DOE OSTI · 3423445
Data for Mitochondrial ATP Generation is More Proteome Efficient than Glycolysis
Abstract
Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.
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Shen, Yihui [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA] (ORCID:0000000184906413), Dinh, Hoang [Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA] (ORCID:000000023861357X), Cruz, Edward [Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Molecular Biology, Princeton University, Princeton, NJ, USA] (ORCID:0000000164541461), Chen, Zihong [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA] (ORCID:0000000215541649), Bartman, Caroline [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA] (ORCID:0000000221476003), Xiao, Tianxia [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA] (ORCID:0000000323247949), Call, Catherine [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA], Ryseck, Rolf-Peter [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA], Pratas, Jimmy [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA], Weilandt, Daniel Robert [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA] (ORCID:0000000205568485), Baron, Heide [Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA], Subramanian, Arjuna [Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA], Fatma, Zia [Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA], Wu, Zong-Yen [US Department of Energy Joint Genome Institute and Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA], Dwaraknath, Sudharsan [US Department of Energy Joint Genome Institute and Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA], Hendry, John [Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA], Tran, Vinh [Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA] (ORCID:0000000289392527), Yang, Lifeng [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA], Yoshikuni, Yasuo [US Department of Energy Joint Genome Institute and Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA] (ORCID:000000028372640X), Zhao, Huimin [Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA; DOE Center for Advanced Bioenergy and Bioproducts Innovation, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA] (ORCID:0000000290696739), Maranas, Costas [Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA; DOE Center for Advanced Bioenergy and Bioproducts Innovation, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA] (ORCID:0000000215081398), Wuhr, Martin [Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Department of Molecular Biology, Princeton University, Princeton, NJ, USA] (ORCID:0000000202448947), Rabinowitz, Joshua [Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA; DOE Center for Advanced Bioenergy and Bioproducts Innovation, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA] (ORCID:0000000212474727). 2026-07-23. Data for Mitochondrial ATP Generation is More Proteome Efficient than Glycolysis. https://doi.org/10.13012/b2idb-7981190_v1
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