High levels of protein production or failure of proper protein folding can increase the burden on the endoplasmic reticulum (ER) and ultimately lead to cell death, which can be prevented by the activation of signalling pathways that alleviate ER stress. Mitochondria maintain a tight relationship with the ER and are also involved in the recovery of the ER from stress, although the underlying mechanisms remain unclear. In their study, Amy Chang and colleagues (Hijazi et al., 2020) demonstrate that retrograde (RTG) signalling, which translates mitochondrial needs into nuclear gene expression to replenish TCA cycle intermediates, is involved in cell survival upon increased ER stress in Saccharomyces cerevisiae. The authors show that, even without glucose shortage, activation of RTG signalling upon ER stress induces the expression of specific mitochondrial proteins such as Cox2, which is involved in the electron transport chain (ETC), with a concomitant increase in cellular respiration. This adaptive response is aimed at avoiding an increase in the levels of reactive oxygen species (ROS); it is independent of the unfolded protein response (UPR) and also does not involve an increase in the number of mitochondria. Furthermore, the authors show that TORC1 is inactivated during ER stress; this induces RTG and Snf1/AMPK signalling, the activation of which also potentiates RTG signalling. Hence, this study unravels a new adaptive mechanism by which cells manage ER stress for their survival.
