Increased mitochondrial respiration promotes survival from endoplasmic reticulum stress.

Citation
Knupp, J., et al. “Increased Mitochondrial Respiration Promotes Survival From Endoplasmic Reticulum Stress.”. Cell Death And Differentiation, pp. 487-501.
Center University of Michigan
Author Jeffrey Knupp, Peter Arvan, Amy Chang
Abstract

Protein misfolding in the endoplasmic reticulum (ER) is accompanied by adaptive cellular responses to promote cell survival. We now show that activation of mitochondrial respiration is a critical component of an adaptive ER stress response, requiring the unfolded protein response (UPR) sensor Ire1, and also calcium signaling via calcineurin. In yeast and mammalian cells lacking Ire1 or calcineurin, respiratory activation is impaired in response to ER stress; accumulation of mitochondrial reactive oxygen species (ROS) triggers cell death as abrogation of ROS by antioxidants or loss of the electron transport chain (in yeast) can rescue cells from death. Significantly, cells are rescued from ER stress-induced death by mitochondrial uncoupling by CCCP to increase O consumption (and increase the efficiency of electron transfer). Remarkably, genetic and pharmacologic strategies to promote mitochondrial biogenesis and increase O consumption also alleviate ER stress-mediated ROS and death in yeast and mammalian cells. Moreover, in a yeast genetic screen, three mitochondrial proteins Mrx9, Mrm1, and Aim19 that increase mitochondrial biogenesis were identified as high copy suppressors of ER stress-mediated cell death. Our results show that enhanced mitochondrial biogenesis, linked to improved efficiency of the electron transport chain, is a powerful strategy to block ROS accumulation and promote cell survival during ER stress in eukaryotic cells.

Year of Publication
2019
Journal
Cell death and differentiation
Volume
26
Issue
3
Number of Pages
487-501
Date Published
12/2019
ISSN Number
1476-5403
DOI
10.1038/s41418-018-0133-4
Alternate Journal
Cell Death Differ.
PMID
29795335
PMCID
PMC6370866