Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer
Abstract
Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.
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BibTeX
@article{cagalinec2026improving,
title = {{Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer}},
author = {Michal Cagalinec and Adnan Mohd and Silvia Borecka and Geert Bultynck and Vinay Choubey and Shira Yanovsky-Dagan and Shlomit Ezer and Daniela Gasperikova and Tamar Harel and Dana Jurkovicova and Allen Kaasik and Jean-Charles Liévens and Tangui Maurice and Marco Peviani and Elodie Marie Richard and Jan Skoda and Martina Skopkova and Pauline Tarot and Robbe van Gorp and Liga Zvejniece and Benjamin Delprat},
journal = {Biochimica et Biophysica Acta - Molecular Cell Research},
year = {2026},
month = sep,
doi = {10.1016/j.bbamcr.2025.119954},
url = {https://hal.umontpellier.fr/hal-05302422v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer
AU - Michal Cagalinec
AU - Adnan Mohd
AU - Silvia Borecka
AU - Geert Bultynck
AU - Vinay Choubey
AU - Shira Yanovsky-Dagan
AU - Shlomit Ezer
AU - Daniela Gasperikova
AU - Tamar Harel
AU - Dana Jurkovicova
AU - Allen Kaasik
AU - Jean-Charles Liévens
AU - Tangui Maurice
AU - Marco Peviani
AU - Elodie Marie Richard
AU - Jan Skoda
AU - Martina Skopkova
AU - Pauline Tarot
AU - Robbe van Gorp
AU - Liga Zvejniece
AU - Benjamin Delprat
PY - 2026
DA - 2026/09/28
JO - Biochimica et Biophysica Acta - Molecular Cell Research
DO - 10.1016/j.bbamcr.2025.119954
UR - https://hal.umontpellier.fr/hal-05302422v1
AB - Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca2+ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca2+, reactive oxygen species and lipids. Particularly, IP3 receptors, intracellular Ca2+-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.
SN - 0167-4889
ER -