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

[SNT Gatchaman]

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)

 

[SNT Gatchaman]

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

 

[SNT Gatchaman]

Abridged selected quotes —

In addition to increasing chaperone levels, another major compensatory mechanism of the ER is the PERK-eIF2a signaling pathway which attenuates global protein translation levels and reduces the total protein load of the ER

hsp-6 knockdown had no impact on xbp-1s overexpression-induced UPR ER, suggesting that the suppression of UPR(ER) occurs upstream of xbp-1, possibly at a membrane level.

One possibility is that hsp-6 knockdown leads to an alteration in membrane fluidity, compromising the dimerization of the UPR(ER) sensors. This is further corroborated by recent findings that the knockdown of ER-resident proteins alters the ER membrane lipid content, increasing mitochondria and ER contact through increasing membrane order.

Furthermore, alterations in lipid content within the ER membrane have been shown to induce UPR(ER) in the absence of aberrant proteostasis, providing further evidence that membrane lipid content can directly influence the UPR(ER) signaling pathways.

 

[SNT Gatchaman]

Here we have identified an unexpected role of MCSR in promoting the balance of proteostasis by regulating the UPR ER signaling pathways in C. elegans. Our study suggests that the knockdown of mitochondrial hsp70 not only coordinates mitochondria to cytosolic stress response, but it also elicits an intercompartmental signaling axis between the mitochondria and the ER.

The suppression of the IRE1 branch of the UPR ER is mediated through perturbations of sphingolipid metabolism, suggesting the possibility of bioactive lipids serving as mediators along this intercompartmental signaling axis.

Proper function of the UPR(ER) is dependent on several signaling cascades. The PERK-eIF2a signaling cascade results in an increase in the phosphorylation of eIF2a, leading to a reduction in global protein translation levels.

We have shown here that reduced UPR ER inducibility is a direct result of increased PERK-dependent eIF2a phosphorylation in combination with decreased ER protein secretion.

 

[SNT Gatchaman]

Mitochondria HSP70 (mtHSP70, mortalin, HSPA9, Grp75, HSP-6) is widely known for its beneficiary functions. It was first described as a substrate for protein translocation into the mitochondrial matrix.

However, as research on the subject has increased, the role of mortalin has begun to expand. Mortalin reduces the formation of reactive oxygen species and lipid peroxidation, protecting the mitochondria from oxidative stress.

In recent cancer research, mortalin has become a target for drug discovery due to its ability to bind P53 and prevent its nuclear localization given the significant changes in lipid metabolism, specifically cardiolipin and ceramide, it is likely that hsp-6 knockdown-induced mitochondrial stress could result in the remodeling of the lipid composition within the mitochondrial membrane.

Cardiolipin is a key regulator in the maintenance of mitochondrial membrane integrity and cristae morphology

 

[SNT Gatchaman]

In conclusion, we have demonstrated for the first time, within our knowledge, the capabilities of a mitochondrial chaperone protein to regulate UPR(ER) signaling through the perturbation of lipid metabolism.

We know that mitochondria and the ER form contact sites in order to modulate membrane lipid composition and proper Ca 2+ homeostasis. The question that remains is how hsp-6 knockdown impacts mitochondria and ER contact.

 

[SNT Gatchaman]

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) —

ER stress normally induces the chaperone protein BiP and suppresses protein translational factor eIF2α via PERK to mitigate the unfolded protein response. However, the muscle samples of ME/CFS patients showed an opposite relationship, implying that abnormal ER stress response may underlie the disruption in mitochondrial metabolism.

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

Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET.

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?

Our cells have developed unique defense mechanisms to detect and resolve misfolded protein stress through the activation of complex signaling pathways. These pathways mediate the upregulation of chaperone proteins to aid in the proper folding of the misfolded proteins in addition to reducing protein load stress by shutting down the global protein translation.

 

[SNT Gatchaman]

Preprint updated to v2 in Dec 2023

 

[Murph]

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.

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.

Increased ER stress would normally be expected to turn down protein translation, but intriguingly, the inhibitory phosphorylation of protein translation factor eIF2α, a target of PERK kinase activity, was unexpectedly lower (i.e., activated) in patient S1 cells (Fig. 6A, lane 2 vs. 1). This finding suggested that there was “ER stress response failure” in patient S1 cells as also observed in the ME/CFS muscle biopsy samples

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....?