Retrograde signaling mediates an adaptive survival response to endoplasmic reticulum stress

One major cause of endoplasmic reticulum (ER) stress is homeostatic imbalance between biosynthetic protein folding and protein folding capacity. Cells utilize mechanisms such as the unfolded protein response (UPR) to cope with ER stress. Nevertheless, when ER stress is prolonged or severe, cell death may occur, accompanied by production of mitochondrial reactive oxygen species (ROS). Using a yeast model, we describe an innate, adaptive response to ER stress to increase select mitochondrial proteins, O2 consumption, and cell survival. The mitochondrial response allows cells to resist additional ER stress. ER stress-induced mitochondrial response is mediated by activation of retrograde (RTG) signaling to enhance anapleurotic reactions of the TCA cycle. Mitochondrial response to ER stress is accompanied by inactivation of the conserved TORC1 pathway, and activation of Snf1/AMPK, the conserved energy sensor and regulator of metabolism. Our results provide new insight into the role of respiration in cell survival in the face of ER stress, and should help in developing therapeutic strategies to limit cell death in disorders linked to ER stress.