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

Sara Alam; Ying Gu; Polina Reichert; Jürg Bähler; Snezhana Oliferenko

doi:doi: 10.1016/j.cub.2023.04.046

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

Sara Alam, Ying Gu, Polina Reichert, Jürg Bähler, Snezhana Oliferenko^*

^*Corresponding author for this work

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Abstract

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 Schizosaccharomyces 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 isotopologue distribution analysis, genetics, and physiological experiments. S. japonicus appears to have optimized 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 eukaryotes, illuminating critical adaptations supporting the preferential use of glycolysis over oxidative phosphorylation.

Original language	English
Pages (from-to)	2175-2186.e5
Journal	Current biology : CB
Volume	33
Issue number	11
Early online date	9 May 2023
DOIs	https://doi.org/doi: 10.1016/j.cub.2023.04.046
Publication status	Published - 5 Jun 2023

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@article{35691a4442e643d9aae5dab0f44db845,

title = "Optimisation of energy production and central carbon metabolism in a non-respiring eukaryote",

abstract = "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 Schizosaccharomyces 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 isotopologue distribution analysis, genetics, and physiological experiments. S. japonicus appears to have optimized 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 eukaryotes, illuminating critical adaptations supporting the preferential use of glycolysis over oxidative phosphorylation.",

author = "Sara Alam and Ying Gu and Polina Reichert and J{\"u}rg B{\"a}hler and Snezhana Oliferenko",

note = "Funding Information: We are grateful to the Oliferenko and B{\"a}hler labs for discussions and to M. Yuneva, L. Fets, E. Makeyev, A. Yuen, and E. Pascual Navarro for suggestions on the manuscript. We thank A. Forbes for assistance with generating the pyk1 S. japonicus strain. We are grateful to K. Ishikawa (NCI, U.S.) for the S. japonicus var versatilis, and to M. Bochman (Indiana University, U.S.) and M. Kawamukai (Shimane University, Japan) for S. japonicus wild isolates. Many thanks to J.I. MacRae and J. Ellis (Crick Metabolomics STP) for invaluable training and assistance. S.A. was supported by the Crick-King's PhD scholarship. Work in S.O.{\textquoteright}s lab was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC0102), by the UK Medical Research Council (CC0102), and by the Wellcome Trust (CC0102). This research was funded, in whole or in part, by the Wellcome Trust (103741/Z/14/Z; 220790/Z/20/Z) and BBSRC (BB/T000481/1) grants awarded to S.O. For the purpose of open access, the author has applied a CC-BY public copyright license to any author-accepted manuscript version arising from this submission. S.A. conceived, performed, and interpreted experiments, generated strains, analyzed data, and co-wrote the manuscript; Y.G. generated gpd1Δ and mdh1Δ S. pombe and S. japonicus strains, designed pyk1-A343T S. japonicus, and edited the manuscript; P.R. assisted with analysis of metabolomics experiments and edited the manuscript; J.B. interpreted experiments and edited the manuscript; S.O. conceived and interpreted experiments, and co-wrote and edited the manuscript. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. Funding Information: We are grateful to the Oliferenko and B{\"a}hler labs for discussions and to M. Yuneva, L. Fets, E. Makeyev, A. Yuen, and E. Pascual Navarro for suggestions on the manuscript. We thank A. Forbes for assistance with generating the pyk1 S. japonicus strain. We are grateful to K. Ishikawa (NCI, U.S.) for the S. japonicus var versatilis, and to M. Bochman (Indiana University, U.S.) and M. Kawamukai (Shimane University, Japan) for S. japonicus wild isolates. Many thanks to J.I. MacRae and J. Ellis (Crick Metabolomics STP) for invaluable training and assistance. S.A. was supported by the Crick-King{\textquoteright}s PhD scholarship . Work in S.O.{\textquoteright}s lab was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( CC0102 ), by the UK Medical Research Council ( CC0102 ), and by the Wellcome Trust ( CC0102 ). This research was funded, in whole or in part, by the Wellcome Trust ( 103741/Z/14/Z ; 220790/Z/20/Z ) and BBSRC ( BB/T000481/1 ) grants awarded to S.O. For the purpose of open access, the author has applied a CC-BY public copyright license to any author-accepted manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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doi = "doi: 10.1016/j.cub.2023.04.046",

language = "English",

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T1 - Optimisation of energy production and central carbon metabolism in a non-respiring eukaryote

AU - Alam, Sara

AU - Gu, Ying

AU - Reichert, Polina

AU - Bähler, Jürg

AU - Oliferenko, Snezhana

N1 - Funding Information: We are grateful to the Oliferenko and Bähler labs for discussions and to M. Yuneva, L. Fets, E. Makeyev, A. Yuen, and E. Pascual Navarro for suggestions on the manuscript. We thank A. Forbes for assistance with generating the pyk1 S. japonicus strain. We are grateful to K. Ishikawa (NCI, U.S.) for the S. japonicus var versatilis, and to M. Bochman (Indiana University, U.S.) and M. Kawamukai (Shimane University, Japan) for S. japonicus wild isolates. Many thanks to J.I. MacRae and J. Ellis (Crick Metabolomics STP) for invaluable training and assistance. S.A. was supported by the Crick-King's PhD scholarship. Work in S.O.’s lab was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC0102), by the UK Medical Research Council (CC0102), and by the Wellcome Trust (CC0102). This research was funded, in whole or in part, by the Wellcome Trust (103741/Z/14/Z; 220790/Z/20/Z) and BBSRC (BB/T000481/1) grants awarded to S.O. For the purpose of open access, the author has applied a CC-BY public copyright license to any author-accepted manuscript version arising from this submission. S.A. conceived, performed, and interpreted experiments, generated strains, analyzed data, and co-wrote the manuscript; Y.G. generated gpd1Δ and mdh1Δ S. pombe and S. japonicus strains, designed pyk1-A343T S. japonicus, and edited the manuscript; P.R. assisted with analysis of metabolomics experiments and edited the manuscript; J.B. interpreted experiments and edited the manuscript; S.O. conceived and interpreted experiments, and co-wrote and edited the manuscript. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. Funding Information: We are grateful to the Oliferenko and Bähler labs for discussions and to M. Yuneva, L. Fets, E. Makeyev, A. Yuen, and E. Pascual Navarro for suggestions on the manuscript. We thank A. Forbes for assistance with generating the pyk1 S. japonicus strain. We are grateful to K. Ishikawa (NCI, U.S.) for the S. japonicus var versatilis, and to M. Bochman (Indiana University, U.S.) and M. Kawamukai (Shimane University, Japan) for S. japonicus wild isolates. Many thanks to J.I. MacRae and J. Ellis (Crick Metabolomics STP) for invaluable training and assistance. S.A. was supported by the Crick-King’s PhD scholarship . Work in S.O.’s lab was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( CC0102 ), by the UK Medical Research Council ( CC0102 ), and by the Wellcome Trust ( CC0102 ). This research was funded, in whole or in part, by the Wellcome Trust ( 103741/Z/14/Z ; 220790/Z/20/Z ) and BBSRC ( BB/T000481/1 ) grants awarded to S.O. For the purpose of open access, the author has applied a CC-BY public copyright license to any author-accepted manuscript version arising from this submission. Publisher Copyright: © 2023 The Author(s)

PY - 2023/6/5

Y1 - 2023/6/5

N2 - 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 Schizosaccharomyces 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 isotopologue distribution analysis, genetics, and physiological experiments. S. japonicus appears to have optimized 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 eukaryotes, illuminating critical adaptations supporting the preferential use of glycolysis over oxidative phosphorylation.

AB - 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 Schizosaccharomyces 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 isotopologue distribution analysis, genetics, and physiological experiments. S. japonicus appears to have optimized 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 eukaryotes, illuminating critical adaptations supporting the preferential use of glycolysis over oxidative phosphorylation.

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DO - doi: 10.1016/j.cub.2023.04.046

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JO - Current biology : CB

JF - Current biology : CB

IS - 11

ER -

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

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