Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

Abstract

Both hypoxia and inhibition of 2-oxoglutarate dehydrogenase complex (OGDHC) are known to change cellular amino acid pools, but the quantitative comparison of the metabolic and physiological outcomes has not been done. We hypothesize that OGDHC inhibition models metabolic changes caused by hypoxia, as both perturb the respiratory chain function, limiting either the NADH (OGDHC inhibition) or oxygen (hypoxia) supply. In the current study, we quantify the changes in the amino acid metabolism after OGDHC inhibition in the highly sensitive to hypoxia cerebellum and compare them to the earlier characterized changes after acute hypobaric hypoxia. In addition, the associated physiological effects are characterized and compared. A specific OGDHC inhibitor succinyl phosphonate (SP) is shown to act similar to hypoxia, increasing levels of many amino acids in the cerebellum of non-pregnant rats, without affecting those in the pregnant rats. Compared with hypoxia, stronger effects of SP in non-pregnant rats are observed on the levels of cerebellar amino acids, electrocardiography (ECG), and freezing time. In pregnant rats, hypoxia affects ECG and behavior more than SP, although none of the stressors significantly change the levels of cerebellar amino acids. The biochemical differences underlying the different physiological actions of SP and hypoxia are revealed by correlation analysis of the studied parameters. The negative correlations of cerebellar amino acids with OGDHC and/or tryptophan, shown to arise after the action of SP and hypoxia, discriminate the overall metabolic action of the stressors. More negative correlations are induced in the non-pregnant rats by hypoxia, and in the pregnant rats by SP. Thus, our findings indicate that the OGDHC inhibition mimics the action of acute hypobaric hypoxia on the cerebellar amino acid levels, but a better prediction of the physiological outcomes requires assessment of integral network changes, such as increases in the negative correlations among the amino acids, OGDHC, and/or tryptophan.

Acute Prenatal Hypoxia in Rats Affects Physiology and Brain Metabolism in the Offspring, Dependent on Sex and Gestational Age

“…Thus, the multiple biochemical changes in the APH-20-exposed female brain are of a compensatory nature. Earlier, we have observed similar features, i.e., multiple biochemical changes accompanied by a better physiological stabilization, when comparing the reactivity to hypoxia or its chemical mimic of non-pregnant and pregnant female rats [34,35].…”

“…In particular, the brain glutamate levels mediate the link between brain OGDHC activity and ECG or behavioral parameters [ 36 , 49 , 52 ]. Moreover, we have recently shown that specific inhibition of OGDHC models the action of APH on the amino acid metabolism, with both actions changing accordingly due to the pregnancy [ 34 , 35 ]. Hence, in addition to the role in the protein acetylation, the opposite changes in brain OGDHC in the male and female offspring exposed to APH-10 may underlie the sex-dependent behavioral changes observed in these offspring.…”

“…Figure 5 demonstrates that the brain malic enzyme activity may serve as an enzymatic indicator of the APH-induced perturbations in both the female and male offspring. Furthermore, the brain amino acid profiles, which are sensitive indicators of the brain neurotransmitter metabolism linker to behavior [34][35][36], have been assessed. From 24 amino acids and dipeptides quantified, the levels of Glu, Gly, Phe, Trp, Ser, Tyr, Asn, and carnosine increase in the cerebral cortex of female offspring, subjected to APH-20, while only those of Phe, Thr, and Trp increase in the APH-20-exposed males (Table 1).…”

Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation

“…Although correlations between specific biochemical and physiological parameters do not manifest causal relationships, analysis of the correlated parameters and their changes in different (patho)physiological settings may help decipher molecular mechanisms of the network changes [50,51]. The interdependencies of the characteristic parameters of the control and treated animals are compared in Figure 4.…”

Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain

“…malate dehydrogenase (MDH) and decarboxylating malic enzyme (ME) important for anaplerosis, and (iii) glutamine synthetase (GS) whose function is linked to the amino acid degradation occurring in the TCA cycle [16]. Accordingly, the profile of the brain amino acids and related compounds is a useful indicator of the TCA cycle substrate fluxes [16,17]. In accordance with the reversibility of the phosphonate inhibitors binding to PDHC [9], no alterations in the activity of PDHC assayed upon a strong dilution of the brain homogenates in the reaction medium, is observed (Figure 2).…”