Haigis Lab identifies a novel program of mitochondrial proteome remodeling

To initiate an immune response against pathogens, a small number of T cells within the polyclonal repertoire need to proliferate rapidly to generate large numbers of effector cells that can clear pathogens. To generate the precursors required for macromolecular synthesis, energy and stress response, the T cells activate anabolic metabolism that is coupled with increased mitochondrial mass. In a recent publication in Cell Metabolism, the Haigis Lab uses T cell activation to address a fundamental question in mitochondrial biology: Does biogenesis merely replicates existing mitochondria, or generates a distinct population of mitochondria with specialized functions? Noga Ron-Harel and co-workers, in collaboration with the Gygi and Sharpe labs, show that naïve T cell activation induces a unique program of synchronized mitochondrial biogenesis and proteome remodeling, giving rise to mitochondria with a distinct proteomic signature that drives one-carbon (1C) metabolism. They demonstrate for the first time that mitochondrial 1C metabolism is important for de-novo purine biosynthesis and redox control in T cells. Genetic inhibition of mitochondrial 1C metabolism impaired antigen-specific T cell proliferation and survival in vitro and in vivo. In sum, this study identifies 1C metabolism as an early and essential metabolic signature of naïve T cell activation, and shows that mitochondrial proliferation gives rise to a new population of organelles with distinct and specialized functions.