Abstract
When glucose is available, many organisms repress mitochondrial respiration in favour of aerobic glycolysis, or fermentation in yeast, that suffices for ATP production. Fission yeast cells, however, rely partially on respiration for rapid proliferation under fermentative conditions. Here, we determined the limiting factors that require respiratory function during fermentation. When inhibiting the electron transport chain, supplementation with arginine was necessary and sufficient to restore rapid proliferation. Accordingly, a systematic screen for mutants growing poorly without arginine identified mutants defective in mitochondrial oxidative metabolism. Genetic or pharmacological inhibition of respiration triggered a drop in intracellular levels of arginine and amino acids derived from the Krebs cycle metabolite alpha‐ketoglutarate: glutamine, lysine and glutamic acid. Conversion of arginine into these amino acids was required for rapid proliferation when blocking the respiratory chain. The respiratory block triggered an immediate gene expression response diagnostic of TOR inhibition, which was muted by arginine supplementation or without the AMPK‐activating kinase Ssp1. The TOR‐controlled proteins featured biased composition of amino acids reflecting their shortage after respiratory inhibition. We conclude that respiration supports rapid proliferation in fermenting fission yeast cells by boosting the supply of Krebs cycle‐derived amino acids.
Highlights
Glucose oxidation in eukaryotic microbes and mammals depends on three core metabolic pathways, glycolysis, the pentose phosphate pathway and the Krebs cycle
Research has put particular emphasis to explain the balance between respiration and fermentation, i.e. the amount of glucose oxidation achieved via anaerobic metabolism versus oxidative metabolism, in which all three pathways are active and feed electrons into the oxygen-consuming respiratory chain (Molenaar et al, 2009)
We show that respiration during fermentative growth in S. pombe is required for the synthesis of arginine and amino acids derived from alpha-ketoglutarate
Summary
Glucose oxidation in eukaryotic microbes and mammals depends on three core metabolic pathways, glycolysis, the pentose phosphate pathway and the Krebs cycle These catabolic processes yield energy in the form of ATP, reducing equivalents in the form of NAD(P)H and FADH, as well as a series of intermediates required for anabolic (biosynthetic) metabolism. The flux distributions between all three pathways are dynamically adjusted by the cell to achieve an optimal level of growth and resilience given a specific lifestyle, stress condition or ecological niche (Ralser et al, 2007; Peralta et al, 2015; Jouhten et al, 2016; Nidelet et al, 2016; Olin-Sandoval et al, 2019) These metabolic adaptations are of fundamental importance for cellular physiology as they determine their tolerance for changing conditions and stress (Lahtvee et al, 2016). Research has put particular emphasis to explain the balance between respiration and fermentation, i.e. the amount of glucose oxidation achieved via anaerobic metabolism (glycolysis and pentose phosphate pathways without oxidative phosphorylation) versus oxidative metabolism, in which all three pathways are active and feed electrons into the oxygen-consuming respiratory chain (Molenaar et al, 2009)
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