bims-mecosi 2026-03-01 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–03–01
fourteen papers selected by
Verena Kohler, Umeå University

The endoplasmic reticulum in mitochondrial protein targeting: A neuronal perspective on organelle crosstalk.
Hoi1 targets BLTP2 to ER-PM contact sites to regulate lipid homeostasis.
Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.
STARD3 regulates lysosome positioning and contacts via a GSK3-controlled phosphorylation switch.
Endoplasmic Reticulum-Mitochondria Calcium Drives Salivary Bioenergetics.
VapA/Scs2 sustains polarized growth in Aspergillus nidulans by maintaining AP-2-mediated apical endocytosis.
NEAT1 drives SARS-CoV-2 N protein-induced inflammation, metabolic reprogramming, and mitochondria-ER stress crosstalk.
Excessive Ca 2+ -dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury.
Unfolded Protein Response at the Crossroads: Integrating Endoplasmic Reticulum Stress with Cellular Stress Networks.
Mapping the scientific landscape of mitochondria-associated membranes: a bibliometric insight into emerging frontiers in aging and diseases.
The Interplay Between Ca2+ Homeostasis, Endoplasmic Reticulum Stress, and the Unfolded Protein Response in Human Diseases.
Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
Organelle communication networks rewire to support lipid metabolism during neuronal differentiation.
Cutamesine attenuates hippocampal damage via sigma-1 receptor activation following oxygen-glucose deprivation in vitro.

Protein Sci. 2026 Mar;35(3): e70506

The endoplasmic reticulum in mitochondrial protein targeting: A neuronal perspective on organelle crosstalk.

J Tabitha Hees, Angelika B Harbauer.

  Neurons depend on tightly regulated spatial proteostasis to maintain function across their extended morphology. The endoplasmic reticulum (ER), traditionally known for its function in protein synthesis, folding, and trafficking, has long been recognized as a central platform for directing proteins to organelles of the secretory and endocytic pathways. In contrast, its involvement in the targeting of mitochondrial proteins, which are not directly connected to classical trafficking routes, remains less well understood and has only recently gained attention. Growing evidence implicates the ER in post-translational delivery of mitochondrial precursors through mechanisms that integrate local translation, chaperone activity, and dynamic organelle contact sites. ER-mitochondria contacts form dynamic platforms for precursor translation, stabilization and transfer, as exemplified by pathways such as ER-SURF. Endolysosomes add an additional layer of regulation by influencing both ER function and mitochondrial proteostasis. However, how these processes are mechanistically coordinated, particularly in neurons with their complex architecture, remains incompletely understood. In this review, we synthesize the current understanding on ER-mediated mitochondrial protein targeting, highlight the role of membrane contact sites between ER, mitochondria and endolysosomes, and discuss how chaperone networks and signaling pathways shape mitochondrial precursor handling. We further explore how disruption of these systems might contribute to neurodegeneration, positioning organelle crosstalk as a critical determinant of mitochondrial proteostasis and neuronal health.

Keywords:  ER‐SURF; endoplasmic reticulum; mitochondrial protein targeting; neurodegeneration; organelle crosstalk

DOI:  https://doi.org/10.1002/pro.70506
J Cell Biol. 2026 May 04. pii: e202502131. [Epub ahead of print]225(5):

Hoi1 targets BLTP2 to ER-PM contact sites to regulate lipid homeostasis.

Samantha K Dziurdzik, Vaishnavi Sridhar, Hailey Eng, Sarah D Neuman, Junran Yan, Michael Davey, Stefan Taubert, Arash Bashirullah, Elizabeth Conibear.

Membrane contact sites between organelles are important for maintaining cellular lipid homeostasis. Members of the recently identified family of bridge-like lipid transfer proteins (BLTPs) span apposing membranes at these contact sites to enable the rapid transfer of bulk lipids between organelles. While the VPS13 and ATG2 family members use organelle-specific adaptors for membrane targeting, the mechanisms that regulate other bridge-like transporters are unclear. Here, we identify the conserved protein Ybl086c, which we name Hob interactor 1 (Hoi1), as an adaptor that targets the yeast BLTP2-like proteins Fmp27/Hob1 and Hob2 to ER-plasma membrane (PM) contact sites. Two separate Hoi1 domains interface with α-helical projections that decorate the central hydrophobic channel on Fmp27, and loss of these interactions alters cellular sterol homeostasis. The mutant phenotypes of BLTP2 and HOI1 orthologs indicate these proteins act in a shared pathway in worms and flies. Together, this suggests that Hoi1-mediated recruitment of BLTP2-like proteins represents an evolutionarily conserved mechanism for regulating lipid transport at membrane contact sites.

DOI: https://doi.org/10.1083/jcb.202502131
Biomolecules. 2026 Feb 10. pii: 280. [Epub ahead of print]16(2):

Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.

Lara Cantarero, Janet Hoenicka, Francesc Palau.

  The mitochondrial outer membrane (OMM) plays a crucial role in maintaining cellular homeostasis by regulating mitochondrial dynamics, organelle interactions, and stress responses. In peripheral neurons-cells with high metabolic demands and long axons-the OMM acts as a vital platform for coordinating bioenergetics, calcium signaling, and redox balance. Ganglioside-induced differentiation-associated protein 1 (GDAP1), an OMM-anchored protein, has emerged as a key regulator of mitochondrial fission and transport, redox homeostasis, and mitochondrial membrane contact sites (MCSs). Genetic variants in GDAP1 cause Charcot-Marie-Tooth disease (CMT), emphasizing its essential role in peripheral nerve function. This review highlights the multifaceted functions of GDAP1 in neuronal physiology and as a model protein that integrates organelle communication and mitochondrial biology. We further discuss how GDAP1 dysfunction leads to structural and functional impairments in peripheral neurons, proposing the OMM and its microenvironment as critical targets for therapeutic intervention in inherited neuropathies.

Keywords:  Charcot-Marie-Tooth disease; GDAP1; axon; axonopathy; glial cells; lysosomes; membrane contact sites; mitochondria; neuroinflammation; neuron; neuropathies; outer mitochondrial membrane; peroxisomes

DOI:  https://doi.org/10.3390/biom16020280
EMBO J. 2026 Feb 25.

STARD3 regulates lysosome positioning and contacts via a GSK3-controlled phosphorylation switch.

Julie Eichler, Corinne Wendling, Sophie Huver, Mehdi Zouiouich, Victor Hanss, Anna Cardinal, Victoria Fimbel, Catherine Birck, Alastair G McEwen, Céline Knorr, Catherine Fromental-Ramain, Maxime Boutry, Marie-Pierre Chenard, Guillaume Drin, Catherine Tomasetto, Fabien Alpy.

  Membrane contact sites (MCS) are dynamic regions where the membranes of two organelles come into close apposition. MCSs play many roles in cellular homeostasis by facilitating inter-organelle lipid exchange and organelle positioning. The late endosome/lysosome (LE/Lys) cholesterol transfer protein STARD3 forms reversible contacts between LE/Lys and the endoplasmic reticulum (ER). This tether protein contains a Phospho-FFAT motif (two phenylalanines in an acidic tract) whose interaction with ER-resident VAPs (vesicle-associated membrane protein-associated proteins) is phosphorylation-dependent. In this study, we identify GSK3α and GSK3β as the kinases responsible for phosphorylating serine 209 within the Phospho-FFAT motif of STARD3. This phosphorylation event is both necessary and sufficient to activate STARD3's tethering activity, thereby promoting ER-LE/Lys contacts. Furthermore, we show that when ER-LE/Lys tethering is prevented, STARD3 triggers LE/Lys homotypic interactions, revealing an additional function for STARD3 on endosome biology. Our findings establish a direct and critical role for GSK3 in regulating MCS via STARD3 phosphorylation, and expand our understanding of the molecular basis of inter-organelle communication.

Keywords:  Endoplasmic Reticulum; Endosome; Lipid Transfer Protein; Membrane Contact Site; Phosphorylation

DOI:  https://doi.org/10.1038/s44318-026-00705-3
J Dent Res. 2026 Feb 24. 220345251411909

Endoplasmic Reticulum-Mitochondria Calcium Drives Salivary Bioenergetics.

S N Min, X D Mao, J Z Su, L L Wu, G Y Yu, X Cong.

  Saliva secretion requires continuous energy supply throughout the day. Mitochondria dynamically adapt to fluctuating energy demands, yet the mechanisms underlying the adaptions remain poorly understood. Here, we employed real-time intravital imaging and fluorescence lifetime imaging microscopy (FLIM) to monitor mitochondria functions in submandibular glands. We revealed distinct mitochondrial distribution patterns; in acinar cells, mitochondria were predominantly distributed near the cell membranes or scattered throughout the cytoplasm with extensive endoplasmic reticulum (ER)-mitochondria contact sites, whereas in ductal cells, mitochondria were densely packed within the cytoplasm. At resting states, mitochondria exhibited larger volumes, fewer numbers, and higher oxidative phosphorylation activity in acinar cells compared with those in ductal cells. Upon stimulation with pilocarpine, mitochondrial motility, NAD(P)H levels, NAD(P)H enzyme-bound fractions, and mitochondrial adenosine triphosphate (ATP) production were significantly elevated. Pilocarpine-induced secretion, mediated by both aquaporin 5 translocation and the opening of paracellular pathway, was markedly attenuated by oligomycin A, an ATP synthase inhibitor. Notably, pilocarpine increased mitochondria-ER contact sites to 1.7 times the control level (from 18% to 31%), and blocking mitochondrial calcium uptake significantly suppressed pilocarpine-induced NAD(P)H and ATP production. These findings highlight the critical role of ER-mitochondria calcium transfer in sustaining bioenergetics required for salivary secretion, providing new insights into mitochondrial functional adaptation and its physiological significance in intact secretory systems.

Keywords:  NADH; energy metabolism; mitochondria associated membranes; muscarinic acetylcholine receptor; secretion; submandibular gland

DOI:  https://doi.org/10.1177/00220345251411909
Microb Cell. 2026 ;13 63-85

VapA/Scs2 sustains polarized growth in Aspergillus nidulans by maintaining AP-2-mediated apical endocytosis.

Xenia Georgiou, Sofia Politi, Sotiris Amillis, George Diallinas.

  Growth of filamentous fungi is highly polarized requiring the coordinated apical delivery of cell wall components and plasma membrane (PM) material, primarily lipids and proteins, to hyphal tips via conventional vesicular secretion. Fungal growth also requires the tight coordination of exocytosis (secretion) with endocytosis and recycling of proteins and lipids, which occurs in a defined region behind the growing tip known as the endocytic collar. Here, we genetically characterized proteins tentatively implicated in the formation of endoplasmic reticulum-plasma membrane (ER-PM) contact sites, including Scs2/VAP, tricalbins and Ist2 homologues, in Aspergillus nidulans. We showed that among these proteins, only the single Scs2/VapA homologue is essential for normal fungal growth, and this requirement is due to the critical role of VapA in maintaining the polarized localization of apical cargoes, such as the lipid flippases DnfA and DnfB or the SNARE protein SynA. In Δ vapA mutants, these cargoes lose their polarized localization, a phenotype that correlates with the mislocalization of the AP-2 cargo adaptor complex, which is essential for the endocytosis and recycling of apical membrane components. Further analysis provides evidence linking the defect in apical cargo endocytosis observed in Δ vapA mutants to altered membrane lipid partitioning, suggesting that VapA contributes to lipid domain organization critical for cargo recycling. Strikingly, deletion of VapA does not impair the localization or endocytosis of non-polarized (subapical) plasma membrane transporters, indicating that the trafficking and biogenesis of polarized (apical) versus non-polarized (subapical) cargoes are differentially dependent on membrane lipid composition and domain-specific organization.

Keywords:  ER-PM membrane contacts; fungi; membrane contact sites; secretion; sorting; traffic

DOI:  https://doi.org/10.15698/mic2026.02.868
Sci Rep. 2026 Feb 25.

NEAT1 drives SARS-CoV-2 N protein-induced inflammation, metabolic reprogramming, and mitochondria-ER stress crosstalk.

Cheng Qing, Huaigang Chen, Shuying Huang, Jianguo Zhang, Chaoqi Zhou, Shichao Zhang, Kaihang Luo, Cheng Wang, Zhiguo Hu, Yuting Yang, Jia Zhou, Zhenguo Zeng.

  SARS-CoV-2 remains a global health concern. Although its nucleocapsid (N) protein supports viral replication and evades host immunity, its role in host metabolic reprogramming and organelle homeostasis is not fully understood. This study aims to elucidate whether the N protein modulates glycolysis and mitochondrial-ER stress crosstalk via the long non-coding RNA NEAT1. We established human bronchial epithelial (HBE) cells stably expressing the N protein. Inflammatory and glycolytic gene expression was analyzed by qRT-PCR and Western blot. ROS levels were measured by flow cytometry, while mitochondrial membrane potential, Ca²⁺ overload, and mitochondria-ER contact sites (MAMs) were assessed by confocal microscopy. NEAT1 knockdown and HK2-VDAC1 interaction studies were performed to explore underlying mechanisms. The N protein induced inflammatory responses, enhanced LPS sensitivity, and triggered mitochondrial dysfunction, ER stress, and MAM formation. It promoted glycolytic reprogramming by upregulating key enzymes (GLUT1, HK2, PKM2). NEAT1 was essential for these effects-N protein increased NEAT1 expression, and NEAT1 knockdown attenuated inflammation, glycolysis, and mitochondrial damage. Mechanistically, NEAT1 silencing restored HK2-VDAC1 association and suppressed VDAC1 oligomerization. The SARS-CoV-2 N protein exacerbates inflammation through a NEAT1-dependent mechanism that drives glycolytic reprogramming and disrupts mitochondrial-ER homeostasis.

Keywords:  COVID-19 inflammation; Glycolytic reprogramming; Long non-coding RNA NEAT1; Mitochondria-ER stress crosstalk; SARS-CoV-2 nucleocapsid protein

DOI:  https://doi.org/10.1038/s41598-026-40957-x
bioRxiv. 2026 Feb 16. pii: 2026.02.13.705622. [Epub ahead of print]

Excessive Ca 2+ -dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury.

David R Eberhardt, Emma C Rekate, Yasmin B Masini, Hannah E Duron, David Mollinedo, Adrian M Velarde, Devorah Stucki, Tara Price, Sandra H J Lee, Enrique Balderas, Neeraj K Rai, Ashley R Bratt, Anthony M Balynas, Chris J Stubben, Ryan Bia, Sudipa Maity, Nicolas Hartel, Xue Yin, Andrea Corbin, Anshu Kumari, Dung M Nguyen, Daisuke Shimura, Vu D Nguyen, Vishaka Vinod, Kamrul H Chowdhury, Francisco Verdeguer, Joel Zvick, Patrice N Mimche, Sihem Boudina, Stavros G Drakos, Ademuyiwa S Aromolaran, Sarah Franklin, Vivek Garg, Robin M Shaw, William L Holland, Scott A Summers, Marcus G Pezzolesi, Jared Rutter, Kimberley J Evason, Dipayan Chaudhuri.

Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca 2+ -dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca 2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-dependent stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca 2+ -dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.

DOI: https://doi.org/10.64898/2026.02.13.705622
Int J Mol Sci. 2026 Feb 19. pii: 1986. [Epub ahead of print]27(4):

Unfolded Protein Response at the Crossroads: Integrating Endoplasmic Reticulum Stress with Cellular Stress Networks.

Sebastian Gawlak-Socka, Edward Kowalczyk, Anna Wiktorowska-Owczarek.

  The endoplasmic reticulum (ER) is a central hub of cellular proteostasis, coordinating protein folding, lipid metabolism, calcium signaling, and inter-organelle communication. Disruptions in ER function activate the unfolded protein response (UPR), an evolutionarily conserved signaling network mediated by PERK, IRE1α, and ATF6. Initially viewed primarily as a stress-mitigating mechanism, the UPR is now recognized as a central coordinator of diverse cellular stress-response pathways. This review focuses on mechanistic insights into UPR signaling, with particular emphasis on its crosstalk with oxidative stress regulation, mitochondrial function and mitochondria-ER contact sites, autophagy, inflammatory signaling, and metabolic sensing. The analysis integrates evidence from biochemical and structural studies, genetic and pharmacological perturbation models, and selected in vivo investigations from PubMed and Google Scholar between 2000 and 2025, focusing on mechanistic, experimental and translational studies addressing UPR signaling and ER stress. Together, these studies demonstrate how transient UPR activation promotes cellular adaptation through coordinated transcriptional, translational, and organelle-specific responses. We further discuss how sustained or unresolved ER stress alters UPR outputs, shifting signaling toward maladaptive outcomes such as mitochondrial dysfunction, dysregulated autophagy, oxidative imbalance, and apoptosis. By placing the UPR within a network of interconnected stress pathways, this work provides a framework for understanding how ER proteostasis is linked to cell fate decisions under stress.

Keywords:  autophagy; endoplasmic reticulum stress; inflammation; metabolic stress; oxidative stress; unfolded protein response

DOI:  https://doi.org/10.3390/ijms27041986
Int J Surg. 2026 Feb 24.

Mapping the scientific landscape of mitochondria-associated membranes: a bibliometric insight into emerging frontiers in aging and diseases.

Jiao Pang, Yunxiang Zhang, Yuan Tian, Xingrui Cao, Xueshu Tao, Cheng Sun, Zhipeng Cao.

   BACKGROUND: Mitochondria-associated membranes (MAMs) are critical hubs coordinating energy metabolism, lipid homeostasis, and Ca2⁺ signaling, thereby regulating cell survival, stress responses, and apoptosis. Increasing evidence links MAMs dysfunction to aging, neurodegenerative diseases, metabolic disorders, and cancer. Although numerous mechanistic studies and narrative reviews have been published, a systematic, mechanism-oriented bibliometric evaluation of the global MAMs research landscape is still lacking.
METHODS: We performed a comprehensive bibliometric analysis of MAMs-related literature indexed in the Web of Science Core Collection from 2009 to 2024, using Bibliometrix, VOSviewer, and CiteSpace to integrate publication trends, collaboration networks, keyword co-occurrence, thematic evolution, and citation impact.
RESULTS: A total of 1199 publications were identified, showing a rapid annual growth rate of 21.57%. Beyond general trend analysis, our study reveals that research hotspots converge on Ca2⁺ homeostasis, ER stress, apoptosis, and mitochondrial dynamics, and progressively shift toward aging-related biological processes. By mapping high-frequency keywords to known MAMs-associated pathways, we identify aging, ER stress, and apoptosis as interconnected emerging themes. Importantly, this analysis highlights specific MAMs-related proteins, including HSP90α, as potential regulatory hubs linking stress responses and aging.
CONCLUSIONS: This study provides the first integrative, mechanism-oriented bibliometric framework of MAMs research, bridging quantitative publication patterns with underlying biological pathways. Our findings not only delineate the intellectual structure and evolving themes of the field but also generate testable hypotheses implicating MAMs and key regulatory proteins in aging-related processes, thereby offering guidance for future mechanistic and translational studies.

Keywords:  MAMs; MAMs-related proteins; aging; bibliometrics; mitochondria

DOI:  https://doi.org/10.1097/JS9.0000000000004989
Cells. 2026 Feb 15. pii: 352. [Epub ahead of print]15(4):

The Interplay Between Ca2+ Homeostasis, Endoplasmic Reticulum Stress, and the Unfolded Protein Response in Human Diseases.

Elia Ranzato, Simona Martinotti.

  The maintenance of endoplasmic reticulum (ER) Ca2+ homeostasis is intrinsically linked to the fidelity of protein folding, forming a functional tether that, when disrupted, triggers the Unfolded Protein Response (UPR). This bidirectional axis serves as a critical rheostat for cellular viability, yet its chronic dysregulation underpins the molecular etiology of numerous pathologies, including neurodegeneration, heart failure, and malignant transformation. This review provides a comprehensive interrogation of the Ca2+-ER Stress-UPR network, delineating how primary stress sensors-PERK, IRE1alpha, and ATF6-engage in complex feedback loops that either reinstate equilibrium or commit the cell to apoptosis. We specifically examine the PERK-CHOP-SERCA2b inhibitory circuit as a central driver of persistent Ca2+ depletion and discuss the role of Mitochondria-Associated Membranes (MAMs) in governing lethal Ca2+ transfer. Notably, we move beyond the classical paradigm of CHOP as a terminal apoptotic executioner, incorporating emerging evidence of its context-dependent adaptive functions. By synthesizing mechanistic insights across diverse disease models, this work highlights the transition from adaptive to maladaptive UPR as a universal pathological checkpoint. Ultimately, we evaluate the therapeutic potential of 'axis-targeted' interventions, such as SERCA activators and selective UPR modulators, aimed at resolving the underlying Ca2+ signaling defects in ER stress-related disorders.

Keywords:  ER stress; calcium dyshomeostasis; unfolded protein response (UPR)

DOI:  https://doi.org/10.3390/cells15040352
Nat Cell Biol. 2026 Feb 26.

Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.

Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.

Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.

DOI: https://doi.org/10.1038/s41556-026-01890-3
bioRxiv. 2026 Feb 11. pii: 2026.02.10.704675. [Epub ahead of print]

Organelle communication networks rewire to support lipid metabolism during neuronal differentiation.

Maria Clara Zanellati, Zachary Coman, Disha Bhowmik, Chih-Hsuan Hsu, Richa Basundra, Shannon N Rhoads, Ngudiankama R Mfulama, Brandie M Ehrmann, Mohanish Deshmukh, Sarah Cohen.

Cell fate transitions require coordinated remodeling of intracellular organelles, but how the organelle interactome rewires during neurogenesis remains unclear. Here we combine multispectral imaging with quantitative organelle signature analysis to simultaneously map eight organelles at single-cell resolution as human induced pluripotent stem cells (iPSCs) differentiate into forebrain-like neurons. We find compartment and time-specific rescaling of organelles and a progressive increase in higher-order membrane contacts, with mitochondria emerging as an early interaction hub. Later, endoplasmic reticulum (ER)-organelle contacts dominate with ER-peroxisome contacts promoting plasmalogen biosynthesis, membrane homeostasis and synapse formation. Disrupting this contact impairs plasmalogen production, synaptic organization, and neuronal activity, identifying the ER-peroxisome axis as a key regulator of neuronal maturation.

DOI: https://doi.org/10.64898/2026.02.10.704675
Brain Res. 2026 Feb 20. pii: S0006-8993(26)00083-1. [Epub ahead of print] 150225

Cutamesine attenuates hippocampal damage via sigma-1 receptor activation following oxygen-glucose deprivation in vitro.

Alba Puente-Sanz, Costanza Mazzantini, Martina Venturini, Francesca Mainolfi, Amanda Herrero-González, Anna Maria Pugliese, Arsenio Fernández-López, Domenico E Pellegrini-Giampietro, Elisa Landucci.

  Cerebral ischemia is a leading cause of death and disability worldwide, due to neuronal energy failure, calcium overload, ER stress and inflammation. Sigma-1 receptor activation regulates calcium signaling between ER and mitochondria and reduces the activation of ER stress and inflammation pathways. In the present study, we investigated the neuroprotective effects of the sigma-1 receptor agonist cutamesine in rat organotypic, and acute hippocampal slices exposed to oxygen-glucose deprivation (OGD), two in vitro models of global ischemia. In organotypic hippocampal slices obtained from both sexes exposed to 30 min of OGD, we evaluated the neuroprotective effects of cutamesine by quantifying CA1 cell death via propidium iodide fluorescence. We also assessed mRNA and protein levels of key ER stress and inflammation markers via RT-qPCR and Western blot. In acute hippocampal slices, we evaluated the effects of cutamesine on recorded extracellular field excitatory postsynaptic potentials following OGD. Cutamesine exhibited neuroprotective effects at 10 µg/mL in organotypic hippocampal slices exposed to 30 min of OGD, and this effect was reduced by the sigma-1 receptor antagonist BD1047. Cutamesine reduced ER stress and inflammation pathways by decreasing GRP78, GRP94, p-p65, and MMP-9 protein levels and these effects were partially decreased by BD1047. Cutamesine also delayed the onset of anoxic depolarization latency on acute hippocampal slices obtained from male rats. These findings evidence the notion that the sigma-1 receptor may be a promising therapeutic target for ischemic injury. Abbreviations: aCSF, artificial cerebrospinal fluid; AD, anoxic depolarization; Cornu Ammonis 1, CA1; ER, endoplasmic reticulum; fEPSP, field excitatory postsynaptic potentials; GRP78, 78-kDa glucose-regulated protein; GRP94, glucose-regulated protein 94; IL-1β, interleukin-1 beta; MAMs, mitochondria-associated membranes; MMP-9, matrix metalloproteinase-9; OGD, oxygen and glucose deprivation; PI, propidium iodide; p-NF-κB, phosphorilated nuclear factor -kappa-B p65 subunit (p-p65); ROS, reactive oxygen species; Sig-1 receptor, sigma-1 receptor; TNF-α, tumor necrosis factor-alpha; UPR, unfolded protein response.

Keywords:  Acute hippocampal slices; Cerebral ischemia; ER stress; MMP-9; Neuroprotection; Organotypic hippocampal slices

DOI:  https://doi.org/10.1016/j.brainres.2026.150225