Abstract
Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.
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Data availability
MS data have been deposited in ProteomeXchange with the primary accession code PXD056351 (http://proteomecentral.proteomexchange.org)50,51. The human cancer data were derived from the TCGA Research Network at http://cancergenome.nih.gov/. The dataset derived from this resource that supports the findings of this study is available in Supplementary Table 1. All other data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank X. Liu (Metabolomics Facility at Tsinghua University Branch of China National Center for Protein Sciences, China) for technical help. This work was supported by the National Natural Science Foundation of China (82325038 and 82030093 to B.L.) and China Postdoctoral Science Foundation (GZB20230454 to R.Y.)
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B.L. conceived the study and designed experiments; X.Z. and R.Y. performed experiments; Q.C. prepared some constructs and cell lines; Z.G., P.H., X.L., C.B. and Z.L. collected and analysed data; L.Q., Y.F. and J.N. provided conceptual advice and gave technical support; B.L. wrote the manuscript; X.Z. and R.Y. edited the manuscript.
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Extended data
Extended Data Fig. 1 Hypoxia promotes glycerol 3-phosphate biosynthesis.
a, The relative abundance of metabolites of glycolysis in HeLa cells under normoxia, hypoxia, or antimycin A (AntA, 2 μM) treatment for 8 h. b, The relative abundance of glycerol 3-phosphate and its precursor DHAP in HeLa cells under normoxia, hypoxia, or AntA (2 μM) treatment for 8 h. c, Isotopomer tracing analysis of glycerol 3-phosphate biosynthesis in HeLa cells cultured with 13C6-glucose (25 mM) or 13C5-glutamine (2 mM) for 8 h. d,e, Using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to modify the hydroxyl groups of glycerol and glycerol 3-phosphate and detect them by gas chromatography-mass spectrometry (GC-MS). f, Isotopomer tracing analysis of excreted glycerol in HeLa cells cultured with 13C6-glucose (25 mM) under normoxia or hypoxia for 8 h. g,h, The levels of excreted glycerol determined by GC-MS or a liquid sample glycerol assay kit in HeLa cells cultured under normoxia and hypoxia for 24 h. Values are shown as mean ± SD, n = 3 biologically independent samples, two-tailed Student’s t-tests.
Extended Data Fig. 2 Hypoxia promotes glucose uptake and lactate excretion.
a, Glucose uptake of several cell types including tumor cells and endothelial cells cultured under normoxia and hypoxia for 24 h. b, Lactate excretion of several cell types including tumor cells and endothelial cells cultured under normoxia and hypoxia for 24 h. c-h, The glycerol excretion, glucose uptake, and lactate excretion in HeLa and A549 cells cultured under hypoxia as indicated. i, Western blot analysis of PGP, GPD1, GPD1L, GPD2, ALDOA, ALDOB, TPI1, and β-Actin expression in different cells as indicated. j, Immunoblot verification of GPD2 knockout in HeLa and A549 cells. k, Effects of GPD2 knockout on glycerol excretion of HeLa cells cultured under normoxia and hypoxia for 24 h. Values are shown as mean ± SD, n = 3 biologically independent samples (a-h, k), two-tailed Student’s t-tests. In i, data are verified in two replicates with similar results.
Extended Data Fig. 3 Effects of glycerol excretion on cell viability under hypoxia.
a, Effects of GPD1 and/or GPD1L knockout on colony formation in HeLa cells cultured for 10 days. b, Effects of PGP knockout and PGP re-expression on colony formation in HeLa cells cultured for 10 days. c, Effects of PGP knockout and PGP re-expression on glycerol excretion of A549 cells cultured under normoxia and hypoxia for 24 h. d, Effects of PGP knockout and PGP re-expression on cell viability of A549 cells cultured under normoxia and hypoxia for 48 h. e, Effects of PGP knockout and PGP re-expression on colony formation of A549 cells cultured for 10 days. f, Effects of PGP knockout and PGP re-expression on glycerol excretion of HepG2 cells cultured under normoxia and hypoxia for 24 h. g, Effects of PGP knockout and PGP re-expression on cell viability of HepG2 cells cultured under normoxia and hypoxia for 48 h. h, Effects of PGP knockout and PGP re-expression on colony formation of HepG2 cells cultured for 10 days. i, Analysis of the mRNA levels of aquaporins (AQPs) based on the data from Cancer Cell Line Encyclopedia (CCLE). j, Effects of AQP3 knockout on glycerol excretion and cell viability of HeLa and A549 cells cultured under normoxia and hypoxia for 24 h (glycerol excretion) or 72 h (cell proliferation). Values are shown as mean ± SD, n = 3 biologically independent samples, two-tailed Student’s t-tests.
Extended Data Fig. 4 Effects of NADH accumulation on glucose uptake, lactate excretion, and glycerol excretion.
a, Immunoblot verification of CHOP and ATF4 activation in GPD1/GPD1L DKO, PGP KO and PGP re-expression HeLa cells cultured under normoxia or hypoxia for 24 h. b, Effects of different concentrations of αKB on glucose uptake and lactate excretion of HeLa, A549, and HepG2 cells under hypoxia for 24 h. c, Effects of different concentrations of LDHi on glucose uptake and lactate excretion of HeLa, A549, and HepG2 cells under normoxia for 24 h. d, Glucose uptake and lactate excretion of HeLa, A549 and HepG2 cells cultured as indicated for 24 h. e, Effects of different concentrations of SC-26196 on the ratios of NADH/NAD+, glycerol excretion, glucose uptake, and lactate excretion of HeLa, A549, and HepG2 cells cultured under normoxia for 8 h (NADH/NAD+ ratios) or 24 h (glycerol excretion, glucose uptake, and lactate excretion). f, Effects of αKB (2 mM) on cell viability of HeLa PGP KO or GPD1/GPD1L DKO cells cultured under hypoxia for 48 h. Values are shown as mean ± SD, n = 3 biologically independent samples (b-f), two-tailed Student’s t-tests. In a, data are verified in three replicates with similar results.
Extended Data Fig. 5 Effects of glucose uptake on glycerol excretion.
a, Western blots for the expression of PKM2, LDHA, GAPDH, and β-Actin in HeLa and A549 cells treated with normoxia, hypoxia, or AntA (2 μM) for 24 h. b, Effects of HIF2α knockdown on glycerol excretion of HeLa and A549 cells cultured under hypoxia for 24 h. c, Immunoblot verification of GLUT1 knockdown in HeLa and A549 cells. d-f, Effects of GLUT1 knockdown on glucose uptake, lactate excretion, and glycerol excretion of HeLa and A549 cells cultured under normoxia and hypoxia for 24 h. g, Immunoblot verification of GLUT1 over-expression in HeLa and A549 cells. h-j, Effects of GLUT1 over-expression on glucose uptake, lactate excretion, and glycerol excretion of HeLa and A549 cells cultured under normoxia, hypoxia, or AntA (2 μM) treatment for 24 h. Values are shown as mean ± SD, n = 3 biologically independent samples (b, d-f, h-j), two-tailed Student’s t-tests. In a, data are verified in two replicates with similar results.
Extended Data Fig. 6 Effects of PGP, GPD1, or GPD1L over-expression on glucose uptake, lactate excretion, glycerol excretion, and cell growth.
a, Effects of PGP, GPD1, or GPD1L over-expression on glucose uptake and lactate excretion of HeLa and A549 cells cultured under normoxia and hypoxia for 24 h. b, Immunoblot verification of LKB1 expression in HeLa, A549, SK-Hep-1, and HCC-LM3 cells. c, Immunoblot verification of over-expression of PGP, GPD1L, or GPD1 in SK-Hep-1 and HCC-LM3 cells. d, Effects of PGP, GPD1, or GPD1L over-expression on glycerol excretion of SK-Hep-1 and HCC-LM3 cells cultured under normoxia and hypoxia for 24 h. e, Effects of PGP, GPD1, or GPD1L over-expression on cell viability of SK-Hep-1 and HCC-LM3 cells cultured with low nutrient medium (10% fetal bovine serum medium containing 2 mM of glucose, without glutamine and pyruvate) under normoxia and hypoxia for 8 h. f, Effects of PGP, GPD1, or GPD1L over-expression on cell viability of SK-Hep-1 and HCC-LM3 cells cultured in normal or nutrient-deprived media. Nutrient-deprived media contained 10% fetal bovine serum but without glucose, glutamine, and pyruvate. g, Effects of PGP, GPD1L, or GPD1 over-expression on AMPK activation in SK-Hep-1 and HCC-LM3 cells cultured in nutrient-deprived medium. h, Tumor formation ability in nude mice of SK-Hep-1 cells with PGP, GPD1, or GPD1L over-expression. Values are shown as mean ± SD, n = 3 biologically independent samples (a,d,e,f) or n = 5 biologically independent mice (h), two-tailed Student’s t-tests. In g, data are verified in two replicates with similar results.
Extended Data Fig. 7 Effects of aldolases and AMPK on glucose uptake, lactate excretion, and glycerol excretion.
a, Effects of ALDOA over-expression on glycerol excretion, glucose uptake, and lactate excretion of HeLa and A549 cells cultured under normoxia and hypoxia for 24 h. b, Effects of ALDOC over-expression on glycerol excretion, glucose uptake, and lactate excretion of HeLa and A549 cells cultured under normoxia and hypoxia for 24 h. c, Effects of A769662 treatment on glycerol excretion, glucose uptake, and lactate excretion of A549, SK-Hep-1, and HCC-LM3 cells cultured under normoxia and hypoxia for 12 h. d, Effects of Compound C on AMPK pathway in HeLa cells. e, Effects of Compound C on glycerol excretion, glucose uptake, and lactate excretion of HeLa and A549 cells cultured under normoxia and hypoxia for 12 h. f, Effects of AMPKα knockdown and AMPKα1 re-expression on glycerol excretion, glucose uptake, and lactate excretion of A549 cells cultured under normoxia and hypoxia for 24 h. g. Immunoprecipitation (IP) analysis of the interaction between endogenous ALDOB, GPD1 and GPD1L in HepG2 cells with anti-ADLOB antibody. Rabbit IgG was used as a negative control. WCL, whole-cell lysate. pALDOB T245, AMPK, pAMPK T172, ACC1 and pACC1 S79 were also blotted. Values are shown as mean ± SD, n = 3 biologically independent samples (a-c, e-f), two-tailed Student’s t-tests. In d,g, data are verified in two replicates with similar results.
Extended Data Fig. 8 Inactivation of ADLOB by AMPK-mediated phosphorylation.
a, HEK293T cells were transfected with vector, Flag-GPD1, or Flag-GPD1L plasmids, and then cultured under normoxia or hypoxia for 8 h. IP assays were performed using anti-FLAG affinity M2 beads followed by immunoblotting for the phosphorylation of GPD1 or GPD1L. b, Mass spectrometry was used to detect the phosphorylation site of ALDOB in HeLa cells after treatment with A769662 for 8 h. c, Conservation of the phosphorylation site in ALDOB among different species. Amino acid residues around Thr245 are shown. d, The activity of GST-ALDOB-WT, T245A, and T245D mutants purified from an E. coli expression system incubated with or without active AMPK as indicated. Values are shown as mean ± SD, data are verified in two replicates with similar results (a) and n = 3 biologically independent samples (d).
Extended Data Fig. 9 The trade-off regulation between reductive stress and energy stress.
a, Effects of αKB and LbNOX on AMPK activation of A549 cells cultured under respiratory chain inhibition or hypoxia for 24 h. αKB, 2 mM; Dox, 0.1 μg/mL. b,c, Effects of αKB and LbNOX on cellular NADH/NAD+ ratio (b) and ATP/AMP ratio (c) of A549 cells cultured under respiratory chain inhibition or hypoxia for 24 h. αKB, 2 mM; Dox, 0.1 μg/mL. d, Effects of Torin-1 (0.1 μM) and Rapamycin (1 μM) on AMPK activation of A549 cells cultured under respiratory chain inhibition or hypoxia for 24 h. e,f, Effects of Torin-1 (0.1 μM) and Rapamycin (1 μM) on cellular NADH/NAD+ ratio (e) and ATP/AMP ratio (f) of A549 cells cultured under respiratory chain inhibition or hypoxia for 24 h. g, Effects of Compound C (2 μM) on cell death of A549 cells cultured in nutrient-deprived medium under respiratory chain inhibition or hypoxia for 12 h. h, Immunoblot verification of AMPKα knockout and AMPKα re-expression in HeLa cells. i, The effect of metformin (100 mg/kg/day, i.g.) or Compound C (20 mg/kg/day, i.p.) treatment alone or in combination on tumor formation ability in nude mice of HeLa cells. Metformin (Metf, 4 mM) and Ant A (2 μM) were used. Values are shown as mean ± SD, n = 3 biologically independent samples (b,c,e,f,g) or n = 6 biologically independent mice (i), two way ANOVA (i), and two-tailed Student’s t-tests for others. In a,d, data are verified in two replicates with similar results.
Extended Data Fig. 10 The working model for trade-off between reductive stress and energy stress.
a, Schematic diagram illustrating hypoxic regulation of glycerol biosynthesis. Hypoxia promotes glycerol biosynthesis and excretion by inducing NADH accumulation and glucose uptake. Glycerol biosynthesis consumes NADH to reduce reductive stress, but this process is accompanied by ATP consumption and thus may potentially provoke an energy crisis. Cells have evolved a negative feedback loop to suppress glycerol synthesis through AMPK-mediated phosphorylation of ALDOB. b, The trade-off regulation between reductive stress and energy stress. Reductive stress induced by hypoxia or ETC inhibition primarily contributes to energy stress and AMPK activation. To alleviate reductive stress, some metabolic pathways are promoted to consume NADH, along with ATP. In turn, the activated AMPK negatively regulates these metabolic reactions to prevent catastrophic energy depletion.
Supplementary information
Supplementary Table 1
Survival P-value analysis based on TCGA datasets.
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Zhai, X., Yang, R., Chu, Q. et al. AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress. Nat Cell Biol 27, 141–153 (2025). https://doi.org/10.1038/s41556-024-01549-x
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DOI: https://doi.org/10.1038/s41556-024-01549-x
