Mitochondria–ER contact sites are immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells

Glycolysis is linked to the rapid recall capacity of memory CD8+ T cells, but the pathways that glucose fuels and the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are not known. We found that mitochondria–ER contact sites are immunometabolic hubs that integrate mTORC2-initiated signaling with glucose metabolism and mitochondrial respiration in memory CD8+ T cells. Specifically, in this subcellular compartment, mTORC2, Akt and Gsk-3β were present by default. Rapid activation of Akt by mTORC2 led to inhibition of Gsk-3β at mitochondria–ER junctions, enabling recruitment of hexokinase I (HK-I) to the mitochondrial channel, VDAC. Binding of HK-I to VDAC promoted cellular respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic …