Up-regulation of 2-oxoglutarate dehydrogenase as a stress response.
2-Oxoglutarate dehydrogenase multienzyme complex (OGDHC) operates at a metabolic cross-road, mediating Ca(2+)- and ADP-dependent signals in mitochondria. Here, we test our hypothesis that OGDHC plays a major role in the neurotransmitter metabolism and associated stress response. This possibility was assessed using succinyl phosphonate (SP), a highly specific and efficient in vivo inhibitor of OGDHC. Animals exposed to toxicants (SP, ethanol or MnCl(2)), trauma or acute hypoxia showed intrinsic up-regulation of OGDHC in brain and heart. The known mechanism of the SP action as OGDHC inhibitor pointed to the up-regulation triggered by the enzyme impairment. The animal behavior and skeletal muscle or heart performance were tested to correlate physiology with the OGDHC regulation and associated changes in the glutamate and cellular energy status. The SP-treated animals exhibited interdependent changes in the brain OGDHC activity, glutamate level and cardiac autonomic balance, suggesting the neurotransmitter role of glutamate to be involved in the changed heart performance. Energy insufficiency after OGDHC inhibition was detectable neither in animals up to 25 mg/kg SP, nor in cell culture during 24 h incubation with 0.1 mM SP. However, in animals subjected to acute ethanol intoxication SP did evoke energy deficit, decreasing muscular strength and locomotion and increasing the narcotic sleep duration. This correlated with the SP-induced decrease in NAD(P)H levels of the ethanol-exposed neurons. Thus, we show the existence of natural mechanisms to up-regulate mammalian OGDHC in response to stress, with both the glutamate neurotransmission and energy production potentially involved in the OGDHC impact on physiological performance. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.
Department of Physiology of Biology Faculty of Lomonosov Moscow State University, Leninskije Gory 1, 119992 Moscow, Russian Federation. stasy_gr@pochta.ru
Anastasia
A
Graf
Lidia
L
Trofimova
Alexandra
A
Loshinskaja
Garik
G
Mkrtchyan
Anastasiia
A
Strokina
Maxim
M
Lovat
Adam
A
Tylicky
Slawomir
S
Strumilo
Lucien
L
Bettendorff
Victoria I
VI
Bunik
D000818:Animals; D001921:Brain / Q000201:enzymology*; D004734:Energy Metabolism; D005260:Female; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000502:physiology*; D015854:Up-Regulation
D018698:Glutamic Acid; D007655:Ketoglutarate Dehydrogenase Complex