Role of Leu and Val synthesis in sensing mitochondrial nutrient and energy availability

How cells integrate nutrient availability to coordinate metabolism and growth remains poorly understood. Here, we identify branched-chain amino acid (BCAA) synthesis as a metabolic sensing system linking mitochondrial activity to translational and transcriptional control. Yeast limits Leu and Val import and instead relies on their synthesis, allowing BCAA production to reflect mitochondrial anabolic capacity. Reduced Val synthesis activates Gcn2, whereas reduced Leu synthesis inhibits TORC1, together decreasing translation efficiency and restricting growth. This response lowers levels of the transcriptional repressor Mig1, suppressing the Warburg/Crabtree effect and promoting alternative carbon source utilization. Remarkably, pharmacological inhibition of Leu/Val synthesis induces this metabolic reprogramming even in nutrient-rich medium, indicating that mitochondrial BCAA synthesis can partially override other nutrient-sensing pathways. Thus, BCAA synthesis couples mitochondrial anabolic capacity to Gcn2 and TORC1 activity and, through translational control of transcription factor abundance, shapes cellular metabolism.