Model of ISR and mTOR suppression after ceramide-EV blockade. (1) Pharmacologic or genetic inhibition of neutral sphingomyelinase results in deficits in EV secretion of mitochondrial cargo. (2) Mitochondrial ROS accumulation leads to (3) activation of the ISR via eIF2α phosphorylation, subsequent ATF4 translation, upregulation of CHOP and REDD1, (4) downstream inhibition of mTOR phosphorylation, and (5) resultant quiescence, relative lymphoid bias, and enhanced fitness after transplantation.