Preprint Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response MERSR and its Impact on Proteostasis, 2023, Li et al.

Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response MERSR and its Impact on Proteostasis
Jeson J Li; Nan Xin; Chunxia Yang; Larrisa A Tavizon; Ruth Hong; Travis I Moore; Rebecca G Tharyan; Adam Antebi; Hyun-Eui Kim

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 ER9s 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.


Link | PDF (Preprint: BioRxiv)

 

Builds on their prior work Lipid Biosynthesis Coordinates a Mitochondrial-to-Cytosolic Stress Response (2016, Cell)

 

Abridged selected quotes —

 

So this indicates there is signalling between mitochondria and endoplasmic reticulum and suggests the possibility that dysregulated lipid metabolism could impair the function of ER stress sensors and the UPR.

This may be relevant to findings in WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome (2023) —

Another question that might follow relates to findings in Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients 2023.

If metabolites are not being excreted in the urine as they are in healthy sedentary controls, does that mean that they are not being produced when they should? Is part of the explanation an exercise-induced pathological upregulation of the ER's UPR, which stops protein translation? Not because there are misfolded proteins that require the UPR, but because abnormal signalling is inducing the UPR?

 

Preprint updated to v2 in Dec 2023

 

A detail in Hwang's 2023 WASF3 paper is that the UPR he found isn't working right. While PERK is switched on, there's no phosphorylation of eiF2a.

if eiF2a doesn't pick up its phosphate, it doesn't do its job and the PERK signalling presumably gets stuck on. I believe UPR activation that doesn't result in actual proper resolution of the misfolded protein overload will flip those muscle cells to apoptosis and necrosis after a period of time. Say 12-24 hours or so. If a large number of muscle cells flipped to apoptotis / necrosis that could, I'm guessing, make the person feel really bad. So if this mechanism was in play, a person could expect to feel amazingly bad about 12h-24h after a stressor, which could be, i don't know ... exercise....?