bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–12–28
nine papers selected by
Verena Kohler, Umeå University
  1. More than just membranes: membrane contact sites as crossroads for infections.
  2. Publisher Correction: Toxoplasma effector TgROP1 establishes membrane contact sites with the endoplasmic reticulum during infection.
  3. Landscape Expansion Microscopy Reveals Interactions between Membrane and Phase-Separated Organelles.
  4. Basic Science and Pathogenesis.
  5. Protrudin acts at ER-endosome contacts to promote KIF5-mediated endosomal tubule fission.
  6. Basic Science and Pathogenesis.
  7. The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
  8. Sigma1R restores mitochondrial energy metabolism via the IRE1α/XBP1 pathway.
  9. Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
  1. Trends Microbiol. 2025 Dec 23. pii: S0966-842X(25)00364-6. [Epub ahead of print]
    More than just membranes: membrane contact sites as crossroads for infections.
    Britta Bonde, Lina Herhaus.
      Membrane contact sites (MCSs), tethering zones between organelles, have emerged as critical hubs for regulating cellular metabolism, homeostasis, and immune responses. Recent discoveries reveal that a wide range of intracellular pathogens, including bacteria, viruses, parasites, and fungi, exploit MCSs to establish and maintain their replicative niches within host cells. By co-opting the host MCS machinery, these pathogens create specialized interfaces between their vacuoles, replication complexes, or cytosolic domains and host organelles, enabling nutrient acquisition, immune evasion, and spatial signaling. This review highlights how intracellular pathogens, such as Salmonella and others, subvert MCS architecture and function. Furthermore, emerging concepts and tools in the study of pathogen-MCS interactions are discussed, along with how these insights influence the development of host-directed therapies against infectious diseases.
    Keywords:  infection; membrane contact sites; pathogen–host interaction
    DOI:  https://doi.org/10.1016/j.tim.2025.12.001
  2. Nat Microbiol. 2025 Dec 22.
    Publisher Correction: Toxoplasma effector TgROP1 establishes membrane contact sites with the endoplasmic reticulum during infection.
    Chahat Mehra, Jesús Alvarado Valverde, Ana Margarida Nogueira Matias, Francesca Torelli, Tânia Catarina Medeiros, Julian Straub, James D Asaki, Peter J Bradley, Katja Luck, Steffen Lawo, Moritz Treeck, Lena Pernas.
      
    DOI:  https://doi.org/10.1038/s41564-025-02256-5
  3. bioRxiv. 2025 Dec 13. pii: 2025.12.10.693600. [Epub ahead of print]
    Landscape Expansion Microscopy Reveals Interactions between Membrane and Phase-Separated Organelles.
    Yinyin Zhuang, Zhao Zhang, Zhipeng Dai, Xiaoyu Shi.
      Landscape Expansion Microscopy (land-ExM) is a light microscopy technique that visualizes both lipid and protein ultrastructural context of cells. Achieving this level of detail requires both superresolution and a high signal-to-noise ratio. Although expansion microscopy (ExM) provides superresolution, obtaining high signal-to-noise images of both proteins and lipids remains challenging. Land-ExM overcomes this limitation by using self-retention trifunctional anchors to significantly enhance protein and lipid signals in expanded samples. This improvement enables the accurate visualization of diverse membrane organelles and phase separations, as well as the three-dimensional visualization of their contact sites. As a demonstration, we revealed triple-organellar contact sites among the stress granule, the nuclear tunnel, and the nucleolus. Overall, land-ExM offers a high-contrast superresolution platform that advances our understanding of how cells spatially coordinate interactions between membrane organelles and phase separations.
    eTOC Summary: Zhuang et al. introduce land-ExM, a super-resolution approach that simultaneously maps protein and lipid ultrastructure in cells with high contrast. This method visualizes 3D interactions between membrane-bound organelles and phase-separated condensates, uncovering organelle contact sites such as stress granules at nuclear tunnels adjacent to nucleoli.
    DOI:  https://doi.org/10.64898/2025.12.10.693600
  4. Alzheimers Dement. 2025 Dec;21 Suppl 1 e101226
    Basic Science and Pathogenesis.
    Kevin R Shen, George C Shum, Abby C Woods, Tayler B Belton, Eric D Leisten, Yvette C Wong.
       BACKGROUND: Alzheimer's disease (AD) is characterized by the pathological accumulation of both amyloid-beta (Aβ) and cytoplasmic tau, but their mechanistic crosstalk remains to be further investigated. Moreover, while cholesterol dyshomeostasis has been implicated in AD, its role is still not completely understood. Cholesterol homeostasis is tightly regulated at the endoplasmic reticulum (ER), a highly dynamic and structurally complex organelle, where the enzyme ACAT1 turns over cholesterol into cholesteryl esters. Importantly, the ER also dynamically tethers to microtubules via ER-microtubules contact sites, and are implicated in dendritic spine stability and memory. However, whether ACAT1 functionally interacts with Aβ to regulate ER cholesterol and ER structure, and its downstream regulation of ER-microtubule contact sites and tau dynamics have never been studied.
    METHOD: We utilized super-resolution live Lattice SIM2 microscopy to uncover a new mechanistic pathway connecting cholesterol turnover, Aβ function, and tau aggregation in AD. We examined the role of ER cholesterol in modulating ER ultrastructure and dynamics over time, and a converging role for Aβ production and Aβ42 versus Aβ40 in regulating this pathway. We further conducted in silico structural multimer modeling of Aβ42 and Aβ40's structural interactions with ACAT1's catalytic pocket. Finally, we investigated cholesterol's role in modulating ER-microtubule contact site tethering via STIM1-EB binding, and its impact on downstream tau microtubule dynamics and aggregation.
    RESULT: We found that accumulation of ER cholesterol resulted in the dynamic formation of ER spheres as a novel structural component of the ER network. Remarkably, inhibition of Aβ generation also induced ER sphere formation, supporting a role for Aβ regulation of ER cholesterol's turnover. Mechanistically, Aβ42 but not Aβ40 structurally interacted with key catalytic residues of ACAT1 to promote ACAT1's turnover of cholesterol, which was supported by reduced ER sphere formation in AD-associated mutant APP with increased Aβ42 production. Functionally, ER cholesterol resulted in the downstream untethering of ER-microtubule contact sites mediated by STIM1 and EB, ultimately leading to tau dissociation from microtubules and oligomerization.
    CONCLUSION: Our work provides evidence for a unifying mechanism linking Aβ function with tau dynamics through cholesterol-mediated ER dynamics, and identifies a novel cellular pathway underlying AD pathogenesis.
    DOI:  https://doi.org/10.1002/alz70855_101226
  5. Neurobiol Dis. 2025 Dec 20. pii: S0969-9961(25)00448-6. [Epub ahead of print] 107231
    Protrudin acts at ER-endosome contacts to promote KIF5-mediated endosomal tubule fission.
    Julia Kleniuk, Aishwarya G Nadadhur, Catherine Rodger, Emily Wolfenden, Isabelle A Hall, Samuel R Cheers, Eliska Zlamalova, Evan Reid.
      Defective endosomal sorting and trafficking are increasingly recognised as key drivers of neurodegeneration, including hereditary spastic paraplegia (HSP) and other motor neuron disorders. Early endosomal tubule fission (ETF) is essential for sorting cargoes for recycling and retrograde transport, yet the mechanisms coordinating this process are incompletely defined. Here, we identify the endoplasmic reticulum (ER)-resident protein protrudin-previously shown to promote axonal regeneration after injury-as a key regulator of ETF. Using CRISPR interference in human cells, we show that loss of protrudin causes marked accumulation of elongated endosomal tubules, caused by defective fission. Protrudin-mediated ETF required its ability to interact with ER-localised VAP proteins, endosomal phosphoinositides, and the kinesin motor KIF5, indicating a function at ER-endosome contact sites. The endosomal tubulation phenotype depended on dynamic microtubules and dynein and was phenocopied by KIF5 depletion, suggesting that protrudin coordinates opposing microtubule motor forces to drive fission. Beyond this direct role, protrudin connects multiple ETF machineries implicated in lipid transfer, actin regulation, and ER shaping, positioning it as a central scaffold for ETF. Importantly, depletion of protrudin or the HSP-associated kinesin KIF5A produced similar endosomal tubulation defects in human cortical neurons, underscoring the neurophysiological and disease relevance of this pathway. These findings identify protrudin as a key molecular link between ER-endosome communication, neuronal membrane trafficking, and axonal maintenance-processes whose disruption underlies neurodegenerative disease.
    Keywords:  Endoplasmic reticulum; Endosomal sorting; Endosomal tubule fission; Organelle contacts
    DOI:  https://doi.org/10.1016/j.nbd.2025.107231
  6. Alzheimers Dement. 2025 Dec;21 Suppl 1 e103247
    Basic Science and Pathogenesis.
    Kriti Shukla, Zhi Zhang, Casandra Salinas, Dominika Siodlak, Samah Houmam, Dylan Barber, Jialing Lin, Heather C Rice.
       BACKGROUND: Mitochondrial dysfunction is a key feature of Alzheimer's disease (AD). Amyloid Precursor Protein (APP), the precursor to Aβ peptides that form amyloid plaques in AD, has been shown to localize to the mitochondria under certain conditions. However, the precise role of APP in mitochondria is not fully understood, and exploring its protein-protein interactions could provide crucial insights. Recent work by Rice et al. identified PGAM5, a mitochondrial phosphatase, as a candidate interactor of APP. PGAM5 is involved in regulating important mitochondrial processes such as fission, fusion, and mitophagy through interactions with various substrates. We sought to identify the role of APP in mitochondrial functions in health and AD through its interaction with PGAM5.
    METHOD: To characterize the binding between APP and PGAM5, we performed in vitro pull-down assays and isothermal calorimetry (ITC). Proximity ligation assays in mouse brain tissue and primary astrocytes were employed to examine the endogenous interaction of these proteins. Subcellular fractionations were performed to study the processing and localization of APP and PGAM5 in wildtype and APP NL-G-F mice brains.
    RESULT: Pull-down assays revealed that the linker region of APP binds to either the multimerization motif or the Keap-1 binding domain of PGAM5. ITC demonstrated an interaction between APP and PGAM5. Endogenous interactions between APP and PGAM5 were detected in the brains of healthy mice and primary astrocytes, with potential location of this interaction being the mitochondria-associated membranes (MAMs). Brain fractionation data demonstrated that both PGAM5 and full-length APP (APP-FL) were present in MAMs, while APP carboxy-terminal fragments (APP-CTF) localized to mitochondria along with PGAM5. Additionally, PGAM5 cleavage was found to be reduced in the brains of older AD mice.
    CONCLUSION: Our findings suggest that APP and PGAM5 interact under physiological conditions. In AD, the decreased cleavage of PGAM5 may impair mitophagy, contributing to the mitochondrial dysfunction seen in AD pathogenesis. Precise understanding of the interaction of APP with other proteins, like PGAM5 is critical to ensure the long-term safety of potential treatments like APP knockdown in AD patients.
    DOI:  https://doi.org/10.1002/alz70855_103247
  7. bioRxiv. 2025 Dec 16. pii: 2025.12.13.693635. [Epub ahead of print]
    The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
    Bryanna Shao, Bartosz Kula, Han Le, Prasanna Venkhatesh, Prasanna Katti, Andrea G Marshall, Siddharth Chittaranjan, Suraj Thapilyal, Namdar Hari Kalpana, C Nivedya, Adam Roszczyk, Harrison Mobley, Mason Killion, Emelina St John, Pamela Martin, Benjamin Rodrigiuez, Markis' Hamilton, LaCara Bell, Sunjay M Wyckoff, Laurent A Moran, Mark Philips, David Hubert, Briar Tomeau, Jeremiah M Afolabi, Annet Kirabo, Ismary Blanco, Samantha Reasonover, Lauren E Drake, Ethan S Lippmann, Chantell Evans, Monica M Santisteban, Taneisha G Cheairs, Sepiso Mesenga, Celestine Wanjalla, Jennifer Gaddy, Ronald McMillan, Calixto P Hernandez Perez, Htet Htet Paing, Jenny C Schafer, Bret Mobley, Julia Berry, Amber Crabtree, Oleg Kovtun, Shawn Goodwin, Edgar Garza Lopez, Chandravanu Dash, Dao-Fu Dai, Tyne W Miller-Fleming, Antentor Hinton, Nathan A Smith.
      Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.
    DOI:  https://doi.org/10.64898/2025.12.13.693635
  8. Sci Rep. 2025 Dec 20.
    Sigma1R restores mitochondrial energy metabolism via the IRE1α/XBP1 pathway.
    Wei Yan, Tongyuan Deng, Da Huang, Bailu Deng, Hong Ling, Zhile Li.
      To investigate the role of Sigma1 receptor (Sigma1R) in mitochondrial energy metabolism remodeling in atrial myocytes, elucidate the associated molecular mechanisms, and evaluate its therapeutic potential in atrial fibrillation (AF). HL-1 atrial myocytes were subjected to tachypacing at 5 Hz for 24 h to establish an AF model. Lentiviral vectors were used to modulate Sigma1R and IRE1α expression. Cell viability was assessed by CCK-8 assay, apoptosis by Annexin V-FITC/PI staining and flow cytometry, mitochondrial function by TMRE staining for membrane potential, MitoSOX Red for reactive oxygen species (ROS) detection, and ATP assays. Calcium dynamics were measured using Fura-2/AM and Fluo-3/AM imaging. Protein expression was analyzed by Western blot, and subcellular localization was confirmed by fluorescence in situ hybridization (FISH). Tachypacing induced significant damage in atrial myocytes, including a 32.16% apoptosis rate, decreased Sigma1R expression, mitochondrial swelling, a 38% reduction in ATP levels, a 37% increase in mitochondrial ROS, and a 122% increase in cytosolic calcium compared to control cells. Overexpression of Sigma1R significantly mitigated these effects: cell viability increased by 55% (P < 0.001), apoptosis was reduced by 55% (P < 0.01), ATP levels were restored to 84% of control values (P < 0.01), and mitochondrial ROS decreased by 55% (P < 0.05). Mechanistically, Sigma1R overexpression normalized calcium homeostasis, reducing cytosolic calcium to 134 ± 11 nM from 218 ± 16 nM in the AF group (P < 0.01) and suppressed pathological expansion of endoplasmic reticulum-mitochondria contact sites. The activation of the IRE1α/XBP1 pathway was inhibited by Sigma1R, as evidenced by reductions in IRE1α, phosphorylated IRE1α, and XBP1s protein levels by 39-47% (P < 0.05). Conversely, IRE1α overexpression abrogated the protective effects of Sigma1R, leading to a 22% increase in apoptosis (P < 0.01) and exacerbating mitochondrial and calcium dysfunction. Sigma1R protects atrial myocytes from tachypacing-induced injury by enhancing mitochondrial function, reducing oxidative stress, and regulating calcium homeostasis at mitochondria-associated membranes, primarily through inhibition of the IRE1α/XBP1 pathway. These findings highlight Sigma1R as a promising therapeutic target for mitigating mitochondrial remodeling in AF.
    Keywords:  Atrial fibrillation; Calcium homeostasis; IRE1α/XBP1 pathway; Mitochondria; Sigma1 receptor
    DOI:  https://doi.org/10.1038/s41598-025-31500-5
  9. Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01499-8. [Epub ahead of print]45(1): 116727
    Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
    Lilia Colina-Tenorio, Patrick Horten, Enzo Scifo, Susanne E Horvath, Rhena F U Klar, Chantal Priesnitz, Fabian den Brave, Martin van der Laan, Thomas Becker, Kuo Song, Heike Rampelt.
      Mitochondrial cytochrome c oxidase, complex IV (CIV) of the respiratory chain, is assembled in a modular fashion from mitochondrial as well as nuclear-encoded subunits, guided by numerous assembly factors. This intricate process is further complicated by the characteristic architecture of the inner mitochondrial membrane. The mitochondrial contact site and cristae organizing system (MICOS) maintains the stability of crista junctions that connect the cristae, the site of mitochondrial respiration, with the inner boundary membrane, where newly imported respiratory subunits first arrive. Here, we report that MICOS facilitates specific assembly steps of CIV and associates with intermediates of the Cox1 and Cox3 modules. Moreover, MICOS recruits a variety of assembly factors even in the absence of ongoing CIV biogenesis, directly or via the mitochondrial multifunctional assembly (MIMAS). Our results establish MICOS as an important agent in efficient respiratory chain assembly that promotes CIV biogenesis within the compartmentalized inner membrane architecture.
    Keywords:  CP: Cell biology; CP: Metabolism; MICOS; MIMAS; Mic60; cristae; cytochrome c oxidase; mitochondria; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2025.116727
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