Effect of lactate accumulation on translation and transcription in MDA-MB-231 breast cancer cells

Yet it remains unclear whether this rapid communication depends on complex regulatory signaling pathways or can be governed by a single molecule. Here, we show that intracellular accumulation of lactate, a central product of glycolysis, is sufficient to acutely repress mRNA translation.

Mechanistically, lactate is charged to the 3′ end of tRNA, a site canonically reserved for amino acids, generating translation-defective lactyl-tRNAs. This mechanism may have evolved to restrict protein synthesis during metabolic imbalance, such as when glycolytic activity exceeds lactate clearance, and is particularly relevant in highly glycolytic cancer cells, which frequently experience prolonged hypoxia and elevated lactate levels.