Hypoxic Adaptation of Mitochondrial Metabolism in Rat Cerebellum Decreases in Pregnancy.

Anastasia Graf,Victoria Bunik,Lyudmila Baratova,Lidia Trofimova,Alexander Ksenofontov

doi:10.3390/cells9010139

Anastasia Graf, Victoria Bunik + Show 3 more

Open Access

https://doi.org/10.3390/cells9010139

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Journal: Cells	Publication Date: Jan 7, 2020
Citations: 11	License type: CC BY 4.0

Affiliation: Lomonosov Moscow State University, Sechenov University

Abstract

Function of brain amino acids as neurotransmitters or their precursors implies changes in the amino acid levels and/or metabolism in response to physiological and environmental challenges. Modelling such challenges by pregnancy and/or hypoxia, we characterize the amino acid pool in the rat cerebellum, quantifying the levels and correlations of 15 amino acids and activity of 2-oxoglutarate dehydrogenase complex (OGDHC). The parameters are systemic indicators of metabolism because OGDHC limits the flux through mitochondrial TCA cycle, where amino acids are degraded and their precursors synthesized. Compared to non-pregnant state, pregnancy increases the cerebellar content of glutamate and tryptophan, decreasing interdependence between the quantified components of amino acid metabolism. In response to hypoxia, the dependence of cerebellar amino acid pool on OGDHC and the average levels of arginine, glutamate, lysine, methionine, serine, phenylalanine, and tryptophan increase in non-pregnant rats only. This is accompanied by a higher hypoxic resistance of the non-pregnant vs. pregnant rats, pointing to adaptive significance of the hypoxia-induced changes in the cerebellar amino acid metabolism. These adaptive mechanisms are not effective in the pregnancy-changed metabolic network. Thus, the cerebellar amino acid levels and OGDHC activity provide sensitive markers of the physiology-dependent organization of metabolic network and its stress adaptations.

Highlights

Many amino acids and/or their derivatives are neurotransmitters
One should take into account that generation of nitric oxide involves an intercept between metabolism of lysine and arginine [3], which, in their turn, are tightly linked to other amino acids through multiple intercepts
The present study demonstrates that the metabolic interdependence of the brain amino acids and oxoglutarate dehydrogenase complex (OGDHC) provides systemic markers of different physiological and pathological states, which complement the information based on analysis of traditional metabolic markers, such as average levels of metabolites or enzymatic activities

Summary

Introduction

Many amino acids and/or their derivatives are neurotransmitters. metabolic perturbations in the brain, affecting the levels of amino acids, often have neurological consequences, and vice versa.systemic consequences of changed levels of specific amino acids or related enzymes are not predictable. Many amino acids and/or their derivatives are neurotransmitters. Metabolic perturbations in the brain, affecting the levels of amino acids, often have neurological consequences, and vice versa. Systemic consequences of changed levels of specific amino acids or related enzymes are not predictable. Administration of arginine or nitric oxide synthase inhibitors at cerebral infarction may cause opposite physiological outcomes [1]. The glutamate-induced excitotoxicity could be either aggravated [2] or alleviated [1] by nitric oxide signaling. One should take into account that generation of nitric oxide involves an intercept between metabolism of lysine and arginine [3], which, in their turn, are tightly linked to other amino acids through multiple intercepts

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Conclusion