/28 09:00
PHST- 2009/04/28 09:00 [entrez]
PHST- 2009/05/07 09:00 [pubmed]
PHST- 2009/05/22 09:00 [medline]
AID - JNC5942 [pii]
AID - 10.1111/j.1471-4159.2009.05942.x [doi]
PST - ppublish
SO  - J Neurochem. 2009 May;109 Suppl 1:222-9. doi: 10.1111/j.1471-4159.2009.05942.x.