Abstract
Cells balance glycolysis with respiration to support their metabolic needs in different environmental or physiological contexts. With abundant glucose, many cells prefer to grow by aerobic glycolysis or fermentation. Using 161 natural isolates of fission yeast, we investigated the genetic basis and phenotypic effects of the fermentation–respiration balance. The laboratory and a few other strains depended more on respiration. This trait was associated with a single nucleotide polymorphism in a conserved region of Pyk1, the sole pyruvate kinase in fission yeast. This variant reduced Pyk1 activity and glycolytic flux. Replacing the “low‐activity” pyk1 allele in the laboratory strain with the “high‐activity” allele was sufficient to increase fermentation and decrease respiration. This metabolic rebalancing triggered systems‐level adjustments in the transcriptome and proteome and in cellular traits, including increased growth and chronological lifespan but decreased resistance to oxidative stress. Thus, low Pyk1 activity does not lead to a growth advantage but to stress tolerance. The genetic tuning of glycolytic flux may reflect an adaptive trade‐off in a species lacking pyruvate kinase isoforms.
Highlights
Inter-linked pathways for carbon metabolism generate both energy in the form of ATP and fulfil key anabolic roles
Increased respiration dependence is associated with a missense pyruvate kinase (PYK) variant Treating aerobic glycolysis as a complex, quantitative trait, we assessed the amount of residual respiration on glucose-rich media across a set of genotypically and phenotypically diverse wild S. pombe isolates
The standard laboratory strain 972 hÀ shows a moderate reduction in maximum growth rate and biomass yield in this condition (Malecki & Bahler, 2016; Malecki et al, 2016)
Summary
Inter-linked pathways for carbon metabolism generate both energy in the form of ATP and fulfil key anabolic roles. Organisms tune their carbon metabolism to environmental conditions, including stress or available nutrients, which affects fundamental biological processes such as cell proliferation, stress resistance and ageing (New et al, 2014; Valvezan & Manning, 2019). In the presence of glucose, many microbes suppress respiration and grow preferentially by glycolysis, even with oxygen being available This metabolic state, called aerobic glycolysis (Crabtree, 1929), appears paradoxical, because only full glucose oxidation via the citric acid cycle and respiration will maximise the ATP yield generated per glucose. Proposed explanations for how aerobic glycolysis allows faster proliferation involve efficient resource allocation (Basan et al, 2015; Mori et al, 2019), molecular crowding (Andersen & von Meyenburg, 1980; Zhuang et al, 2011; Vazquez & Oltvai, 2016; Szenk et al, 2017), an upper limit to the cellular Gibbs energy dissipation rate (Niebel et al, 2019), among others (Dai et al, 2016; de Alteriis et al, 2018; de Groot et al, 2019)
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