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.
Highlights
Molecular mechanisms of complex pathophysiological phenomena are often studied in their chemical models
Changes in the Levels of Free Amino Acids in Cerebella of the succinyl phosphonate (SP)-Exposed vs. Control Female Rats Depend on Pregnancy, Similar to the Changes After Acute Hypobaric Hypoxia
Pregnant rats mostly do not differ from non-pregnant rats in their cerebellar amino acid levels, with only glutamate and tryptophan being higher in the pregnant vs. non-pregnant rats [9]
Summary
Molecular mechanisms of complex pathophysiological phenomena are often studied in their chemical models. Pentylenetetrazol is widely employed to model epilepsy [1], while mitochondrial impairment in neurodegenerative diseases is often modeled by exposure of animals to inhibitors of the respiratory chain [2, 3]. Some of the rotenone actions may be caused by targeting complex I of the respiratory chain [3, 7]. Translational value of the results obtained in the chemical models of pathologies essentially depends on the knowledge of molecular features of the complex pathophysiology, which are reproduced by the model, and those which characterize the substance-specific action. Mitochondrial impairment occurs upon inhibition of either complex I or II, different downstream pathways are activated by each of specific mitochondrial inhibitors, potentially reproducing the symptoms specific for particular neurodegenerative diseases [8]
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