Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming

Activated effector T (T-E) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (T-M) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that T-E cells have punctate mitochondria, while T-M cells maintain fused networks. The fusion protein Opa1 is required for TM, but not T-E cells after infection, and enforcing fusion in TE cells imposes T-M cell characteristics and enhances antitumor function. Our data suggest that, by altering cristae morphology, fusion in T-M cells configures electron transport chain (ETC) complex associations favoring oxidative phosphorylation (OXPHOS) and FAO, while fission in T-E cells leads to cristae expansion, reducing ETC efficiency and promoting aerobic glycolysis. Thus, mitochondrial remodeling is a signaling mechanism that instructs T cell metabolic programming.