bims-mecosi Biomed News
on Membrane contact sites
Issue of 2026–08–16
seven papers selected by
Verena Kohler, Umeå University
  1. Advanced imaging of membrane contact sites.
  2. Research progress on drugs targeting mitochondria‑associated membranes for the treatment of atherosclerosis (Review).
  3. New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.
  4. Initial Molecular Detection of Membrane Damage in Post-Golgi Compartments.
  5. LIMK1 and PKM as Integratively Identified Transcriptomic Signatures in Inflammatory Bowel Disease.
  6. SARS-CoV-2 nucleocapsid protein drives pulmonary injury by enhancing GRP75-dependent ER-mitochondria tethering and reprogramming of alveolar macrophages.
  7. Thiram Disrupts Hepatic and Tibial Calcium Homeostasis via ER Stress-Mediated IP3R1/VDAC1 Hyperactivation.
  1. Nat Cell Biol. 2026 Aug;28(8): 1612-1625
    Advanced imaging of membrane contact sites.
    Riccardo Filadi, Ambra Bertocco, Michela Rossini, Paola Pizzo.
      Organelle membrane contact sites (MCSs) coordinate key cell activities and their alterations are associated with several high-incidence disorders, prompting an increasing interest in their study. However, the investigation of MCSs is challenging, mostly because of their nanometric size and dynamic nature. Here we highlight the methods that are available for analysing MCSs. We focus on advanced imaging techniques and discuss their advantages and limitations, providing practical guidance for researchers approaching this field. We propose to study MCSs through a combination of different methodologies, complementing their visualization with investigation of the associated functions. To this end, we also discuss the need to develop innovative biosensors.
    DOI:  https://doi.org/10.1038/s41556-026-02003-w
  2. Mol Med Rep. 2026 Oct;pii: 276. [Epub ahead of print]34(4):
    Research progress on drugs targeting mitochondria‑associated membranes for the treatment of atherosclerosis (Review).
    Shaoying An, Wenhui Sun, Lizhou Shi, Hai Chen, Zhongcheng Mo.
      Mitochondria‑associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum and mitochondria, and serve as the structural foundation for material exchange and signal transduction between these two organelles. MAMs serve critical roles in lipid metabolism, calcium homeostasis, mitochondrial dynamics, autophagy and inflammatory regulation, all of which are closely involved in the pathogenesis of atherosclerosis (AS). Dysregulation of MAM function can promote oxidative stress and chronic inflammation, thereby accelerating atherosclerotic progression. The present review focuses on the molecular mechanisms through which MAMs regulate key cellular processes and influence AS development. Advances in therapeutic agents that target MAMs are summarized, including metformin, statins, 4‑phenylbutyric acid and traditional Chinese medicine compounds, which exert anti‑atherosclerotic effects by restoring MAM integrity, modulating calcium signalling and inhibiting inflammasome activation. By integrating the current knowledge on MAM biology and pharmacology, the present review aims to provide novel strategies for the prevention and treatment of AS through targeted regulation of MAMs.
    Keywords:  atherosclerosis; autophagy; calcium homeostasis; lipid metabolism; mitochondria‑associated membranes
    DOI:  https://doi.org/10.3892/mmr.2026.13987
  3. Autophagy. 2026 Aug 12. 1-3
    New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.
    Sabrina Chumpen Ramirez, Dmitry Shvarev, Fulvio Reggiori, Christian Ungermann.
      Atg9-Atg2-Atg18 complexes are essential for the biogenesis of the autophagosome as they mediate the elongation of the phagophore, the precursor structure of autophagosomes. This event occurs by the transfer of lipids through a membrane contact site (MCS) between the phagophore and the endoplasmic reticulum exit sites (ERES). The bridge-like lipid-transfer protein (BLTP) Atg2 interacts with the Atg9 and phosphatidylinositol-3-phosphate (PtdIns3P) on the phagophore and acts as a tether to establish this MCS. While not essential to form the phagophore-ERES MCS, Atg18 plays a crucial role in the phagophore elongation by stimulating Atg2 lipid transfer activity, based on in vitro experiments. To understand the molecular basis of this regulation, we recently solved the structure of the yeast Atg2-Atg18 complex using cryo-electron microscopy (cryo-EM) and identified the critical region in Atg2 required for the Atg2-Atg18 complex formation. Importantly, we applied structure-function analyses to unveil the molecular mechanism behind the Atg18-mediated stimulation of Atg2. We showed that Atg18 binding to Atg2 induces a structural repositioning of the hydrophobic cavity of Atg2 toward the membrane, which allows efficient transfer of lipids from the endoplasmic reticulum to the phagophore. Here, we summarize our recent work and extend our discussion on the molecular regulation of the lipid transfer activity, highlighting open questions concerning the function of the Atg9-Atg2-Atg18 module in the phagophore-ERES MCS.Abbreviations: ATG, autophagy related; BLTP, bridge-like lipid-transfer protein; cryo-EM, cryo-electron microscopy; ER, endoplasmic reticulum; ERES, ER exit sites; MCS, membrane contact site; PAS, phagophore assembly site; PtdIns3P, phosphatidylinositol-3-phosphate; TRAPPIII, transport protein particle III.
    Keywords:  Atg18; Atg2; Atg9; autophagy; lipid transfer; phosphatidylinositol-3-phosphate
    DOI:  https://doi.org/10.1080/15548627.2026.2716596
  4. Cells. 2026 Jul 30. pii: 1375. [Epub ahead of print]15(15):
    Initial Molecular Detection of Membrane Damage in Post-Golgi Compartments.
    Yoko Shiba, Nana Saito.
      Mammalian cells contain numerous membrane-bound organelles, of which endosomes serve as the initial destination for endocytosed molecules. Therapeutic agents are also internalized by cells and transported to endosomes or phagosomes and subsequently delivered to lysosomes for degradation. Therefore, these agents require drug delivery systems (DDSs) that enable their escape from endosomes into the cytosol before lysosomal degradation; however, endosomal escape is a major limitation of current DDSs. Studies of bacterial phagosomal escape have revealed mechanisms by which host cells detect damage to organelle membranes. These membrane damage-sensing molecules also recognize membrane damage caused by artificial DDSs or physical energy-based insults. In this review, we summarize the molecular mechanisms underlying the early stages of membrane damage in the plasma membrane, lysosomes and bacteria-containing vacuoles (BCVs) to better understand the early stages of endosomal membrane damage in the absence of pathogens. We summarize recent advances in galectins, endosomal sorting complexes required for transport (ESCRT) complexes, sphingomyelin, stress granules, and phosphatidylinositol 4-phosphate (PI4P) at membrane contact sites, as well as annexins. We also discuss the recruitment kinetics of these molecules to damaged membranes. Although the recruitment kinetics vary depending on cell type and experimental conditions, this information provides a timeframe for the events following membrane damage, including damage sensing, membrane repair, and degradation of damaged organelles. We also discuss a potential fourth event, fusion between the plasma membrane and endosomes or lysosomes for membrane repair in the annexin section. Finally, we summarize approaches for inducing "sterile" endosomal membrane damage. Future development of these approaches may facilitate the design of novel DDSs and physical energy-based strategies for manipulating specific organelles.
    Keywords:  ESCRT; PI4P; annexins; galectin; membrane damage; membrane repair by fusion; sphingomyelin
    DOI:  https://doi.org/10.3390/cells15151375
  5. OMICS. 2026 Oct;30(10): 609-630
    LIMK1 and PKM as Integratively Identified Transcriptomic Signatures in Inflammatory Bowel Disease.
    Houshu Tu, Menglin Chen, Panpan Zhu, Ling He, Jing Hong.
      Inflammatory bowel disease (IBD) involves complex immunometabolic dysregulation. Mitochondria-associated endoplasmic reticulum membranes (MAMs) link metabolic adaptation and inflammatory signaling, but gene expression features associated with MAM-related transcriptomic states in IBD remain unclear. Public transcriptomic datasets were integrated with a curated MAM-related gene set and herbal target information. Differential expression analysis, weighted gene coexpression network analysis, and machine learning-assisted feature selection were used to identify candidate genes. A two-gene nomogram was constructed and evaluated in discovery and independent validation datasets. Functional enrichment, immune deconvolution, regulatory network prediction, molecular docking, 200-ns molecular dynamics simulations, and preliminary quantitative polymerase chain reaction validation were performed. LIMK1 and PKM were identified as candidate transcriptomic signature genes associated with IBD status and MAM-related transcriptional states, showing discriminatory performance in independent datasets. Both genes were associated with cytokine-cytokine receptor interaction and drug metabolism-cytochrome P450 pathways and were linked to macrophage-related immune states. Structural analyses suggested stable predicted binding between PKM and 1-(4-hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene-2,7-diol and structurally plausible interactions between LIMK1 and palmatine. Preliminary tissue-level validation supported the disease-associated expression pattern of PKM, whereas LIMK1 showed a consistent but nonsignificant upward trend. LIMK1 and PKM may represent candidate transcriptomic signatures associated with MAM-related regulatory states in IBD. These findings should be interpreted as hypothesis-generating associations rather than evidence of MAM localization, functional causality, or therapeutic efficacy. Further protein-level and functional validation is required.
    Keywords:  LIMK1; PKM; inflammatory bowel disease; medical genomics; mitochondria-associated endoplasmic reticulum membrane; transcriptomic signatures
    DOI:  https://doi.org/10.1177/15578100261472246
  6. Life Sci. 2026 Aug 08. pii: S0024-3205(26)00434-0. [Epub ahead of print]403 124625
    SARS-CoV-2 nucleocapsid protein drives pulmonary injury by enhancing GRP75-dependent ER-mitochondria tethering and reprogramming of alveolar macrophages.
    Ruoxi Zang, Yichao Ren, Jiangmei Wang, Zhenkai Le, Jie Xia, Ruoqiong Huang, Guoping Zheng, Guanguan Qiu, Huifeng Qian, Qiang Shu, Jianguo Xu.
       AIMS: To determine whether the SARS-CoV-2 nucleocapsid (N) protein promotes lung injury by augmenting GRP75-dependent endoplasmic reticulum (ER)-mitochondria tethering and reprogramming alveolar macrophages (AMϕs).
    MATERIALS AND METHODS: MAMs, ER, and mitochondria were isolated from mouse lungs. Bone marrow-derived and RAW264.7 macrophages were stimulated with recombinant N protein ± lentiviral GRP75 knockdown. ER-mitochondria interactions, tethering complex formation, mitochondrial Ca2+ dynamics, and function were assessed by confocal imaging, transmission electron microscopy, proximity ligation assay, co-immunoprecipitation, and biochemical approaches. In vivo, GRP75 was knocked down in C57BL/6 mouse lungs prior to intratracheal N protein challenge. Lung injury, AMϕ polarization, mitochondrial function, and single-cell transcriptomic changes were assessed.
    KEY FINDINGS: N protein promoted redistribution of GRP75 to MAMs without altering total lung GRP75 levels. It enhanced ER-mitochondria contacts and IP3R1-GRP75-VDAC1 complex assembly, resulting in excessive mitochondrial Ca2+ accumulation, membrane depolarization, increased mitochondrial reactive oxygen species, ATP depletion, and proinflammatory cytokine production. GRP75 knockdown reversed these defects, restoring mitochondrial function and suppressing inflammation. In vivo, pulmonary GRP75 knockdown alleviated N protein-induced lung injury, inflammatory cell infiltration, cytokine release, M1 polarization, and mitochondrial dysfunction in AMϕs. Single-cell RNA sequencing further demonstrated that GRP75 knockdown reversed N protein-induced AMϕ transcriptional reprogramming by reducing the proinflammatory Car4+ subset while expanding an anti-inflammatory CD74+ subset.
    SIGNIFICANCE: These findings establish GRP75-dependent ER-mitochondria tethering as a critical mechanism by which N protein disrupts AMϕ homeostasis and promotes COVID-19-associated lung injury, identifying GRP75-mediated MAM signaling as a potential therapeutic target.
    Keywords:  Endoplasmic reticulum; GRP75; Lung injury; Mitochondria; Mitochondria-associated membranes; SARS-CoV-2 nucleocapsid protein; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.lfs.2026.124625
  7. Environ Toxicol. 2026 Aug 14.
    Thiram Disrupts Hepatic and Tibial Calcium Homeostasis via ER Stress-Mediated IP3R1/VDAC1 Hyperactivation.
    Shah Nawaz, Quan Mo, Zhao Zhang, Muhammad Farhan Rahim, Farah Ijaz, Chuxian Quan, Muhammad Asif, Mudassar Iqbal, Md F Kulyar, Jiakui Li.
      Thiram is an agricultural fungicide known to disrupt cellular calcium homeostasis by inducing endoplasmic reticulum (ER) stress and mitochondrial calcium overload in hepatic and growth plate (GP) tissues. Current study investigated thiram-induced alterations at mitochondria-associated membranes (MAMs) and their impact on inter-organ calcium signaling. Following thiram exposure in chickens, hepatic ER stress markers GRP78 and CHOP, along with key calcium-transfer proteins mediating ER-mitochondrial coupling, including inositol 1,4,5-trisphosphate receptor 1 (IP3R1) and voltage-dependent anion channel 1 (VDAC1), were significantly upregulated. Importantly, hepatic ER stress driven hyperactivation of IP3R1/VDAC1 signaling was accompanied by parallel calcium dysregulation and mitochondrial stress responses in the tibial growth plate, providing direct evidence that liver ER stress acts upstream of skeletal calcium imbalance. These findings establish a previously unrecognized liver-bone axis in which thiram-induced hepatic ER stress propagates calcium signaling disturbances to the growth plate, thereby disrupting chondrocyte calcium homeostasis and bone development. Collectively, this study elucidates a mechanistic framework linking MAM-mediated calcium-transfer, ER stress, and cross-organ communication, offering new insights into how toxicant-induced hepatic stress orchestrates systemic calcium metabolism and skeletal pathology.
    Keywords:  NLRP3; calcium signaling; endoplasmic reticulum; inflammasome; liver‐bone axis; thiram
    DOI:  https://doi.org/10.1002/tox.70182
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒13 at 13:14.