Purinosomes and mitochondria: Dynamic interactomes at the crossroads of metabolism, cell structure, and disease

Mitochondria are central hubs of cellular metabolism, integrating nutrient catabolism, ATP production, redox balance, and biosynthetic precursor supply. Recent work has revealed that their influence extends beyond canonical bioenergetics to include intimate connections with cytosolic multi-enzyme assemblies. Among these, the purinosome, the complex dedicated to de novo purine biosynthesis, has emerged as a paradigmatic example of how metabolic pathways achieve efficiency through spatial and functional coupling. This Review highlights the dynamic interplay between purinosomes and mitochondria. We describe how mitochondrial metabolism supplies key substrates, including aspartate, glycine, and formate, while oxidative phosphorylation provides the ATP required for nucleotide synthesis. We discuss how purinosomes assemble through liquid-liquid phase separation, position near mitochondria in response to energetic stress, and act as adaptive metabolic hubs that sense and integrate growth and nutrient signals. Finally, we examine how disruption of this mitochondrion-purinosome axis contributes to disease, from rare neurodevelopmental disorders to cancer and neurodegeneration.