bims-mecosi 2026-04-19 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–04–19
eight papers selected by
Verena Kohler, Umeå University

Bridging the gap between organelles: Membrane contact sites as regulator of endocytic dynamics.
MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.
Organellar insights in ageing and longevity.
Subchronic exposure to decabromodiphenyl ethane impairs cognitive function and induces neuronal ferroptosis via disruption of mitochondria-associated endoplasmic reticulum membranes.
The PVAT-MAMs Axis in Atherosclerosis: A Hypothesis-Driven Cross-Scale Conceptual Framework.
TP53 links mitochondria-endoplasmic reticulum crosstalk and ferroptosis in septic cardiomyopathy: Protective modulation by nicorandil.
AlphaFold-driven discovery of oxysterol-binding protein-related protein-phosphoinositide 3-, 4-, and 5-phosphatase interactions using new generation confidence scores.
Pulling the Back to Steer Cell Migration: Mechanisms of Structural Polarity in Confining Signaling and Protrusion.

Curr Opin Cell Biol. 2026 Apr 11. pii: S0955-0674(26)00029-3. [Epub ahead of print]100 102641

Bridging the gap between organelles: Membrane contact sites as regulator of endocytic dynamics.

Giorgia Miloro, Margherita Caputo, Pier Paolo Di Fiore, Sara Sigismund.

Endocytosis controls the internalization of molecules, receptors and membrane components, thereby regulating nutrient uptake, signaling and membrane composition. Increasing evidence shows that trafficking of endocytic cargo is coordinated by membrane contact sites (MCSs). Rather than passive bridges, MCSs act as dynamic platforms that organize communication between organelles, integrating metabolic and biochemical signals with spatial precision. Their ability to locally remodel membranes and generate spatially confined signaling domains directly shapes endocytic and endo-lysosomal trafficking. MCSs are also highly adaptive: they remodel in response to extracellular cues such as growth factors and can be exploited by pathogens to create replication-permissive niches, positioning MCSs as central hubs of intracellular organization and communication.

DOI: https://doi.org/10.1016/j.ceb.2026.102641
Aging Dis. 2026 Apr 02.

MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.

Giacoma Galizzi.

Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca2+) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.

DOI: https://doi.org/10.14336/AD.2025.1342
Nat Cell Biol. 2026 Apr 17.

Organellar insights in ageing and longevity.

Philip Mannino, Mooncheol Park, Meng Carla Wang.

Metabolic processes shape ageing and longevity at multiple levels. Emerging evidence shows that many of these processes are orchestrated within and between cellular organelles. Organelles function not only as metabolic reactors but also as signalling hubs, and their coordination plays crucial roles in maintaining cellular homeostasis and promoting organismal fitness. Rather than acting in isolation, organelles engage in dynamic crosstalk through membrane contact sites, metabolite exchange and signalling interplay. In recent years, organelles have been increasingly recognized as critical regulators of ageing and longevity. Here we summarize age-related organellar changes, highlight organelle-mediated intra- and intercellular signalling communication in lifespan and healthspan regulation, and discuss the active roles of organelles in microbiome-host interactions and transgenerational inheritance in regulating longevity. We further outline how longevity-promoting interventions influence organelles, and provide perspectives on how future technological advances may further accelerate progress in this emerging research topic.

DOI: https://doi.org/10.1038/s41556-026-01927-7
J Hazard Mater. 2026 Apr 10. pii: S0304-3894(26)01014-9. [Epub ahead of print]509 142036

Subchronic exposure to decabromodiphenyl ethane impairs cognitive function and induces neuronal ferroptosis via disruption of mitochondria-associated endoplasmic reticulum membranes.

Yuanteng Sun, Fei Xiong, Lingjie Wu, Zhihui Liu, Pingping Liu, Wenhao Li, Juan Zhang, Rongli Sun.

  Decabromodiphenyl ethane (DBDPE), a novel brominated flame retardant, poses a recognized neurotoxic hazard, yet its mechanistic underpinnings in mammals remain largely undefined. This study aimed to elucidate the molecular mechanisms of DBDPE-induced neurotoxicity, and identify potential mitigation strategies. Subchronic oral exposure to DBDPE significantly increased hippocampal malondialdehyde (MDA), downregulated key neurotrophic and tight junction proteins, and elicited anxiety-like behavior alongside impairment in learning and memory ability. Mechanistically, DBDPE activated PERK-mediated endoplasmic reticulum stress (ERS), disrupted the structure and function of mitochondria-associated endoplasmic reticulum membranes (MAMs), as evidenced by downregulation of PACS2 and Mfn2. This disruption aberrantly activated the IP3R-GRP75-VDAC1 signaling pathway, promoting excessive Ca²⁺ transfer from the ER to mitochondria. The resultant mitochondrial Ca²⁺ overload triggered NCOA4-mediated ferritinophagy, exacerbating neuronal ferroptosis through Fe²⁺ accumulation and GPX4 depletion. Molecular docking experiments further revealed that DBDPE interacted with the low-affinity Ca²⁺-binding site of IP3R, maintaining it in a constitutively open state. Crucially, the IP3R inhibitor 2-APB significantly attenuated DBDPE-induced MAM dysfunction, mitochondrial damage, and ferroptosis in HT22 cells, supporting the critical contribution of IP3R to this toxicological process. In conclusion, our findings delineate a novel mechanistic pathway linking DBDPE exposure to neuronal ferroptosis via MAM disruption and Ca²⁺ dysregulation, and nominate IP3R as a potential therapeutic target for intervention.

Keywords:  Decabromodiphenyl ethane; Ferroptosis; IP(3)R; Mitochondria-Associated Endoplasmic Reticulum Membranes; Neurotoxicity

DOI:  https://doi.org/10.1016/j.jhazmat.2026.142036
Int J Mol Sci. 2026 Mar 25. pii: 2998. [Epub ahead of print]27(7):

The PVAT-MAMs Axis in Atherosclerosis: A Hypothesis-Driven Cross-Scale Conceptual Framework.

Sixiang Zhang, Yuhan Li, Yingrui Wang, Bingqi Guo, Zixuan Liu, Zheng Liu.

  Atherosclerosis (AS) is the leading cause of cardiovascular disease worldwide, yet its clinical heterogeneity and close association with metabolic disorders are not fully explained by the classical "endothelial injury-lipid deposition-inflammatory amplification" paradigm. In this review, we introduce the PVAT-MAMs axis as a hypothesis-driven, cross-scale conceptual framework linking extravascular metabolic dysfunction to intracellular stress signaling in vascular cells. We propose that, under metabolic stress, dysfunctional perivascular adipose tissue (PVAT) may influence mitochondria-associated endoplasmic reticulum membranes (MAMs) via the release of inflammatory, lipotoxic, and oxidative mediators. Accumulating experimental and associative evidence suggests that perturbation of MAMs is associated with dysregulated calcium handling, lipid metabolism, inflammatory signaling, and redox imbalance, processes implicated in AS progression. Although direct causal relationships remain to be fully established. By synthesizing current findings, this framework provides an integrative perspective on disease heterogeneity and highlights testable pathogenic nodes spanning from PVAT to subcellular MAMs. Finally, we discuss how this conceptual axis may inform hypothesis-driven therapeutic strategies. Importantly, the PVAT-MAMs axis is presented as a hypothesis-driven conceptual model rather than an established signaling pathway, and its mechanistic architecture requires rigorous experimental and translational validation.

Keywords:  atherosclerosis; inflammation; metabolic disease; metabolic homeostasis; mitochondria-associated endoplasmic reticulum membranes; mitochondrial signaling; perivascular adipose tissue

DOI:  https://doi.org/10.3390/ijms27072998
Cell Signal. 2026 Apr 15. pii: S0898-6568(26)00189-0. [Epub ahead of print] 112537

TP53 links mitochondria-endoplasmic reticulum crosstalk and ferroptosis in septic cardiomyopathy: Protective modulation by nicorandil.

Jinshuai Lu, Yuxia Tao, Jinxian Li, Wubuaila Mawulang, Jianhao Wang, Nan Li.

   BACKGROUND: Septic cardiomyopathy (SCM) is a major contributor to sepsis-related mortality, with limited targeted therapies. Ferroptosis and mitochondria-associated endoplasmic reticulum membranes (MAMs) have emerged as important regulators of cardiac injury. TP53 can influence ferroptosis and MAM function, but its role in SCM remains unclear. This study investigated the involvement of TP53 in MAM-associated ferroptosis and the potential protective effects of nicorandil (Nic).
METHODS: Bioinformatics analyses were performed to identify key SCM-related genes. Functional validation was conducted in LPS-induced H9C2 cells and a rat SCM model using pharmacological and genetic interventions, including Nic, GSK2656157, TP53 overexpression, and TP53 knockdown. Mitochondrial function, oxidative stress, calcium homeostasis, ferroptosis, and ER-mitochondria interactions were assessed.
RESULTS: TP53 was identified as a hub gene associated with ferroptosis and mitochondrial-related pathways. LPS stimulation increased TP53 expression and transcriptional activity, accompanied by enhanced ER-mitochondria proximity, calcium dysregulation, oxidative stress, and ferroptosis-related changes. Nic significantly attenuated myocardial injury, reduced lipid peroxidation and iron accumulation, and restored GPX4 and SLC7A11 expression (P < 0.01). TP53 overexpression weakened these protective effects, whereas TP53 knockdown alleviated LPS-induced injury and ferroptosis-related changes. In addition, the ferroptosis inhibitor ferrostatin-1 partially recapitulated the protective effects of Nic. Combined treatment with GSK further improved ER stress-related alterations and calcium homeostasis.
CONCLUSION: These findings suggest that TP53 is functionally involved in SCM and is associated with MAM-related alterations, calcium dysregulation, and ferroptosis. Nic confers cardioprotective effects in vitro and in vivo, at least in part through modulation of TP53-associated stress signaling and ferroptosis. Targeting TP53-related subcellular stress pathways may represent a potential therapeutic strategy for septic cardiomyopathy.

Keywords:  Calcium homeostasis; Ferroptosis; Mitochondria–ER contact; Nicorandil; Septic cardiomyopathy; TP53

DOI:  https://doi.org/10.1016/j.cellsig.2026.112537
Protein Sci. 2026 May;35(5): e70572

AlphaFold-driven discovery of oxysterol-binding protein-related protein-phosphoinositide 3-, 4-, and 5-phosphatase interactions using new generation confidence scores.

Filippo Dall'Armellina, Sylvie Urbé, Daniel J Rigden.

  Non-vesicular lipid transport contributes to the regulation of membrane composition and organelle function at membrane contact sites. OSBP-related proteins (ORPs) are central to this process, yet their interaction networks remain incompletely defined. Here, we systematically screened potential interactions between ORPs and phosphoinositide 3-, 4-, and 5-phosphatases using AlphaPulldown2, AlphaFold2-Multimer, and AlphaFold3. We established a protocol for model generation by combining AlphaFold2-Multimer predictions (including five-replicates) with an AlphaPulldown2 interaction screen across around 200 protein pairs, and with AlphaFold3 predictions including lipid-bound and multimeric assemblies. Interface confidence was assessed for consistency using the weighted ipTM + pTM metric, actifpTM, new generation ipSAE scoring, and FoldSeek-Multimer clustering. We further evaluated the protein pairs' biological plausibility based on subcellular localization data, in silico membrane insertion, evolutionary conservation via ConSurf, and protein binding interface analysis using the deep learning tool PeSTo. This integrative protocol uncovered functionally conserved binding modes in the SAC1 lipid phosphatase with the ORP family, particularly with ORP11, and predicted functionally relevant protein-lipid interfaces.

Keywords:  AlphaFold structural prediction; ORPs; SAC1; membrane contact sites; non‐vesicular lipid transport

DOI:  https://doi.org/10.1002/pro.70572
Cold Spring Harb Perspect Biol. 2026 Apr 13. pii: a041740. [Epub ahead of print]

Pulling the Back to Steer Cell Migration: Mechanisms of Structural Polarity in Confining Signaling and Protrusion.

Bo Gong, Tobias Meyer.

Directed cell migration is a coordinated process mediated by membrane protrusion at the front and contractile retraction at the back. This review compares a local excitation and global inhibition (LEGI) model and an emerging structural polarity of receptor activation (SPRA) model. The LEGI model posits that locally excitable signals generate membrane protrusions that become a single front through uncharacterized global inhibition that suppress competing protrusions. In contrast, the SPRA model proposes a central role of structural polarization, particularly membrane proximal F-actin, endoplasmic reticulum (ER)-plasma membrane (PM) contact sites, as well as actomyosin and nuclear positioning. In this model, the structural asymmetry ultimately sets up a stable front-to-back signal gradient, by enhancing receptor activity at the front and diminishing it at the back. Local differences in receptor sensitivity explains how uniform receptor stimuli initiate protrusions and trigger persistent cell migration. We discuss the mechanistic evidence for the two directed migration models and key open questions.

DOI: https://doi.org/10.1101/cshperspect.a041740