Abstract
The Gansu zokor (Eospalax cansus) is a subterranean rodent species that is unique to China. These creatures inhabit underground burrows with a hypoxia environment. Metabolic energy patterns in subterranean rodents have become a recent focus of research; however, little is known about brain energy metabolism under conditions of hypoxia in this species. The mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) coordinates eukaryotic cell growth and metabolism, and its downstream targets regulate hypoxia inducible factor-1α (HIF-1α) under conditions of hypoxia to induce glycolysis. In this study, we compared the metabolic characteristics of hypoxia-tolerant subterranean Gansu zokors under hypoxic conditions with those of hypoxia-intolerant Sprague-Dawley rats with a similar-sized surface area. We exposed Gansu zokors and rats to hypoxia I (44 h at 10.5% O2) or hypoxia II (6 h at 6.5% O2) and then measured the transcriptional levels of mTORC1 downstream targets, the transcriptional and translational levels of glycolysis-related genes, glucose and fructose levels in plasma and brain, and the activity of key glycolysis-associated enzymes. Under hypoxia, we found that hif-1α transcription was upregulated via the mTORC1/eIF4E pathway to drive glycolysis. Furthermore, Gansu zokor brain exhibited enhanced fructose-driven glycolysis under hypoxia through increased expression of the GLUT5 fructose transporter and ketohexokinase (KHK), in addition to increased KHK enzymatic activity, and utilization of fructose; these changes did not occur in rat. However, glucose-driven glycolysis was enhanced in both Gansu zokor and rat under hypoxia II of 6.5% O2 for 6 h. Overall, our results indicate that on the basis of glucose as the main metabolic substrate, fructose is used to accelerate the supply of energy in Gansu zokor, which mirrors the metabolic responses to hypoxia in this species.
Highlights
Mammals are largely intolerant of hypoxia and their brains exhibit exquisite sensitivity to hypoxia, a few species, such as subterranean rodents, inhabit hypoxic niches and are able to survive hypoxia (Su et al, 2013; Nayak et al, 2016; Grimes et al, 2017; Altwasser et al, 2019; Li et al, 2019; Pamenter et al, 2019; Dong et al, 2020)
We observed that the expression of mtor mRNA was significantly increased in the hypoxia II group (P < 0.01) (Figure 2B), while the expression levels of 4e-bp1 and eif4e, which are downstream genes in the mTORC1 pathway, decreased gradually with as the oxygen concentration was reduced (Figures 2C,D)
Expression of hif-1α mRNA was significantly increased in the hypoxia I group (P < 0.01), with a slight increase in the hypoxia II group (Figure 2E)
Summary
Mammals are largely intolerant of hypoxia and their brains exhibit exquisite sensitivity to hypoxia, a few species, such as subterranean rodents, inhabit hypoxic niches and are able to survive hypoxia (Su et al, 2013; Nayak et al, 2016; Grimes et al, 2017; Altwasser et al, 2019; Li et al, 2019; Pamenter et al, 2019; Dong et al, 2020). The mammalian (or mechanistic) target of rapamycin (mTOR), which is a serine/threonine protein kinase in the PI3K-related kinase (PIKK) family, plays a vital role in energy metabolism and cell growth. It exists in two complexes: mTORC1 and mTORC2 (Saxton and Sabatini, 2017; Yan et al, 2017). In the fructose-driven glycolysis pathway, ketohexokinase (KHK) catalyzes the direct phosphorylation of fructose to form fructose 1-phosphate, bypassing the PFK regulatory block and allowing continued glycolytic flux independent of cellular energy status (Park et al, 2017)
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