Optimization of energy production and central carbon metabolism in a non-respiring eukaryote

Most eukaryotes respire oxygen, using it to generate biomass and energy. However, a few organisms have lost the capacity to respire. Understanding how they manage biomass and energy production may illuminate the critical points at which respiration feeds into central carbon metabolism and explain possible routes to its optimization. Here, we use two related fission yeasts, Schizosaccharomyces pombe and Schizosaccharomy-ces japonicus, as a comparative model system. We show that although S. japonicus does not respire oxygen, unlike S. pombe, it is capable of efficient NADH oxidation, amino acid synthesis, and ATP generation. We probe possible optimization strategies through the use of stable isotope tracing metabolomics, mass isoto-pologue distribution analysis, genetics, and physiological experiments. S. japonicus appears to have opti-mized cytosolic NADH oxidation via glycerol-3-phosphate synthesis. It runs a fully bifurcated TCA pathway, sustaining amino acid production. Finally, we propose that it has optimized glycolysis to maintain high ATP/ ADP ratio, in part by using the pentose phosphate pathway as a glycolytic shunt, reducing allosteric inhibition of glycolysis and supporting biomass generation. By comparing two related organisms with vastly different metabolic strategies, our work highlights the versatility and plasticity of central carbon metabolism in eukary-otes, illuminating critical adaptations supporting the preferential use of glycolysis over oxidative phosphor-ylation.

Automated summary

Most eukaryotes rely on oxygen respiration for biomass and energy production, but some organisms have lost this capacity. Studying how these organisms manage biomass and energy production can provide insights into the optimization of respiration and central carbon metabolism. In this study, two related fission yeasts, S. pombe and S. japonicus, were compared. It was found that S. japonicus, which does not respire oxygen, has optimized NADH oxidation, amino acid synthesis, and ATP generation through glycerol-3-phosphate synthesis, bifurcated TCA pathway, and optimized glycolysis. This research highlights the versatility and plasticity of central carbon metabolism in eukaryotes and the adaptations that support the preferential use of glycolysis over oxidative phosphorylation.