Mitochondrial ATP generation is more proteome efficient than glycolysis

Yihui Shen; Hoang V Dinh; Edward R Cruz; Zihong Chen; Caroline R Bartman; Tianxia Xiao; Catherine M Call; Rolf-Peter Ryseck; Jimmy Pratas; Daniel Weilandt; Heide Baron; Arjuna Subramanian; Zia Fatma; Zong-Yen Wu; Sudharsan Dwaraknath; John I Hendry; Vinh G Tran; Lifeng Yang; Yasuo Yoshikuni; Huimin Zhao; Costas D Maranas; Martin Wühr; Joshua D Rabinowitz

doi:10.1038/s41589-024-01571-y

Mitochondrial ATP generation is more proteome efficient than glycolysis

Nat Chem Biol. 2024 Mar 6. doi: 10.1038/s41589-024-01571-y. Online ahead of print.

Authors

Yihui Shen^{1

2}, Hoang V Dinh³, Edward R Cruz^{2

4}, Zihong Chen^{1

2

5}, Caroline R Bartman^{1

2

5}, Tianxia Xiao^{1

2}, Catherine M Call^{1

2}, Rolf-Peter Ryseck^{1

2}, Jimmy Pratas^{1

2}, Daniel Weilandt^{1

2}, Heide Baron², Arjuna Subramanian², Zia Fatma^{6

7}, Zong-Yen Wu⁸, Sudharsan Dwaraknath⁸, John I Hendry³, Vinh G Tran^{6

7}, Lifeng Yang^{1

2}, Yasuo Yoshikuni⁸, Huimin Zhao^{6

7}, Costas D Maranas³, Martin Wühr^{9

10}, Joshua D Rabinowitz^{11

12

13}

Affiliations

¹ Department of Chemistry, Princeton University, Princeton, NJ, USA.
² Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
³ Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA.
⁴ Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
⁵ Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA.
⁶ Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
⁷ Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
⁸ US Department of Energy Joint Genome Institute and Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
⁹ Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA. wuhr@princeton.edu.
¹⁰ Department of Molecular Biology, Princeton University, Princeton, NJ, USA. wuhr@princeton.edu.
¹¹ Department of Chemistry, Princeton University, Princeton, NJ, USA. joshr@princeton.edu.
¹² Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA. joshr@princeton.edu.
¹³ Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ, USA. joshr@princeton.edu.

PMID: 38448734
DOI: 10.1038/s41589-024-01571-y

Abstract

Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although 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 (that is, 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 yeast strains, 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 promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. We accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

Grants and funding

R35 GM128813/GM/NIGMS NIH HHS/United States