Tetraspanins interweave EV secretion, endosomal network dynamics and cellular metabolism

Tetraspanin proteins organize membrane nanodomains related to cell adhesion and migration. An essential feature conserved along the superfamily is their cone-shaped tertiary structure, which allows tetraspanins to be enriched in highly curved membrane structures. Their conical shape, together with their ability to associate to transmembrane receptors and to bind to cystoskeletal and signaling scaffolds, are key in their ability to regulate endosomal network dynamics and Extracellular Vesicle biogenesis and cargo selection. Recent evidence suggests that tetraspanins have a relevant impact in mitochondria turnover and regulation of cellular metabolism. In this review we highlight those reports that point to tetraspanins as key regulators in the communication between the endosomal network, EVs and the cellular metabolism. •Tetraspanins regulate endosomal network dynamics.•Cellular metabolism regulates endosomal dynamics for metabolic adaption.•Tetraspanins are involved in different mechanisms of mitochondrial turnover.•Tetraspanin nanodomains are involved in Extracellular Vesicles biogenesis and cargo selection.