Abstract
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.
Highlights
Glucose (Glc) and glutamine (Gln) are two central metabolic nutrients that maintain cellular metabolism
In the present study we aimed to address Gln homeostasis in primary skin cells that were harvested from Spalax that were captured in the wild, in comparison with primary skin cells that were taken from a laboratory rat (Rattus norvegicus) under regular oxygen content (~20% O2, normoxia) and under hypoxia (1% O2)
Oxygen is the keystone of this system; Glc and Gln starvation can be rescued via gluconeogenesis, glycogenosis, or proteolysis, whereas hypoxia can be tolerated only for short periods
Summary
Glucose (Glc) and glutamine (Gln) are two central metabolic nutrients that maintain cellular metabolism. Replenishing of the TCA cycle with Gln-derived carbons, termed Gln anaplerosis (Gln-An), is the only known way to maintain appropriate levels of Citr and anabolic processes in case of a Glc-derived Ac-CoA deficit [8]. Gln-An can furnish the cells’ necessities by several ways, e.g., conversion to malate (Mal) and further to pyruvate (Pyr) via a malic enzyme (ME) reaction thereby maintaining NADPH+ level. Pyr can be converted to lactate (Lact) for maintaining the cytosolic NAD+ pool and is released outside, otherwise, returns to the TCA cycle via pyruvate dehydrogenase (PDH) for producing Ac-CoA. The metabolism of de novo produced Pro and hydroxyproline (HPro) (as a product of collagen degradation) is suggested as an alternative way for canonical bioenergetics and signaling under hypoxia and starvation conditions for tumor cells. Further investigations of Pro and HPro metabolism shed light on its antioxidant [17], signaling [18,19,20,21], and bioenergetics [22,23] roles in the cellular homeostasis under stress condition
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