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Large enrichments in fatty acid ²H/¹H ratios distinguish respiration from aerobic fermentation in yeast Saccharomyces cerevisiae.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 5/14/2024, Vol. 121 Issue 20, p1-9, 30p
- Publication Year :
- 2024
-
Abstract
- Shifts in the hydrogen stable isotopic composition (²H/¹H ratio) of lipids relative to water (lipid/water ²H-fractionation) at natural abundances reflect different sources of the central cellular reductant, NADPH, in bacteria. Here, we demonstrate that lipid/water ²H-fractionation (²ε<subscript>fattyacid/water</subscript>) can also constrain the relative importance of key NADPH pathways in eukaryotes. We used the metabolically flexible yeast Saccharomyces cerevisiae, a microbial model for respiratory and fermentative metabolism in industry and medicine, to investigate ²ε<subscript>fattyacid/water</subscript>. In chemostats, fatty acids from glycerol-respiring cells were >550‰ ²H-enriched compared to those from cells aerobically fermenting sugars via overflow metabolism, a hallmark feature in cancer. Faster growth decreased ²H/¹H ratios, particularly in glycerol-respiring cells by 200%. Variations in the activities and kinetic isotope effects among NADP<superscript>+</superscript>-reducing enzymes indicate cytosolic NADPH supply as the primary control on ²ε<subscript>fattyacid/water</subscript>. Contributions of cytosolic isocitrate dehydrogenase (cIDH) to NAPDH production drive large ²H-enrichments with substrate metabolism (cIDH is absent during fermentation but contributes up to 20 percent NAPDH during respiration) and slower growth on glycerol (11 percent more NADPH from cIDH). Shifts in NADPH demand associated with cellular lipid abundance explain smaller ²ε<subscript>fattyacid/water</subscript> variations (<30%) with growth rate during fermentation. Consistent with these results, tests of murine liver cells had ²H-enriched lipids from slower-growing, healthy respiring cells relative to fast-growing, fermenting hepatocellular carcinoma. Our findings point to the broad potential of lipid ²H/¹H ratios as a passive natural tracker of eukaryotic metabolism with applications to distinguish health and disease, complementing studies that rely on complex isotope-tracer addition methods. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 121
- Issue :
- 20
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 177440326
- Full Text :
- https://doi.org/10.1073/pnas.2310771121