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

Abstract

Maintaining protein homeostasis is essential for cellular health. During times of protein stress, cells deploy unique defense mechanisms to achieve resolution. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response (MCSR), a unique 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-eIF2a signaling pathway, increasing phosphorylation of eIF2a and improving the ER's capacity to manage greater proteostasis load. MERSR activation in both poly-glutamine (poly-Q) and amyloid-beta (Abeta) C. elegans disease models also leads 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.

Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT

“…Where PTC transcripts persist, our data are more consistent with ribosomal readthrough and incorporation of missense substitutions tolerated to differing degrees, than generation of peptides truncated at the PTC. In patient cells, where aberrant protein expression would be low, governed not only by low level RNA transcripts but also by usually rapid endoplasmic reticulum–associated degradation (ERAD) 96 and/or lysosomal 97 degradation, further studies will be required to establish whether and when levels are negligible or not negligible, and whether this differs between missense variants for which cellular processes can adapt to chronic proteotoxic loads, 98 , 99 and PTC variants for which levels are more fluctuant.…”