Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax

Oxidative metabolism is fine-tuned machinery that combines two tightly coupled fluxes of glucose and glutamine-derived carbons. Hypoxia interrupts the coordination between the metabolism of these two nutrients and leads to a decrease of the system efficacy and may eventually cause cell death. The su...

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Autores principales:	Dmitry Miskevich, Anastasia Chaban, Maria Dronina, Ifat Abramovich, Eyal Gottlieb, Imad Shams
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	glutamine metabolome hypoxia proline cycle GSH adaptation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e505625c13b8457cbce56f7e3b798404
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spelling	oai:doaj.org-article:e505625c13b8457cbce56f7e3b7984042021-11-25T18:20:41ZGlutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax10.3390/metabo111107552218-1989https://doaj.org/article/e505625c13b8457cbce56f7e3b7984042021-10-01T00:00:00Zhttps://www.mdpi.com/2218-1989/11/11/755https://doaj.org/toc/2218-1989Oxidative metabolism is fine-tuned machinery that combines two tightly coupled fluxes of glucose and glutamine-derived carbons. Hypoxia interrupts the coordination between the metabolism of these two nutrients and leads to a decrease of the system efficacy and may eventually cause cell death. The subterranean blind mole rat, <i>Spalax</i>, is an underexplored, underground, hypoxia-tolerant mammalian group which spends its life under sharply fluctuating oxygen levels. Primary <i>Spalax</i> cells are an exceptional model to study the metabolic strategies that have evolved in mammals inhabiting low-oxygen niches. In this study we explored the metabolic frame of glutamine (Gln) homeostasis in <i>Spalax</i> skin cells under normoxic and hypoxic conditions and their impacts on the metabolism of rat cells. Targeted metabolomics employing liquid chromatography and mass spectrometry (LC-MS) was used to track the fate of heavy glutamine carbons (<sup>13</sup>C<sub>5</sub> Gln) after 24 h under normoxia or hypoxia (1% O<sub>2</sub>). Our results indicated that large amounts of glutamine-originated carbons were detected as proline (Pro) and hydroxyproline (HPro) in normoxic <i>Spalax</i> cells with a further increase under hypoxia, suggesting a strategy for reduced Gln carbons storage in proteins. The intensity of the flux and the presence of HPro suggests collagen as a candidate protein that is most abundant in animals, and as the primary source of HPro. An increased conversion of αKG to 2 HG that was indicated in hypoxic <i>Spalax</i> cells prevents the degradation of hypoxia-inducible factor 1α (HIF-1α) and, consequently, maintains cytosolic and mitochondrial carbons fluxes that were uncoupled via inhibition of the pyruvate dehydrogenase complex. A strong antioxidant defense in <i>Spalax</i> cells can be attributed, at least in part, to the massive usage of glutamine-derived glutamate for glutathione (GSH) production. The present study uncovers additional strategies that have evolved in this unique mammal to support its hypoxia tolerance, and probably contribute to its cancer resistance, longevity, and healthy aging.Dmitry MiskevichAnastasia ChabanMaria DroninaIfat AbramovichEyal GottliebImad ShamsMDPI AGarticleglutaminemetabolomehypoxiaproline cycleGSHadaptationMicrobiologyQR1-502ENMetabolites, Vol 11, Iss 755, p 755 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glutamine metabolome hypoxia proline cycle GSH adaptation Microbiology QR1-502
spellingShingle	glutamine metabolome hypoxia proline cycle GSH adaptation Microbiology QR1-502 Dmitry Miskevich Anastasia Chaban Maria Dronina Ifat Abramovich Eyal Gottlieb Imad Shams Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax
description	Oxidative metabolism is fine-tuned machinery that combines two tightly coupled fluxes of glucose and glutamine-derived carbons. Hypoxia interrupts the coordination between the metabolism of these two nutrients and leads to a decrease of the system efficacy and may eventually cause cell death. The subterranean blind mole rat, <i>Spalax</i>, is an underexplored, underground, hypoxia-tolerant mammalian group which spends its life under sharply fluctuating oxygen levels. Primary <i>Spalax</i> cells are an exceptional model to study the metabolic strategies that have evolved in mammals inhabiting low-oxygen niches. In this study we explored the metabolic frame of glutamine (Gln) homeostasis in <i>Spalax</i> skin cells under normoxic and hypoxic conditions and their impacts on the metabolism of rat cells. Targeted metabolomics employing liquid chromatography and mass spectrometry (LC-MS) was used to track the fate of heavy glutamine carbons (<sup>13</sup>C<sub>5</sub> Gln) after 24 h under normoxia or hypoxia (1% O<sub>2</sub>). Our results indicated that large amounts of glutamine-originated carbons were detected as proline (Pro) and hydroxyproline (HPro) in normoxic <i>Spalax</i> cells with a further increase under hypoxia, suggesting a strategy for reduced Gln carbons storage in proteins. The intensity of the flux and the presence of HPro suggests collagen as a candidate protein that is most abundant in animals, and as the primary source of HPro. An increased conversion of αKG to 2 HG that was indicated in hypoxic <i>Spalax</i> cells prevents the degradation of hypoxia-inducible factor 1α (HIF-1α) and, consequently, maintains cytosolic and mitochondrial carbons fluxes that were uncoupled via inhibition of the pyruvate dehydrogenase complex. A strong antioxidant defense in <i>Spalax</i> cells can be attributed, at least in part, to the massive usage of glutamine-derived glutamate for glutathione (GSH) production. The present study uncovers additional strategies that have evolved in this unique mammal to support its hypoxia tolerance, and probably contribute to its cancer resistance, longevity, and healthy aging.
format	article
author	Dmitry Miskevich Anastasia Chaban Maria Dronina Ifat Abramovich Eyal Gottlieb Imad Shams
author_facet	Dmitry Miskevich Anastasia Chaban Maria Dronina Ifat Abramovich Eyal Gottlieb Imad Shams
author_sort	Dmitry Miskevich
title	Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax
title_short	Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax
title_full	Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax
title_fullStr	Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax
title_full_unstemmed	Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax
title_sort	glutamine homeostasis and its role in the adaptive strategies of the blind mole rat, spalax
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e505625c13b8457cbce56f7e3b798404
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Glutamine Homeostasis and Its Role in the Adaptive Strategies of the Blind Mole Rat, Spalax

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