Xin, N. | bioRxiv Science

bioRxiv2023

Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis

Maintaining protein homeostasis is essential for cellular health. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response, activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPRER), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPRER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2 signaling pathway, increasing phosphorylation of eIF2 and improving the ERs ability to handle proteostasis. MERSR activation in both polyglutamine and amyloid-beta peptide-expressing C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provide further evidence for the importance of intercompartmental signaling.

cell biology↗

bioRxiv2020

The UPRmt Preserves Mitochondrial Import to Extend Lifespan

SummaryThe mitochondrial unfolded protein response (UPRmt) is dedicated to promote mitochondrial proteostasis and is linked to extreme longevity in worms, flies, and mice. The key regulator of this process is the transcription factor, ATFS-1. In the absence of mitochondrial stress, ATFS-1 is transported to the mitochondria and degraded. During conditions of mitochondrial stress, ATFS-1 is excluded from the mitochondria and enters the nucleus to regulate the expression of UPRmt genes. However, there exists a dichotomy in regards to induction of the UPRmt and mitochondrial import. The repair proteins synthesized as a direct result of UPRmt activation must be transported into damaged mitochondria that had previously excluded ATFS-1 due to reduced import efficiency. To address this conundrum, we analyzed the role of the import machinery under conditions where the UPRmt was induced. Using in vitro biochemical assays of mitochondrial import and in vivo analysis of mitochondrial proteins, we surprisingly find that the efficiency of mitochondrial import increases when the UPRmt is activated in an ATFS-1 dependent manner, even though membrane potential is reduced. The import machinery is upregulated at the transcription and translation level, and intact import machinery is essential for UPRmt-mediated increase and lifespan extension. With age, import capacity decreases, and activation of the UPRmt delays this decline and increases longevity. Finally, we find that ATFS-1 has a significantly weaker mitochondrial targeting sequence (MTS), allowing for dynamic subcellular localization during the initial stages of UPRmt activation.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cell biology↗