bims-mecosi 2025-08-10 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–08–10
fourteen papers selected by
Verena Kohler, Umeå University

PDZD8 links organelle crosstalk to synaptic remodeling via autophagy.
Crystal structure of Fis1 and Bap31 provides information on protein-protein interactions at mitochondria-associated ER membranes.
Establishment of the phagophore-ERES membrane contact site initiates phagophore elongation.
Emerging roles of lipid transfer protein dimerization.
The complex web of membrane contact sites in brain aging and neurodegeneration.
Canagliflozin ameliorates diabetic podocyte damage via enriching mitochondria-associated endoplasmic reticulum membranes.
Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
High-Fat Diet Impairs Translocation of Phosphatidylserine From Mitochondria-Associated Membranes (MAM) Into Mitochondria by the Conservative Mechanism From Fish to Tetrapod.
Cadmium-Induced Mitochondrial and MAMs Dysregulation in Rat Testis: The Protective Role of D-Aspartate.
Calcium signaling in postsynaptic mitochondria: mechanisms, dynamics, and role in ATP production.
Cradles of cellular architecture: ER nests as hubs for organelle birth.
Programmable DNA Nanocages Enable Adaptive Spatiotemporal Organization of Biomimetic Organelle Networks.
Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.
Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.

Autophagy. 2025 Aug 03. 1-2

PDZD8 links organelle crosstalk to synaptic remodeling via autophagy.

Rajan S Thakur, Kate M O'Connor-Giles.

  Synapse formation and plasticity require coordinating cellular processes from signaling to protein turnover over long distances, placing high demands on intracellular communication. Membrane contact sites (MCSs) between organelles are specialized compartments for coordinating cellular processes, yet their functions in the developing nervous system remain poorly understood. Through an in vivo CRISPR screen in Drosophila, we identified the conserved endoplasmic reticulum (ER) MCS tethering protein Pdzd8 as a regulator of activity-dependent synapse development. Our in vivo studies demonstrate that Pdzd8 functions at ER-late endosome/lysosome MCSs to promote lysosomal maturation and increase autophagic flux during periods of high demand such as prolonged neuronal activity.

Keywords:  Autophagy; PDZD8; lipid transfer; lysosomes; membrane contact sites; synapse

DOI:  https://doi.org/10.1080/15548627.2025.2537983
Commun Biol. 2025 Aug 06. 8(1): 1161

Crystal structure of Fis1 and Bap31 provides information on protein-protein interactions at mitochondria-associated ER membranes.

Minh Duc Nguyen, Yonghyeok Kim, Seung-Hyun Bae, Soeun Kim, Hyun Ku Yeo, Nam-Chul Ha, Ginam Cho, Sunghyun Moon, Kwang-Hwi Cho, Hyonchol Jang, Seoung Min Bong, Byung Il Lee.

In eukaryotic cells, mitochondria and the endoplasmic reticulum (ER) form close contacts at mitochondria-associated ER membranes (MAMs), which are involved in diverse cellular processes. The outer mitochondrial membrane protein Fis1, known for its role in mitochondrial fission, has been reported to interact with the ER-resident protein Bap31. Here, we present crystal structures of the cytosolic domain of human Fis1 in two distinct conformations, along with a co-crystal structure of Fis1 bound to the C-terminal region of the Bap31_vDED domain. One Fis1 structure resembles monomeric yeast Fis1 and features a characteristic N-terminal "Fis1 arm" conformation, which may indicate an autoinhibitory function. In the co-complex, the Bap31_vDED region engages the convex surface of Fis1's tetratricopeptide repeat (TPR) domain. These findings provide structural insight into the interaction between Fis1 and Bap31 at ER-mitochondria contact sites.

DOI: https://doi.org/10.1038/s42003-025-08625-4
Nat Struct Mol Biol. 2025 Aug 07.

Establishment of the phagophore-ERES membrane contact site initiates phagophore elongation.

Rubén Gómez-Sánchez, Sabrina Chumpen Ramirez, Prado Vargas Duarte, Yan Hu, Muriel Mari, Katharina Olschewski, Ralph Hardenberg, J Christopher Fromme, Christian Ungermann, Fulvio Reggiori.

The de novo generation of membrane contact sites (MCSs) between the phagophore and the endoplasmic reticulum exit sites (ERES) is important for the acquisition of the lipids necessary for phagophore elongation and autophagosome formation during autophagy. However, it is currently unclear how these MCSs are established. Here, we show that the TRAPPIII complex, the guanine nucleotide exchange factor of the Rab GTPase Ypt1, localizes to and regulates the formation of the MCS between the phagophore and the ERES. In particular, TRAPPIII and the lipid transfer protein Atg2 appear equally essential for the association of the phagophore with the ERES, TRAPPIII activation and Ypt1 activation onto the phagophore. Ypt1 redistributes over the entire surface of the phagophore and promotes its elongation through both stimulation of the local biosynthesis of phosphatidylinositol-3-phosphate and recruitment of the downstream effectors Atg18 and Atg21. Our data suggest that de novo generation of the phagophore-ER MCSs and subsequent Ypt1 activation initiates phagophore elongation.

DOI: https://doi.org/10.1038/s41594-025-01621-6
J Cell Sci. 2025 Aug 01. pii: jcs263971. [Epub ahead of print]138(15):

Emerging roles of lipid transfer protein dimerization.

Shalom Borst Pauwels, Jacques Neefjes, Birol Cabukusta.

  The unique lipid composition of organelles defines their identity and is fundamental to their function. Lipid transfer proteins perform non-vesicular trafficking of lipids among cellular membranes to maintain their lipid compositions. Lipid transfer protein-mediated lipid trafficking is also essential for creating sub-organellar nano-domains that can recruit functional proteins or change the biophysical properties of membranes. The latest research focusing on the homo- and hetero-dimerization of lipid transfer proteins highlights the functional implications and the clinical significance of these events. Dimerization promotes lipid transfer protein localization at membrane contact sites and mediates the assembly of lipid transfer protein super-complexes to synchronize the transfer of different lipid types between organelles. Meanwhile, abnormal lipid flows caused by disarrangements in lipid transfer protein dimerization disturb organelle lipid landscapes, which has clinical consequences. This Review discusses the latest developments regarding the dimerization of lipid transfer proteins and their adaptor proteins that are critical for lipid trafficking between the organelles of the cell.

Keywords:  Dimerization; Lipid transfer proteins; Membrane contact sites; Non-vesicular trafficking

DOI:  https://doi.org/10.1242/jcs.263971
Cell Mol Life Sci. 2025 Aug 08. 82(1): 301

The complex web of membrane contact sites in brain aging and neurodegeneration.

Domenico Azarnia Tehran, Paola Pizzo.

  To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for cellular communication, mediating a broad range of physiological processes, including calcium signalling, lipid synthesis and bioenergetics. MCS are particularly abundant and indispensable in polarized and long-lived cells, such as neurons, where they support both structural and functional integrity. In this review, we explore the functional diversity, molecular composition, and dynamic regulation of key mammalian MCS: endoplasmic reticulum (ER)-plasma membrane, ER-mitochondria and contact sites involving lipid droplets. We highlight their central role in neuronal health and discuss how MCS dysfunction has increasingly been recognized as a hallmark of brain aging and various neurodegenerative diseases, most notably Alzheimer's disease, where altered MCS dynamics contribute to pathogenesis. Finally, we emphasize the therapeutic potential of targeting MCS and outline key unanswered questions to guide future research.

Keywords:  Inter-organelle crosstalk; Neuronal homeostasis; Organelle contacts; Synaptic dysfunction; Therapeutic targets

DOI:  https://doi.org/10.1007/s00018-025-05830-6
Cell Signal. 2025 Jul 31. pii: S0898-6568(25)00453-X. [Epub ahead of print]135 112038

Canagliflozin ameliorates diabetic podocyte damage via enriching mitochondria-associated endoplasmic reticulum membranes.

Ting Zheng, Liman Luo, Xing Wang, Xuan Deng, Mei Xue.

  Sodium-glucose cotransporter 2 (SGLT2) inhibitors have renoprotective properties in diabetic kidney disease (DKD) that extend beyond blood glucose-lowering effects; however, the underlying mechanism remains unclear. Recent studies suggest that the altered homeostasis of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) was closely associated with the progression of DKD. In the current study, we investigated the effects of canagliflozin on diabetic podocyte injury and MAM formation in db/db mice and high glucose-induced podocytes. Eight weeks of canagliflozin treatment (30 mg/kg/day) decreased body weight and blood glucose level, and urinary albumin excretion of diabetic mice. Diabetes-associated renal histopathological changes and podocyte injury of db/db mice were also obviously improved by canagliflozin. In addition, a significant decrease in the MAM area and an increase in the fragmented mitochondria were observed in the podocytes of diabetic kidneys, while canagliflozin enhanced MAM formation and decreased fragmented mitochondria. Furthermore, canagliflozin-treated diabetic mice presented with amelioration of mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and apoptosis. Interestingly, no significant difference was observed after insulin treatment, although its glucose-lowering effect was comparable to that of canagliflozin. In vitro, canagliflozin reversed HG-induced MAM disruption, fragmented mitochondria, podocyte injury, mitochondrial dysfunction, ER stress, and apoptosis in podocytes. However, the above beneficial effects of canagliflozin on podocytes were offset by co-overexpression of FATE1, an uncoupler of MAM, under HG conditions. Taken together, these findings indicate that canagliflozin improves diabetic podocyte injury via modulating MAM structure and function.

Keywords:  Canagliflozin; Diabetic kidney disease; Mitochondria-associated endoplasmic reticulum membranes; Podocyte injury

DOI:  https://doi.org/10.1016/j.cellsig.2025.112038
bioRxiv. 2025 Jul 29. pii: 2025.07.28.667051. [Epub ahead of print]

Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.

Casadora Boone, Sophie Judge, Ahmad Shami, Bezawit Danna, Andrea B Ball, Tejashree Pradip Waingankar, Hera Saqub, Ajit S Divakaruni, Samantha C Lewis.

Fatty acids are trafficked between organelles to support membrane biogenesis and act as signaling molecules to rewire cellular metabolism in response to starvation, overnutrition, and environmental cues. Mitochondria are key cellular energy converters that harbor their own multi-copy genome critical to metabolic control. In homeostasis, mitochondrial DNA (mtDNA) synthesis is coupled to mitochondrial membrane expansion and division at sites of contact with the endoplasmic reticulum (ER). Here, we provide evidence from cultured hepatocytes that mtDNA synthesis and lipid droplet biogenesis occur at spatially and functionally distinct ER-mitochondria membrane contact sites. We find that, during saturated lipid stress, cells pause mtDNA synthesis and mitochondrial network expansion secondary to rerouted fatty acid trafficking through the ER and lipid droplet biogenesis, coincident with a defect in soluble protein import to the ER lumen. The relative composition of fatty acid pools available to cells is critical, as monounsaturated fatty acid supplementation rescued both ER proteostasis and mtDNA synthesis, even in the presence of excess saturated fat. We propose that shutoff of mtDNA synthesis conserves mtDNA-to-mitochondrial network scaling until cells can regain ER homeostasis.
Summary: Overnutrition of cultured human cells causes endoplasmic reticulum dysfunction, which downregulates mitobiogenesis in turn by constraining mtDNA synthesis.

DOI: https://doi.org/10.1101/2025.07.28.667051
FASEB J. 2025 Aug 15. 39(15): e70889

High-Fat Diet Impairs Translocation of Phosphatidylserine From Mitochondria-Associated Membranes (MAM) Into Mitochondria by the Conservative Mechanism From Fish to Tetrapod.

Xiao-Hong Lai, Guang-Li Feng, Nan-Jun Hu, Fei-Fei Zheng, Yu-Feng Song.

  High-fat diet (HFD)-induced hepatic steatosis represents a significant global health challenge, yet the precise role of phospholipid (PLs) dysregulation in its pathogenesis remains unclear. Although the critical role of mitochondria-associated membranes (MAMs) in maintaining PL homeostasis is increasingly recognized, the molecular mechanisms underlying MAM-mediated inter-organelle PLs translocation and the resulting functional consequences remain poorly understood. Additionally, whether MAM-mediated PLs homeostasis represents a conserved mechanism across vertebrates has yet to be determined. To address these knowledge gaps, this study investigated the mechanistic and evolutionary basis of MAM-mediated PLs translocation in hepatic lipid metabolism using an in vivo model of yellow catfish (Pelteobagrus fulvidraco) fed either a control or HFD for 8 weeks, followed by comparative validation in tetrapods (frogs, chickens, mice and human beings) in vitro. The key findings include: (1) HFD primarily disrupts hepatic phosphatidylserine (PS) homeostasis by impairing ER-to-mitochondria translocation via MAMs, rather than by affecting PS biosynthesis; (2) The Ip3r-Grp75-Vdac/Mcu axis coordinates MAM structural integrity and Ca2+ signaling to mediate PS transfer, where dual grp75/mcu overexpression restores PS trafficking under lipotoxic stress; (3) MAM-dependent PS translocation is essential for maintaining mitochondrial dynamics and β-oxidation capacity, while its disruption under HFD promotes hepatic steatosis. Significantly, this study reveals that MAM-mediated PS homeostasis via the Ip3r-Grp75-Vdac/Mcu axis represents a conserved mechanism in tested species, offering new insights into vertebrate adaptations to lipid overload. These findings highlight MAMs as therapeutic targets for metabolic liver diseases through their role in linking PLs metabolism to mitochondrial function.

Keywords:  conservative mechanisms; high‐fat diet; mitochondria‐associated membranes; phosphatidylserine translocation; phospholipid

DOI:  https://doi.org/10.1096/fj.202501506R
Environ Toxicol. 2025 Aug 04.

Cadmium-Induced Mitochondrial and MAMs Dysregulation in Rat Testis: The Protective Role of D-Aspartate.

Debora Latino, Sara Falvo, Massimo Venditti, Alessandra Santillo, Giulia Grillo, Gabriella Chieffi Baccari, Imed Messaoudi, Maria Maddalena Di Fiore.

  Cadmium (Cd), a heavy metal, disrupts the structure of seminiferous tubules and induces cell death at multiple stages of sperm development. Cd also impairs Leydig cells (LCs), resulting in reduced serum testosterone (T) levels. This study primarily examined the impact of Cd on the mitochondrial compartment and mitochondrial-associated endoplasmic reticulum membranes (MAMs) in rat testis. Additionally, the potential of D-aspartate (D-Asp) to mitigate Cd-induced effects on steroidogenesis and spermatogenesis was assessed by administering D-Asp simultaneously or preventively with Cd. The findings demonstrated that Cd exerts reprotoxicity by affecting the mitochondrial compartment and MAMs, evidenced by an imbalance in mitochondrial dynamics, impaired mitophagy pathway, and downregulated mitochondrial biogenesis. Cd exposure also reduced lipid transfer-related factor expression and increased ER stress. Moreover, elevated levels of Ca2+ transfer-related proteins, indicative of perturbed Ca2+ homeostasis, may be associated with enhanced oxidative stress and apoptosis, which are known effects of Cd. Immunofluorescent analysis revealed that the Cd-induced mitochondrial and MAMs damage was prominent in LCs, spermatocytes, and spermatids, confirming the metal's adverse effects on steroidogenesis and spermatogenesis. Conversely, co-administration or preventive administration of D-Asp with Cd preserved mitochondrial homeostasis and functional ER-mitochondria interactions. In conclusion, the study offers novel insights into the cellular mechanisms underlying Cd-induced reprotoxicity. Importantly, it highlights the efficacy of D-Asp in preventing or counteracting testicular damage caused by Cd by enhancing mitochondrial and MAMs functionality.

Keywords:  D‐aspartate; MAMs; cadmium; mitochondria; testis

DOI:  https://doi.org/10.1002/tox.24559
Front Mol Neurosci. 2025 ;18 1621070

Calcium signaling in postsynaptic mitochondria: mechanisms, dynamics, and role in ATP production.

Tatiana Feofilaktova, Liliia Kushnireva, Menahem Segal, Eduard Korkotian.

  While the overall ATP level in neurons remains relatively stable, local fluctuations in synaptic compartments - driven by synaptic potentials - necessitate rapid ATP adjustments. The energy supply for synaptic activity in neurons must be under precise homeostatic control: increased ATP consumption in active synapses requires continuous replenishment, whereas in periods of inactivity, excess ATP production may occur. Overproduction of ATP in thousands of individual synapses is metabolically wasteful, while underproduction threatens to disrupt molecular cascades associated with ongoing synaptic bursts, ion homeostasis, protein synthesis, and neural plasticity. Fine-tuned regulation of ATP synthesis must therefore be controlled locally and dynamically, ensuring metabolic efficiency while preventing disruptions in synaptic bursts, ion homeostasis, and neuronal plasticity. This review summarizes the intricate molecular mechanisms through which mitochondria (MT) interact with their postsynaptic environment to maintain energy balance. We examined the fundamental features of mitochondria in conjunction with their unique properties and roles in nervous tissue, highlighting their ability to dynamically adjust energy production based on local demand rather than maintaining a strictly uniform ATP output. The regulation of ATP synthesis may involve mitochondrial transport, fusion, and fission, as well as changes in mitochondrial shape and molecular structure. This review describes the activity of ATP synthase, the mitochondrial calcium uniporter and other signaling cascades in the context of their uneven distribution within mitochondria. Furthermore, we discuss rapid calcium influxes from postsynaptic membranes and the endoplasmic reticulum into mitochondria-associated membranes (MAMs), their buffering mechanisms, and the generation of dynamic responses. We focus on the role of calcium ion (Ca2+) as a precise regulator of ATP production, particularly in mitochondria located near synaptic regions, where it ensures an adequate energy supply for local activity. Overall, we propose potential pathways of interaction between mitochondria and their postsynaptic microdomains. Given that some of the mechanisms discussed remain hypothetical, we emphasize the urgent need for experimental validation to refine understanding of mitochondrial function in synaptic transmission.

Keywords:  ATP synthase; Ca2+ signaling; MAM; MCU; dendritic spine; endoplasmic reticulum; mitochondria; mitophagy

DOI:  https://doi.org/10.3389/fnmol.2025.1621070
Dev Cell. 2025 Aug 04. pii: S1534-5807(25)00445-9. [Epub ahead of print]60(15): 2027-2028

Cradles of cellular architecture: ER nests as hubs for organelle birth.

Dibyayan Maity, Amit S Joshi.

In this issue of Developmental Cell, Wright et al. uncover discrete ER subdomains termed "ER nests" as sites for peroxisomes and lipid droplet (LD) biogenesis in Arabidopsis seedlings. ER nests are enriched in lipid biosynthetic enzymes, COPII components, and ER-shaping proteins that coordinate the biogenesis and contact between peroxisomes and LDs.

DOI: https://doi.org/10.1016/j.devcel.2025.07.007
Angew Chem Int Ed Engl. 2025 Aug 08. e202511909

Programmable DNA Nanocages Enable Adaptive Spatiotemporal Organization of Biomimetic Organelle Networks.

Pengyan Hao, Xiaoya Sun, Liqiong Niu, Yuanyuan Luo, Di Lu, Biwu Liu, Na Wu, Yongxi Zhao.

  Synthetic organelles have emerged to simulate the multicompartmental organization and communication within cells. However, current synthetic organelles (e.g., lipid vesicles and polymer-based assemblies) often suffer from insufficient structural stability and lack adaptive feedback mechanisms due to the absence of support and dynamic regulation by natural cytoskeletal proteins, which limits the construction of autonomous communication networks. Here, we present a modular and programmable DNA nanocage strategy for constructing stable and adaptive synthetic organelle networks. Using extracellular vesicles (EVs) as a model, we anchored tetrahedral DNA frameworks (TDNs) on the EV surface and assembled a mechanically reinforced biomimetic DNA nanocage via palindromic hybridization chain reaction (PHCR), thereby significantly enhancing vesicle stability and effectively preventing membrane fusion upon contact. The modular design enables the integration of logic-gated DNA elements as dynamic contact sites, allowing environment-responsive reconfiguration of inter-artificial-organelle spatial organization and signaling. This work provides a customizable platform for constructing artificial organelles with adaptive feedback regulation, offering broad potential in synthetic biology, biomedical applications, and smart material design.

Keywords:  Biomimetic organelles; DNA self‐assembly; DNA structures; Membrane contact sites; Vesicles

DOI:  https://doi.org/10.1002/anie.202511909
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667250. [Epub ahead of print]

Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.

Simon Couly, Yuko Yasui, Ioannis Grammatikakis, Yuriko Kimura, Josh Hinkle, Juan Gomez, Hsiang-En Wu, Ghosh Paritosh, Ashish Lal, Michael Michaelides, Brandon Harvey, Tsung-Ping Su.

Sigma-1 receptor (S1R) is a Ca 2+ sensitive, ligand-operated receptor chaperone protein present on the endoplasmic reticulum (ER) membrane and more specifically at the mitochondria-associated ER membrane (MAM). Upon activation by ER calcium depletion or ligand binding, S1R can increase calcium efflux from the ER into the mitochondria by chaperoning IP3 receptor type3 (Ip3R3). Mitochondrial metabolism has an intricate relationship with glycolysis. Despite S1R affecting mitochondria, the relevance of S1R to glycolysis and its impact on the overall cellular energy metabolism is not known. This study utilizes wild-type (Wt) and S1R knockout (S1R KO) Neuro2a (N2a) cells and Wt and S1R KO mice for primary culture of cortical neurons studies and longitudinal in-vivo imaging. In this manuscript we describe the fundamental functions of S1R on glycolysis, mitochondrial activity and NAD + /NADH metabolism, keystone coenzymes essential for glycolysis and for mitochondrial activity. Both N2a cells and cortical neurons lacking S1R had reduced glycolytic activity, and increased mitochondria complex I protein GRIM19 but no change in mitochondrial oxygen consumption. Furthermore, we observed an increased NAD + /NADH ratio in S1R KO condition. Positron emission tomography revealed decreased [ 18 F]fluorodeoxyglucose brain uptake in S1R KO mice. We observed that knocking down GRIM19 in S1R KO condition rescued the glycolysis deficit. Altogether, these data show for the first time that S1R modulates glycolysis and NAD metabolism in various neuronal systems. This new insight on the S1R function may lead to new therapeutic applications of S1R ligands where compromised glycolysis and cellular NAD+/NADH ratios occur such as aging and neurodegeneration.

DOI: https://doi.org/10.1101/2025.07.28.667250
EMBO Mol Med. 2025 Aug 05.

Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.

Curran Landry, James P Costanzo, Miguel Mitne-Neto, Mayana Zatz, Ashleigh E Schaffer, Maria Hatzoglou, Alysson R Muotri, Helen C Miranda.

  Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.

Keywords:  ALS (Amyotrophic Lateral Sclerosis); ER-MAM (Endoplasmic Reticulum Mitochondria Associated Membrane); ISR (Integrated Stress Response); Neurodegeneration; VAPB ((Vesicle Associated Membrane Protein Associated Protein B)

DOI:  https://doi.org/10.1038/s44321-025-00279-3