bims-mecosi 2026-05-24 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–05–24
eleven papers selected by
Verena Kohler, Umeå University

Kv2-VAP interactions enhance presynaptic ER and mitochondrial calcium influx and the mobilization of vesicles from the reserve pool.
Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.
Genetically Encoded Tools to Monitor and Interrogate Membrane Contact Sites.
S-palmitoylation regulates the function of the mitochondria-associated endoplasmic reticulum membrane to alleviate the senescence of nucleus pulposus cells.
Porphyromonas gingivalis outer membrane vesicles drive neuroinflammation via TGM2-mediated mitochondria-associated endoplasmic reticulum membranes.
Sieve elements. Hidden corners, fierce debates, future prospects.
Novel Organelle-Based Intracellular Immunity with Mechanistic and Therapeutic Implications.
From Natural Drug Regulation to Precise Targeted Intervention: Anti-Heart Failure Mechanisms Based on the Reconstruction of Calcium-Lipid Homeostasis via Mitochondria-Endoplasmic Reticulum Structural Coupling.
Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.
Gene Expression Analysis of Mitochondria-Associated Membrane (MAM)-Related Genes in ER Stress and Alzheimer's Disease.
Atg18 interaction positions Atg2 for efficient lipid transfer into phagophore elongation.

bioRxiv. 2026 May 07. pii: 2026.05.04.722784. [Epub ahead of print]

Kv2-VAP interactions enhance presynaptic ER and mitochondrial calcium influx and the mobilization of vesicles from the reserve pool.

Cameron D Paton, Michael B Hoppa.

In neurons, the endoplasmic reticulum (ER) forms an extensive network that establishes membrane contact sites (MCSs) with various organelles including the plasma membrane (PM). While MCSs are known to regulate lipid exchange and Ca 2+ signaling, their specific roles in synaptic transmission remain poorly understood. Here, we demonstrate that the ER resident proteins VAPA and VAPB are essential for organizing presynaptic Ca 2+ exchange and mobilizing synaptic vesicles. We show that the loss of VAP impairs Ca 2+ loading into both the ER and mitochondria during electrical activity. This regulation occurs primarily through VAP interactions with voltage-gated potassium channels (Kv2) at the PM. Our data suggest that the Kv2-VAP complex organizes presynaptic Ca 2+ signaling outside of the active zone. Without this scaffold, synaptic vesicles become trapped in the reserve pool and fail to participate in exocytosis. These findings reveal a novel role for Kv2-VAP MCSs in coordinating organelle Ca 2+ signaling and the synaptic vesicle cycle.

DOI: https://doi.org/10.64898/2026.05.04.722784
J Cell Commun Signal. 2026 Jun;20 e70080

Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.

Luyang Jiang, Gongsang Cuomu, Sang Jijia, Yumei Yang, Jufen Liu, Yumin Tao.

  Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are hallmarks of many ophthalmic diseases; however, they have traditionally been examined as isolated pathological processes. Recent evidence indicates that these organelles are inextricably coupled through mitochondria-endoplasmic reticulum contact sites, also known as mitochondria-associated membranes (MAMs), which coordinate Ca2+ signaling, lipid transfer, mitochondrial dynamics, redox balance, and cell death decisions. Consequently, dysregulated ER-mitochondria communication has emerged as a key vulnerability that links the cellular stress responses among diverse ocular tissues, including lens epithelial cells, retinal ganglion cells, the retinal pigment epithelium, and corneal endothelial cells. In this review, we summarize the recent advances involving the molecular architecture and regulatory function of ER-mitochondria crosstalk. We focus on how the unfolded protein response signaling, pathological MAM remodeling, Ca2+ dysregulation, and disrupted mitochondrial quality control collectively drive disease progression. By integrating evidence from cataract, glaucoma, diabetic retinopathy, age-related macular degeneration, and Fuchs endothelial corneal dystrophy, we reveal that these disorders are not driven by a uniform mechanism of organelle failure, but rather by the dominance of pathological nodes along the ER-mitochondria axis. We propose that ophthalmic diseases should be stratified based on these distinct failure nodes, which provides a mechanistic framework for developing therapeutics. Within this context, interventions targeting maladaptive ER stress, MAM destabilization, bioenergetic failure, or defective mitophagy should be considered complementary and context-dependent strategies. By reframing ophthalmic disorders as diseases of inter-organelle stress integration, this review positions the ER-mitochondria axis as a modifiable upstream determinant of ocular cell fate, which provides a foundation for stage-specific precision therapies.

Keywords:  calcium signaling; endoplasmic reticulum–mitochondria crosstalk; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; ophthalmic diseases; unfolded protein response

DOI:  https://doi.org/10.1002/ccs3.70080
Contact (Thousand Oaks). 2026 Jan-Dec;9:9 25152564261451667

Genetically Encoded Tools to Monitor and Interrogate Membrane Contact Sites.

Yuepeng Ke, Tien-Hung Lan, Thomas Ahn, Yubin Zhou.

  Membrane contact sites (MCSs) are dynamic subcellular compartments formed between organelles that coordinate diverse aspects of cellular communication, including signaling, metabolism, and membrane organization. Tools capable of monitoring and controlling the spatially localized and dynamic properties of MCSs are needed to dissect their regulatory mechanisms and physiological roles. Recent advances in protein engineering have begun to address this need. Proximity-based reporters, chemogenetic approaches, and optogenetic systems have been developed to enable the visualization, interrogation, and manipulation of inter-organelle contacts with improved spatial and temporal precision. This minireview highlights key developments in these molecular toolkits and their representative applications in studying MCS biology. These approaches provide new insights into organelle crosstalk and may inform future therapeutic strategies targeting MCSs.

Keywords:  cellsignaling; chemically induced proximity; chemogenetics; membrane contact sties (MCSs); optogenetics; proximity-based labeling

DOI:  https://doi.org/10.1177/25152564261451667
PLoS One. 2026 ;21(5): e0348801

S-palmitoylation regulates the function of the mitochondria-associated endoplasmic reticulum membrane to alleviate the senescence of nucleus pulposus cells.

Qi Liang, Jianfeng Zhang, Jingchuan Yan, Weidong Guo, Jian Zhao, Li Lin, Shuang Li, Daxiong Feng, Bo Liao.

Intervertebral disc degeneration (IVDD) is the primary cause of spinal degenerative diseases. Nucleus pulposus (NP) cell senescence is a significant pathological manifestation of IVDD. Here, we constructed a hypoxia-induced NP cell model to clarify the mechanisms by which S-palmitoylation is involved in NPC senescence. The IP3R S-palmitoylation of NP cells was significantly reduced under hypoxic conditions, contributing to abnormalities in mitochondria-associated membranes (MAMs). The study found that cellular expression of Bax, Bcl-2, Cleaved-Caspase8, Cleaved-Caspase3, MMP3, and MMP13 was promoted, while COL2 and AGG expression was inhibited. The up-regulated palmitoylation-modifying enzyme DHHC6 can promote IP3R S-palmitoylation modification and regulate GRP75, VDAC1, Drp1, and Mfn2 expression. It can inhibit apoptosis in NP cells, reduce intracellular calcium and ROS levels, elevate mitochondrial membrane potential, and reduce γ-H2AX expression levels. It also inhibited the protein expression levels of hypoxia-induced apoptosis molecules, matrix-degrading enzymes, and up-regulated extracellular matrix protein expression. These results suggested that hypoxia-induced IP3R depalmitoylation might play a role in structural and functional abnormalities in MAMs, which trigger senescence in NP cells.

DOI: https://doi.org/10.1371/journal.pone.0348801
BMC Oral Health. 2026 May 19.

Porphyromonas gingivalis outer membrane vesicles drive neuroinflammation via TGM2-mediated mitochondria-associated endoplasmic reticulum membranes.

Pengye Zhang, Qingyu Zhu, Kairun Zhang, Shengcai Qi.

   BACKGROUND: Porphyromonas gingivalis (P.g), a key periodontal pathogen, is implicated in Alzheimer's disease (AD). Given that mitochondrial dysfunction is a common event happened in neurodegenerative diseases, mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) play a potential role in AD pathology. This study aimed to investigate the impact of P.g derived outer membrane vesicles (P.g-OMVs) on neuroinflammation in the onset and progression of AD, and to elucidate the underlying mechanism.
METHODS: Eight-week-old male C57BL/6 mice received bilateral gingival injections of P.g-OMVs (4 × 10⁸ particles) 3 times weekly for 8 weeks to assess cognitive impairment and neuroinflammation. RNA-seq identified differentially expressed genes (DEGs) and enriched pathway in brain tissues. In vitro, HT22 cells were treated with P.g-OMVs (5 µg/mL), and the expressions of inflammatory cytokines, transglutaminase 2 (TGM2) and ferroptosis markers were quantified. MAM formation and mitochondrial function regulated by TGM2, including mitochondrial Ca2+ accumulation and membrane potential, were assessed, which further elucidated after knocking down TGM2 by siRNA.
RESULTS: P.g-OMVs induced significant cognitive impairment and neurodegeneration in mice, evidenced by escape latency in the MWM (p < 0.001) and accumulation of amyloid β plaques and hyperphosphorylated tau. RNA-seq highlighted DEGs enriched in mitochondrial pathways, notably targeting TGM2. In vitro, P.g-OMVs triggered inflammation evidenced by increased pro-inflammatory cytokines (IL-1β, IL-17, etc.) and reduced levels of IL-10 (p < 0.05), and led to the upregulation of TGM2 (p < 0.05). Crucially, co-localization of mitochondria and ER suggested that P.g-OMVs promoted MAM formation in neurons, accompanied by aberrant mitochondrial Ca2+ levels and membrane potential. Additionally, altered expressions of ferroptotic markers were observed, including increased level of ACSL4 (p < 0.01) and decreased levels of GPX4 and xCT (p < 0.01). TGM2 knockdown reversed the inflammation, ferroptosis, mitochondrial dysfunction and MAM formation.
CONCLUSIONS: Our findings demonstrate that P.g-OMVs drive neuroinflammation and neuronal ferroptosis through a MAMs-associated mechanism. TGM2 acts as a key mediator, promoting MAM formation and subsequent mitochondrial dysfunction. These findings highlight TGM2 represents a potential therapeutic target for neuroinflammatory conditions linked to oral pathogens.

Keywords:   Porphyromonas gingivalis ; Mitochondria; Neuroinflammation; Outer membrane vesicle; TGM2

DOI:  https://doi.org/10.1186/s12903-026-08458-5
Protoplasma. 2026 May 21.

Sieve elements. Hidden corners, fierce debates, future prospects.

Aart J E van Bel, Jens B Hafke, Katrin Ehlers, Alexandra C U Furch.

Sieve elements (SEs) represent one of the most specialized cell types in plants, yet several fundamental aspects of their structure, regulation, and physiological integration remain incompletely understood. Despite recent advances that refined our understanding of SE function, persistent questions and controversies remain concerning key aspects of SE biology, such as the disputed presence of a proteolytic machinery and a cytoskeleton, the functions of plastids and mitochondria, the roles of sieve-element reticulum (SER) and its membrane contact sites, the mechanisms and significance of sieve-element occlusion by SEOs and SEORs and phloem protein (PP) families, the nature and operation of Ca2+ channels involved in sieve-tube occlusion and electrical signal propagation, and the mechanisms that compensate for SE enucleation. Here, we examine current concepts of SE biology, with particular emphasis on unresolved, conflicting, and emergent issues. We highlight experimental and conceptual approaches that may help resolve outstanding questions and to test hypotheses derived from existing data sets. Rather than providing a comprehensive catalogue of phloem functions, this review aims to delineate key conceptual bottlenecks and to outline future directions required to achieve a mechanistic understanding of SE function within the living plant. To this end, several hypothetical models of SE-functioning are included for further exploration.

DOI: https://doi.org/10.1007/s00709-026-02197-8
Barrier Immun. 2026 May 04.

Novel Organelle-Based Intracellular Immunity with Mechanistic and Therapeutic Implications.

Keman Xu, Shih-Yu Hung, Fatma Saaoud, Ying Shao, Yifan Lu, Juanjuan Liu, Bo Yuan, Haiyan Xiang, Hong Wang, Xiaofeng Yang.

Immunity has traditionally been viewed through the lens of extracellular pathogen recognition and intercellular immune communication. However, emerging evidence reveals that immune regulation extends deeply into the intracellular space, where organelles function and metabolism as active immune signaling platforms. In this review, we synthesize recent advances that redefine immunity as a multiscale system integrating extracellular, intercellular, and intracellular immune mechanisms. We first outline the functional modules of intracellular immune sensing and inflammatory signaling, including plasma membrane recognition, cytosolic surveillance, inflammasome activation, membrane execution, and secretome-mediated outputs. We then present a systematic framework of organelle-based platforms that regulate intracellular immunity and inflammation. Among these, mitochondria emerge as central immune organelles that coordinate metabolic reprogramming, danger/damage signal sensing, and inflammatory activation. Beyond their canonical role in bioenergetics, mitochondria engage in dynamic organelle crosstalk, transmit immune signals through soluble mediators, metabolites and contact sites, and participate in intercellular mitochondrial transfer. We classify mitochondrial immune signaling into three principal modes: indirect signaling via soluble mediators, direct organelle crosstalk at mitochondrial contact sites, and intercellular mitochondrial transfer, highlighting how these mechanisms integrate metabolism with immune regulation. Finally, we summarize current clinical and translational immunotherapies across multiple immune layers, spanning barrier immunity, innate immunity, adaptive immunity, and intracellular immunity. Collectively, this review provides a new conceptual and mechanistic framework for intracellular immune regulation and underscores emerging therapeutic opportunities arising from targeting organelle-based immune pathways.

DOI: https://doi.org/10.1002/dni2.70011
Pharmacol Res. 2026 May 20. pii: S1043-6618(26)00174-X. [Epub ahead of print] 108259

From Natural Drug Regulation to Precise Targeted Intervention: Anti-Heart Failure Mechanisms Based on the Reconstruction of Calcium-Lipid Homeostasis via Mitochondria-Endoplasmic Reticulum Structural Coupling.

Qin Zhang, Yi Wei, Haijing Li, Wei Wang, Yong Wang.

  Heart failure (HF) pathogenesis fundamentally stems from disrupted multi-organelle crosstalk within cardiomyocytes. Mitochondria-endoplasmic reticulum contact sites (MERCs) have emerged as central hubs orchestrating intracellular Ca2+ homeostasis and lipid metabolism-processes critical to cardiac energetics and cell survival. During HF progression, the structural and functional impairment of MERCs triggers a "calcium-lipid" vicious cycle, characterized by Ca2+ dysregulation and lipotoxicity, which accelerates cardiac deterioration. Consequently, targeting MERCs to restore metabolic equilibrium represents a promising frontier for HF therapy. This review systematically elucidates the structural architecture and functional networks of MERCs, emphasizing their critical role in orchestrating calcium signaling and lipid metabolism-disturbances of which are hallmarks of HF. We highlight the therapeutic potential of natural medicines, with a specific focus on preliminary structural insights into their potential modulation of MERC protein complexes. Emerging evidence suggests that diverse natural bioactive compounds confer cardioprotection by fine-tuning MERC tethering distance and abundance, thereby stabilizing Ca2+ flux, alleviating lipotoxicity, and exerting synergistic antioxidant effects. Furthermore, we critically discuss the current limitations of natural compounds research, including the challenges in establishing definitive structure-activity relationships, and address the major challenges in clinical translation and therapeutic delivery. By integrating mechanistic insights with pharmacological intervention, this review aims to provide a comprehensive theoretical framework for the development of precise, natural product-based therapies targeting the MERC-HF axis.

Keywords:  Calcium Homeostasis; Cardiomyocytes; Endoplasmic Reticulum; Heart Failure; Lipid Homeostasis; Mitochondria

DOI:  https://doi.org/10.1016/j.phrs.2026.108259
Autophagy. 2026 May 18.

Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.

Yu B Ko, Minjeong Ko, Marius Ueffing, Hye Jin Kang, Ho Jeong Kwon.

  Disruption of proteostasis is a defining feature of cancer and other chronic diseases. The AAA+ ATPase VCP/p97 (valosin containing protein) is a key regulator of proteostasis by disassembling ubiquitinated substrates for degradation. VCP overexpression supports cancer cell survival and correlates with poor prognosis, promoting the development of VCP inhibitors as anti-cancer agents. However, the molecular basis for cancer-selective vulnerability of VCP inhibition remains unclear. Here, we demonstrate that allosteric VCP inhibition triggers cell- type specific macroautophagy/autophagy through dynamic reorganization of organelle contact sites. In human umbilical vein endothelial cells (HUVECs), VCP inhibition induces adaptive autophagy through coordinated reorganization of plasma membrane (PM)-ER-mitochondria contacts. Controlled opening of the mitochondrial permeability transition pore (mPTP) releases calcium into the cytosol, activating AMP-activated protein kinase (AMPK) and TFEB pathways, collectively enhancing autophagic flux and sustaining endothelial survival. Critically, calcium-activated kinase inhibitor or calcium chelators blocked VCP inhibitor-induced autophagy in HUVECs, confirming calcium signaling as the central mediator of adaptive autophagy. In contrast, HCT116 colon cancer cells fail to maintain calcium homeostasis under VCP inhibition, leading to mitochondrial calcium overload, defective autophagy, and cell death. Together, our findings identify organelle contact reorganization and calcium homeostasis as key determinants of cell fate under conditions of proteotoxic stress, revealing how VCP inhibition selectively suppresses tumor progression while preserving vascular integrity that could enhance drug delivery and reduce tumor hypoxia.

Keywords:  Autophagy; VCP/p97 inhibition; calcium signaling; cancer selectivity; organelle contact reorganization; proteostatic stress

DOI:  https://doi.org/10.1080/15548627.2026.2677184
Cell Mol Neurobiol. 2026 May 19.

Gene Expression Analysis of Mitochondria-Associated Membrane (MAM)-Related Genes in ER Stress and Alzheimer's Disease.

A Anjana Mohan, Priti Talwar.

  Alzheimer's Disease (AD) is a devastating neurodegenerative disease, strongly linked to cellular stress originating from the accumulation of the Amyloid-beta (Aβ) peptide and phosphorylated tau protein. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) are reported as early events in the AD pathology. Mitochondria-Associated Membrane (MAM) is a proteinaceous tethering between the ER and mitochondria that plays a role in regulating ER stress and related responses. A high level of ER-mitochondria tethering, thereby mitochondrial Calcium (Ca2+) overload and cell death, has been reported in AD brain cells. Despite the independent recognition of these pathways, a precise mechanism that integrates MAM activity, ER stress response, and AD pathogenesis remains elusive. We used three transcriptomic datasets collected from the NCBI-Gene Expression Omnibus (GEO) database, which deal with AD, ER stress, and MAM, and processed them with a multi-layered bioinformatics approach combining differential gene expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), protein interaction network construction, and identification of hub genes using different cytoHubba topological algorithms. Four hub genes, namely Calreticulin (CALR), Calnexin (CANX), Heat Shock Protein 90 Beta Family Member 1 (HSP90B1), and Valosin-Containing Protein (VCP), were identified. CALR, CANX, and HSP90B1 are known chaperones that regulate proteostasis. VCP is an ER ATPase that induces autophagy. These genes are not only associated with MAM regulation and ER stress but also with AD pathology. The results suggest hub genes as a new set of biomarkers and the likely existence of a 'three-component system' among MAM, ER stress, and Neurodegeneration. The study highlights the potential of MAM-related genes as therapeutic targets of AD.

Keywords:  Alzheimer’s disease; Biomarkers; Differential gene expression; ER stress; Hub genes; MAM; WGCNA

DOI:  https://doi.org/10.1007/s10571-026-01726-6
EMBO J. 2026 May 20.

Atg18 interaction positions Atg2 for efficient lipid transfer into phagophore elongation.

Sabrina Chumpen Ramirez, Dmitry Shvarev, Prado Vargas Duarte, Yara Ahmed, Jana Milach, Emma Lang, Stefan Kuchenbuch, Stefano Vanni, Fulvio Reggiori, Arne Moeller, Christian Ungermann.

During macroautophagy, the de novo formation of the autophagosome at a membrane contact site (MCS) with the endoplasmic reticulum requires directional lipid flux for the growth of the initial phagophore before its sealing into an autophagosome and subsequent fusion with the lysosome/vacuole. It remains unclear, however, how the formation of this specialized MCS and the directionality of the lipid flux are controlled. Here, we present the structure of the key lipid transfer protein Atg2 from yeast solved together with its Atg18 binding partner, a phosphatidylinositol-3-phosphate (PtdIns3P) effector, using cryo-electron microscopy. We reveal a new interface in Atg2 that, together with PtdIns3P, is required for Atg18 recruitment and lipid transfer activity. Furthermore, we visualize lipid densities along the internal hydrophobic cavity of Atg2, providing structural evidence that Atg2 cavity is filled with lipids throughout the entire length, even when Atg2 is cytosolic. Finally, molecular dynamics simulations show that the complex generates membrane curvature, efficiently positioning the lipid channel of Atg2 towards the membrane to promote lipid transfer into the elongating phagophore.

DOI: https://doi.org/10.1038/s44318-026-00802-3