ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk—Signaling Beyond (ER) Stress Response, 2021, Kumar and Maity

Hutan

Hutan

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https://www.mdpi.com/2218-273X/11/2/173/htm

Abstract
Recent studies undoubtedly show the importance of inter organellar connections to maintain cellular homeostasis. In normal physiological conditions or in the presence of cellular and environmental stress, each organelle responds alone or in coordination to maintain cellular function. The Endoplasmic reticulum (ER) and mitochondria are two important organelles with very specialized structural and functional properties. These two organelles are physically connected through very specialized proteins in the region called the mitochondria-associated ER membrane (MAM).

The molecular foundation of this relationship is complex and involves not only ion homeostasis through the shuttling of calcium but also many structural and apoptotic proteins. IRE1alpha and PERK are known for their canonical function as an ER stress sensor controlling unfolded protein response during ER stress. The presence of these transmembrane proteins at the MAM indicates its potential involvement in other biological functions beyond ER stress signaling.

Many recent studies have now focused on the non-canonical function of these sensors. In this review, we will focus on ER mitochondrial interdependence with special emphasis on the non-canonical role of ER stress sensors beyond ER stress.
 
Paraphrasing the paper:
Mitochondria are tethered to the ER. During environmental stress, the contact sites become even tighter. Calcium and many structural and apoptotic proteins are shuttled between the organelles.

Some mitochondrial proteins can regulate ER stress and Unfolded Protein Response (UPR) pathways.

The endoplasmic reticulum is involved in the production and degradation of proteins. Many exogenous and endogenous factors such as UV radiation, reactive oxygen species, hypoxia, protein mutations, lipid homeostasis, deletion of genes and nutrient starvation can cause accumulation of misfolded proteins resulting in ER stress.

In mammals there are three major proteins involved in controlling ER stress response: IRE1, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6). These ER stress sensors get activated upon the presence of misfolded proteins. If UPR fails to rescue the cellular protein homeostasis, the cells undergo apoptosis.

There is a detailed diagram of some of the proteins involved at the mitochondria/ER interface. WASF3 is one of the proteins.


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Some paragraphs I thought were interesting wrt ME/CFS:
Hamasaki et al., have performed imaging studies to show that autophagosomes form at the ER-mitochondria contact sites. The data revealed that the autophagosome marker ATG14, part of the PI3K complex that is essential for autophagosome formation, was found to be localized at the MAM during the starved condition of the cell [98,99] and is placed on the ER under normal conditions but during starvation, it diffuses through the ER membrane [100,101]. Electron tomographic studies showed that in presence of sufficient amino acid there was no localization of ATG14 on MAM but during starvation, accumulation of ATG14 was markedly observed at the MAM along with double FYVE domain-containing protein (DFCP1), a protein that can act as a platform for autophagosome formation [102]. Localization towards ER and mitochondria were seen throughout the process but the association with ER was stable while that with mitochondria was found only during amino acid starvation. ATG14 complex, as well as DFCP1, re-localizes to the MAM fractions during starvation. By these results, Axe et al. (2008) proved that ER gave the stage for autophagosome formation, while mitochondria have a role in providing components required for the same [102]. Live-cell imaging also showed that eventually when the expression of mitochondrial protein VDAC1 was increasing, the expression of ATG14 slowly decreased showing the end of autophagy. This again proves that the process of autophagy occurs at the MAM site [103]. Another ER protein known as STX17, it is known to be a Qa-SNARE protein, also localized at MAM during starvation but its exact function is not known yet [104]. It was also proved that STX17 was upstream of ATG14 and is responsible for the recruitment of ATG14 to MAM during any stressful conditions.
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It has been found that the AKT-mTOR signaling axis modulates the dynamics of IRE1 RNAse activity by regulating ER-mitochondria contact. The study demonstrated a two-step mechanism of IRE1 attenuation. The auto-phosphorylation first initiates the termination of IRE1 RNAse activity but the complete cessation of RNAse activity only occurs if ER-mitochondria contacts are reformed after their initial uncoupling by ER stress [138]. IRE1 controls expression of GRP78 upon ER stress. During ER stress GRP78 plays a significant role in the stabilization of WASF3 on mitochondrial membranes. Interestingly another MAM protein ATAD3 forms a ternary complex involving ATAD3A, WASF3 and MAM associates GRP78. ATAD3A, acts as a crucial mediator to promote cell invasion in breast and colon cancer via regulating GPR78-mediated stabilization of WASF3 [146].
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Starvation or nutrient deprivation has a significant impact on mitochondrial morphology and enhances mitochondrial hyper fusion to balance mitochondrial bioenergetic efficiency [160]. Nutrient stress due to glucose starvation demands a cellular energetic shift from cytosolic glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) system in order to maintain cellular growth and survival [161]. Moreover, nutrient starvation can also enable ER stress by disrupting protein folding and glycosylation in the ER. In a recent study, Balsa et al. demonstrated how ER communicates with OXOPHOS system to increase ATP production and promote proteostasis in the cell through a previously unknown mechanism controlled by PERK. The study found that PERK activation during ER stress and glucose deprivation stimulates mitochondrial bioenergetics through the formation of respiratory supercomplexes (SCs). PERK activation mediated increase in SCs elevates mitochondrial respiration in cells expressing PERK but not in PERK depleted cells. Additionally, PERK activation also resulted in changes in cristae formation and the formation of cristae is absolutely required in SC formation during nutrient and ER stress.
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The absence of a biomarker in ME/CFS has often been commented on - may not be a surprise (I guess) if the disease pathology is something like this --- I assume these things wouldn't turn up on routine tests.

I wonder if GWAS could provide confirmation/clues on underlying cause?
 
Interesting - this stood out for me as glycolysis has been shown to be an issue


"Nutrient stress due to glucose starvation demands a cellular energetic shift from cytosolic glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) system in order to maintain cellular growth and survival [161]. Moreover, nutrient starvation can also enable ER stress by disrupting protein folding and glycosylation in the ER. "

I have very limited biological knowledge ,and this could be complete codswallop but does there seem to be some aspects from different research coming into play? .

Calcium signalling - issues found / proposed previously - how would this affect ER stress or is this because of ER stress ?

If females are more prone to using proteins / amino Acids as fuel ( due to glycolysis issues) does this suggest a potential difference / impact on ER re availability / starvation response ? Is there a difference between sexes ?

How does mitochondrial electron transport chain function when ER is stressed ( we have suggestions of overcompensation in one part of mitochondria chain ( 1) to try and compensate for underperformance in another (5) .

Misfolded proteins have been proposed as part of the mechanism before , does this perhaps provide more of a hint for a clue ( or should I buy some new biology books) ?

 
Some parts from my research using #AI methods regarding ER Stress and MAMs:


1) ER Stress identified in 2015 as potential research target. Shared with a number of researchers.

https://www.s4me.info/threads/2022-...n-me-cfs-wasf3-wave3.28365/page-3#post-463798

2) Mitochondria-associated membranes (MAMs) . See the following post regarding some possible associations with MECFS :

https://www.s4me.info/threads/acute...tera-gwi-2008-hokama-et-al.15367/#post-264646

Also an interaction with Bhupesh Prusty regarding MAMs. @Amw66 you mention calcium issues (which I believe is important), please see below regarding ABCC6.



3) And also :

4) MFN2 :
 
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