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Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat

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Science  21 Apr 2017:
Vol. 356, Issue 6335, pp. 307-311
DOI: 10.1126/science.aab3896
  • Fig. 1 Extreme hypoxia and anoxia resistance in naked mole-rats.

    (A) Mouse (top) and naked mole-rat (bottom). (B and C) Time breathing in 5% O2 (cut-off time: 300 min) (B) or in anoxia (0% O2, cut-off: last breath) (C). Naked mole-rats always survived; mice did not (n = 4 to 6 animals per group, **P < 0.01; Fisher’s exact test). Survival rate after exposure to 0% O2 was significantly different between species (**P < 0.001; Student’s t test). (D) Respiration and (E) heart rate during 18 min of 0% O2 (n = 4 animals per species). (F) Survival plotted against duration of complete anoxia for mice and naked mole-rats (n = 3 to 12 animals per species and time point). (G) Left ventricular developed pressure (LVDP) measured in isolated hearts after a 30-min period of hypoxia induced by stopping the coronary flow. Results were compared with baseline values (**P < 0.01; two-way ANOVA with Bonferroni post hoc test; n = 3 animals per group). Mean ± SEM (error bars).

  • Fig. 2 Fructose and sucrose in anoxia-exposed naked mole-rats.

    (A) Experimental design. (B and C) Metabolic intermediates were quantified using GC-MS. P, phosphate; PEP, phosphoenolpyruvate. (C) Increased fructose in anoxia-exposed naked mole-rat kidneys (chromatograms of species triplicates). A.U., arbitrary units. (D) Quantification of fructose, sucrose, and fructose-1-phosphate (F-1-P) levels (concentrations or peak intensity) before and after anoxia. N, normoxia; A, anoxia; ND, not detected (n = 3 animals per species; error bars indicate SEM; *P < 0.05; **P < 0.01, ***P < 0.001 using a two-way ANOVA with Bonferroni’s post hoc test). (E) Expression level of GLUT5 mRNA transcripts in mouse and naked mole-rat tissues evaluated by qPCR (n = 3 animals per species; error bars indicate SEM; *P < 0.05; ***P < 0.001; two-tailed unpaired t test). (F) Western blot for GLUT5 in brain and heart tissues from both species (three biological replicates). GAPDH, glyceraldehyde-3-phosphate dehydrogenase. (G) Bar graphs showing results of qPCR designed to detect KHK-C and KHK-A isoforms (n = 3 animals per species; error bars indicate SEM; *P < 0.05; **P < 0.01; two-tailed unpaired t test).

  • Fig. 3 Role of fructose in maintaining brain and heart function in naked mole-rats.

    (A) Field excitatory postsynaptic potentials (fEPSPs) were recorded in hippocampal brain slices. fEPSP amplitude declined to zero when fructose replaced glucose in mouse slices but was maintained in naked mole-rat slices. Example traces are shown at left below the diagram [scale bar, 1 mV (vertical) and 10 msec (horizontal)]. A two-way repeated measures ANOVA with Bonferroni post hoc test (**P < 0.01) revealed significant effects for species (F1,4 = 19.8, P = 0.0114) and time (F99,396 = 43.43, ***P < 0.0001). The interaction between group and time was also significant (F99,396 = 6.16, ***P < 0.0001). n = 3 animals per species; error bars indicate SEM. (B) LVDP was measured for isolated hearts after glucose replacement with fructose. Naked mole-rat LVDP was maintained but mouse LVDP declined, especially after a second exposure to fructose. Statistical significance was calculated with a two-way ANOVA. Error bars indicate SEM.

  • Fig. 4 Metabolic flux of fructose metabolites in the hypoxic brain.

    (A) Glycolysis pathway. Glucose enters the brain via GLUT1 and is converted via phosphofructokinase (PFK). Fructose enters cells via GLUT5 and is phosphorylated by ketohexokinase (KHK) to fructose-1-phosphate (F1P) at a much higher efficiency than by hexokinase (HK). F1P is directly metabolized into trioses via aldolase B (ALDOB) or aldolase C (ALDOC), bypassing feedback inhibition. GA3P, glyceraldehyde-3-phosphate; TCA, tricarboxylic acid. (B to H) Incorporation of 13C-fructose–derived carbons was measured during acute hypoxia (~5% O2) at 0, 5, 15, and 30 min. Labeled quantities of the different metabolic intermediates (in blue) are shown. (B) Dihydroxyacetone phosphate (DHAP). (C) Phosphoglyceric acid (3PGA). (D) Pyruvate. (E) Citrate. (F) Succinate. (G) Lactate. (H) Glycerol-3-phosphate (Glyc-3-P). n = 3 animals per species; error bars indicate SEM; *P < 0.05; **P < 0.01, ***P < 0.001 using a two-way ANOVA with a Bonferroni’s post hoc test.

Supplementary Materials

  • Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat

    Thomas J. Park, Jane Reznick, Bethany L. Peterson, Gregory Blass, Damir Omerbašić, Nigel C. Bennett, P. Henning J. L. Kuich, Christin Zasada, Brigitte M. Browe, Wiebke Hamann, Daniel T. Applegate, Michael H. Radke, Tetiana Kosten, Heike Lutermann, Victoria Gavaghan, Ole Eigenbrod, Valérie Bégay, Vince G. Amoroso, Vidya Govind, Richard D. Minshall, Ewan St. J. Smith, John Larson, Michael Gotthardt, Stefan Kempa, Gary R. Lewin

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Figs. S1 to S10
    • Table S1
    • References
    • Caption for Data S1
    Table S1
    Excel Datasheet containing mean intensity values for metabolites measured.

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