Matrix-localized substrate-level-phosphorylation is critical for mitochondrial remodeling during CD8+ T cell priming

Oxidative phosphorylation (OXPHOS) is thought to be critical to meet the energetic demand of T cells activation. However, why activated T cells still require OXPHOS in spite of a clear "switch" to aerobic glycolysis remains incompletely understood. Here we show the critical role of OXPHOS-coupled matrix substrate-level-phosphorylation in powering mitochondrial remodeling in activated CD8+ T cell. We demonstrate that shortly upon stimuli, T cell cytoplasmic function becomes independent of mitochondrial ATP outflux. In contrast, OXPHOS restriction leads to arrest of ATP dependent mitochondrial functions, which could be then rescued by restimulation of matrix substrate-level-phosphorylation. Thus, following the switch to glycolysis, OXPHOS acts as an electron sink, facilitating matrix substrate-level-phosphorylation, a primary ATP source for mitochondrial remodeling during T cell activation.