Fig. 5. The UPR induces rewiring of cellular metabolism.
a Schematic depiction of the UPR-induced enzymatic pathway that diverts intermediary metabolites from glycolysis to fuel mitochondrial one-carbon metabolism via serine biosynthesis. PHGDH: phosphoglycerate dehydrogenase, PSAT1: phosphoserine aminotransferase 1, PSPH: phosphoserine phosphatase, SHMT2: serine hydroxymethyltransferase 2, MTHFD2: bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, ALDH1L2: aldehyde dehydrogenase 1 family member L2, THF: tetrahydrofolate, 5,10-meTHF: 5,10-methylene THF. b Analysis of the redox status of the nicotinamide adenine dinucleotide phosphate pool in LN-308 cells after 24 h of control treatment with DMSO (yellow bar), or treatment with TM (green bar). P-value: 0.0003. c Analysis of the cellular concentration of the amino acids serine, proline, and glycine after induction of the UPR (green bars) relative to control treatment with DMSO (yellow bars). Fold-increase values after 24 h of treatment are displayed at the top of each panel. d Analysis of the isotope distribution of serine and glycine 24 h after application of a metabolically labeled serine tracer. Cells were either control treated with DMSO (yellow bars) or stimulated for 24 h with TM (green bars). P-values: Serine M + 7: 0.590, Glycine M + 4: 0.001. e Analysis of the contribution of mitochondrial folate metabolism to thymidylate synthesis in control-treated LN-308 cells (yellow bars), or after induction of the UPR with TM (green bars). The isotope distribution of dTTP was analyzed 24 h after administration of a metabolically labeled serine tracer. P-values: dTTP M + 0: 0.713, dTTP M + 2: 0.038, and dTTP M + 3: 0.002. All data are represented as mean ± SD of three (c–e) or four (b) biologically independent experiments. A Student’s t-test was used for the statistical testing with the following parameters: two-sided, true variance equality and confidence level at 0.95. No adjustment for multiple comparisons was made. n.s. not significant P > 0.05, *P < 0.05, ***P < 0.005. Source data are provided as a Source Data file.