Mitochondrial Import Efficiency of ATFS-1 Regulates Mitochondrial UPR Activation

Abstract

To better understand the response to mitochondrial dysfunction, we examined the mechanism by which Activating Transcription Factor associated with Stress-1 (ATFS-1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPRmt). We found that the key point of regulation was the mitochondrial import efficiency of ATFS-1. In addition to a nuclear localization sequence, ATFS-1 has an amino-terminal mitochondrial targeting sequence, which was essential for UPRmt repression. Normally, ATFS-1 is imported into mitochondria and degraded. However, during mitochondrial stress, import efficiency was reduced allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus. Our results show that cells monitor mitochondrial import efficiency via ATFS-1 to coordinate the level of mitochondrial dysfunction with the protective transcriptional response.

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

“…The control of mitochondrial function and UPR mt during stress in the worm is largely attributable to the activating transcription factor associated with stress, atfs-1 17,18 . Depletion of atfs-1 by RNAi feeding of the GMC101 worms, but not CL2122, caused a severe developmental delay even in absence of the “disease-inducing” temperature shift (Extended Data Fig.…”

“…Depletion of atfs-1 by RNAi feeding of the GMC101 worms, but not CL2122, caused a severe developmental delay even in absence of the “disease-inducing” temperature shift (Extended Data Fig. 3h), phenocopying mitochondrial respiration mutants that rely on atfs-1 for survival and adaption 18 . Comparative analysis of transcripts involved in cytosolic and nuclear adaptation pathways, such as UPR er , HSR, and daf-16, showed also a mild induction of the UPR er and a striking upregulation of the HSR in GMC101 (Extended Data Fig.…”

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…These pathways sense unfolded protein stress in a compartment‐specific manner, and signal to the nucleus for induction of the expression of unfolded protein response (UPR) genes, which are essential for proteostasis (Schinzel & Dillin, 2015). Mitochondrial unfolded protein response (mtUPR) is activated in response to a variety of mitochondrial stress factors including accumulation of unfolded proteins in the mitochondrial matrix (Rath et al., 2012), imbalance between mitochondrial DNA (mtDNA)‐encoded and nuclear‐encoded electron transport chain (ETC) components (Nargund, Pellegrino, Fiorese, Baker & Haynes, 2012; Yoneda et al., 2004), and perturbation of mitochondrial physiology through inhibition of ETC function or accumulation of reactive oxygen species (ROS) (Nargund et al., 2012; Yoneda et al., 2004), and ensures mitochondrial proteostasis by inducing a vigorous transcriptional response that promotes folding, limits import, and reduces translation of mitochondrial proteins (reviewed in Hill & Van Remmen, 2014; Jensen & Jasper, 2014). …”

The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence

“…The UPR mt is a nascent cellular pathway that is activated when cells experience mitochondrial protein folding stress and retrograde signaling from the mitochondria to the nucleus triggers transcriptional activation of nuclear‐encoded mitochondrial chaperones and proteases as well as repression of translation to reestablish proteostasis (Haynes, Fiorese & Lin, 2013; Haynes & Ron, 2010; Mohrin et al., 2015; Munch & Harper, 2016; Zhao et al., 2002). Primarily characterized in C. elegans , the UPR mt is activated during a developmental stage when there is a burst of mitochondrial biogenesis (Houtkooper et al., 2013; Lin et al., 2016; Merkwirth et al., 2016; Nargund, Pellegrino, Fiorese, Baker & Haynes, 2012; Pellegrino et al., 2014; Tian et al., 2016). It is therefore speculated that in stem cells, the UPR mt is activated under a physiological condition when mitochondrial biogenesis is induced.…”