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

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.

 

Relevant to the NIH finding of WASF3 abnormalities as discussed here:
2022: NIH study of mitochondria in ME/CFS- WASF3, WAVE3

This thread may also be relevant:
Muscle endoplasmic reticulum stress in exercise, Marafon et al 2022

 

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.

 

Some paragraphs I thought were interesting wrt ME/CFS: