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

Discussion in 'Other health news and research' started by Hutan, Mar 20, 2023.

  1. Hutan

    Hutan Moderator Staff Member

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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.
     
    sebaaa, merylg, mariovitali and 5 others like this.
  2. Hutan

    Hutan Moderator Staff Member

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  3. Hutan

    Hutan Moderator Staff Member

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    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.


    Screen Shot 2023-03-21 at 6.10.22 am.png
     
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  4. Hutan

    Hutan Moderator Staff Member

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    Some paragraphs I thought were interesting wrt ME/CFS:
     
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  5. FMMM1

    FMMM1 Senior Member (Voting Rights)

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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?
     
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  6. Amw66

    Amw66 Senior Member (Voting Rights)

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    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) ?

     
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  7. mariovitali

    mariovitali Senior Member (Voting Rights)

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    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.

    https://twitter.com/user/status/1234466652374388736


    3) And also : https://twitter.com/user/status/1268174650951045123


    4) MFN2 : https://twitter.com/user/status/1344627139858063362
     
    Last edited: Mar 21, 2023
  8. mariovitali

    mariovitali Senior Member (Voting Rights)

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