Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids

The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surpris-ingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydra-tase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L +R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosyn-thesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.

Automated summary

The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. In this study, researchers found that cells undergoing amino acid starvation show mitochondrial fusion as a response to evade mitophagy, and supplementation of glutamine, leucine, and arginine further enhances this mitochondrial fusion. The fusion response is dependent on mitochondrial fusion proteins Mfn1 and Opa1 but independent of MTORC1. Metabolite profiling indicates that the supplementation replenishes amino acid and nucleotide pools, and inhibition of fumarate hydra-tase, glutaminolysis, or inosine monophosphate dehydrogenase blocks the mitochondrial hyperfusion, suggesting the critical roles of the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses support the idea that supplemented glutamine promotes purine biosynthesis by serving as a donor of amine groups. This study provides insights into a metabolic mechanism that directly senses cellular amino acids to control mitochondrial fusion and cell fate.