Mitochondrial respiration is required to provide amino acids during fermentative proliferation of fission yeast

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. Synopsis Mitochondrial respiration is required for rapid fermentative proliferation of fission yeast cells by supplying amino‐acid derivatives of the Krebs‐cycle metabolite alpha‐ketoglutarate. Inhibition of the respiratory chain reduces growth and intracellular amino‐acid concentrations, most notably arginine. Arginine supplementation, and its catabolism into amino acids that are normally derived from alpha‐ketoglutarate, are sufficient to restore rapid growth. Inhibition of the respiratory chain also triggers a gene‐expression response through TOR inhibition, and the regulated proteins show biased amino‐acid compositions reflecting their shortage in this condition. Graphical Abstract Mitochondrial respiration is required for rapid fermentative proliferation of fission yeast cells by supplying amino‐acid derivatives of the Krebs‐cycle metabolite alpha‐ketoglutarate.