Retrograde signaling mediates an adaptive survival response to endoplasmic reticulum stress in Saccharomyces cerevisiae

Abstract

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 (Saccharomyces cerevisiae), we describe an innate, adaptive response to ER stress to increase select mitochondrial proteins, O 2 consumption and cell survival. The mitochondrial response allows cells to resist additional ER stress. The ER stressinduced mitochondrial response is mediated by activation of retrograde (RTG) signaling to enhance anapleurotic reactions of the tricarboxylic acid 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. This article has an associated First Person interview with the first author of the paper.

Aeration mitigates endoplasmic reticulum stress in Saccharomyces cerevisiae even without mitochondrial respiration

“…In agreement with this observation, the mitochondrial gene expression in wild-type S. cerevisiae cells was drastically decreased by cellular treatment with DTT or tunicamycin [19]. Contrary to the previous observations by others [11,[16][17][18], ER stress may damage the mitochondria under certain situations. The reason for this discrepancy should be addressed in future.…”

“…In agreement with this finding, Knupp et al [11] proposed that, in S. cerevisiae, ER stress increases mitochondrial oxygen consumption, which contributes to cellular survival upon ER stress. It is likely that some intracellular signaling pathways mediate the mitochondrial response to ER stress [17]. In mammalian cells, the ER-mitochondrial spatial connection is increased, leading to enhancement of mitochondrial respiration, in response to ER stress [18].…”

RTG Signaling Sustains Mitochondrial Respiratory Capacity in HOG1-Dependent Osmoadaptation

“…The contribution of mitochondrial retrograde signaling to yeast stress response and cellular adaptation has been described in several cases, including acid stress, endoplasmic reticulum stress, as well as oxidative and osmotic stress [4][5][6][7][8][9]. Particularly noteworthy is the report of the modulation of Rtg1/3 complex activity by the master regulator of Microorganisms 2021, 9, 1894 2 of 12 osmostress response, the HOG1 stress activated protein kinase (SAPK), which points to a direct connection between RTG genes and targets and the high osmolarity glycerol (HOG) signaling system, functionally conserved from yeast to humans [8,10].…”

Neuroserpin Inclusion Bodies in a FENIB Yeast Model

“…It has been argued that NS polymers do not trigger the UPR, but instead lead to an ER overload and activation of the EOR pathway that is associated with the detection of Ca 2+ perturbations and that also involves ROS signaling [ 22 , 23 ]. Whether a true equivalent of the EOR pathway is present in yeast has not been reported, but it is known that during ER stress Ca2+ is released from the ER to enter mitochondria where it is suggested to initiate the activation of a mitochondrial adaptive response that allows coping with moderate levels of ER-stress and that is linked to an increased O 2 consumption, increased mitochondrial membrane potential and an enhanced respiratory capacity [ 58 , 59 , 60 , 61 ].…”