Glutamine homeostasis and its role in the adaptive strategies of the blind mole rat, spalax

Dmitry Miskevich, Anastasia Chaban, Maria Dronina, Ifat Abramovich, Eyal Gottlieb, Imad Shams

Research output: Contribution to journalArticlepeer-review


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, Spalax, is an underexplored, underground, hypoxia-tolerant mammalian group which spends its life under sharply fluctuating oxygen levels. Primary Spalax 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 Spalax 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 (13C5 Gln) after 24 h under normoxia or hypoxia (1% O2). Our results indicated that large amounts of glutamine-originated carbons were detected as proline (Pro) and hydroxyproline (HPro) in normoxic Spalax 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 Spalax 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 Spalax 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.

Original languageEnglish
Article number755
Issue number11
StatePublished - 31 Oct 2021

Bibliographical note

Funding Information:
Acknowledgments: This work is supported by the Israel Science Foundation (Grant # 1935/17 to I.S.), John Templeton Foundation (Grant # 53057 to I.S.), and Kadas Family Charitable Foundation. We thank NIH Scientist Emeritus James M. Phang for his valuable advice and Eyal Gottlieb’s laboratory staff for their support and assistance. Special thank for Hanna Shevalye, Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa—for the help in technical manuscript editing.

Funding Information:
Funding: This work was funded by the Israel Science Foundation (Grant #1935/17 to I.S.), John Templeton Foundation (Grant # 53057 to I.S.), and Kadas Family Charitable Foundation (UK).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Adaptation
  • Bioenergetics
  • Glutamine
  • GSH
  • Hypoxia
  • Metabolome
  • Proline cycle

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology


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