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Posttranslational arginylation enzyme Ate1 is a mitochondrial‐derived master regulator that coordinates glycolysis and respiration in the Warburg effect

In the Warburg effect observed in vast majority of cancer cells, glycolysis is preferred over mitochondrial respiration. However, the role of mitochondria and its relationship with glycolysis in cancer metabolism is poorly understood. Arginyltransferase 1(Ate1) is an evolutionarily conserved enzyme that exist in most eukaryotes and a large subset of bacteria. In eukaryotes, this enzyme mediates arginylation, the posttranslational addition of one extra arginine to a protein. Recently, Ate1 was identified to be down‐regulated in many types of cancer but the significance of such observation remained unclear. Here, by examining classic glycolytic markers such glucose intake rate, sensitivity to glucose starvation, lactate generation, and the effects of glycolysis inhibitors including 2‐DG and 2‐FDG, we found that a deletion of Ate1 gene is sufficient to causes the Warburg effect on the cell level. This effect was reproduced by shRNA‐mediated knockdown of Ate1 and can be reversed by the expression of a recombinant Ate1 in the KO cells. In a screening of typical players involved in glycolysis, we found that the deletion of Ate1 increases of the protein level of hypoxia‐inducible factor 1a (HIF1a), a protein with known role in glycolysis. We found that the knockdown of HIF1a in Ate1‐KO cells was sufficient to reverse the glycolytic phenoytype in these cells, suggesting Ate1 regulates glycolysis through HIF1a. Furthermore, we found that Ate1 regulates the protein level of HIF1a through both conventional and unconventional pathways. In particularly, HIF1a appears to be a previous unknown substrate of Ate1‐mediated arginylation, which promotes the degradation of HIF1a through the N‐end rule. In addition, the deletion of Ate1 generate prominent effects on the morphology and functions of mitochondria, with significant defect on the assembly of mitochondrial complex II and a consequential accumulation of succinate, which is expected to stabilize the HIF1a protein by an inhibition of the PHD proteins. Finally, we found that eukaryotic Ate1 has significant homology to its counterpart in alpha‐proteobacteria, the ancestor of mitochondria. Also, although the majority of Ate1 is located in the cytosol, a detectable portion of Ate1 is located inside mitochondria. These evidence suggest that the Ate1 enzyme was derived from a gene transfer during the domestication of mitochondria, which further explains the previous unknown role of Ate1 as a master regulator of the balance between glycolysis and mitochondrial function.