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 ZhaoCostas D. Maranas, Martin Wühr, Joshua D. Rabinowitz

Research output: Contribution to journalArticlepeer-review


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. (Figure presented.)

Original languageEnglish (US)
JournalNature chemical biology
StateAccepted/In press - 2024

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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