bims-mecosi 2025-02-23 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–02–23
twelve papers selected by
Verena Kohler, Umeå University

Organelle homeostasis requires ESCRTs.
Targeting membrane contact sites to mediate lipid dynamics: innovative cancer therapies.
Plasmodesmata act as unconventional membrane contact sites regulating intercellular molecular exchange in plants.
Visual Analysis of Research Hotspots and Trends on Mitochondria-Associated Membranes in the Past 20 Years-Focused on Neurodegenerative Diseases.
Lipin1 ameliorates cognitive ability of diabetic encephalopathy via regulating Ca2+ transfer through mitochondria-associated endoplasmic reticulum membranes.
The emerging roles of the endoplasmic reticulum in mechanosensing and mechanotransduction.
Multiple interactions mediate the localization of BLTP2 at ER-PM contacts to control plasma membrane dynamics.
Calcium (Ca2+) fluxes at mitochondria-ER contact sites (MERCS) are a new target of senolysis in therapy-induced senescence (TIS).
Mitochondrial Mutation Leads to Cardiomyocyte Hypertrophy by Disruption of Mitochondria-Associated ER Membrane.
Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.
SIRT1 Alleviates Oxidative Stress-Induced Mitochondrial Dysfunction and Mitochondria-Associated Membrane Dysregulation in Stress Urinary Incontinence.
Compositionally unique mitochondria in filopodia support cellular migration.

Curr Opin Cell Biol. 2025 Feb 14. pii: S0955-0674(25)00019-5. [Epub ahead of print]93 102481

Organelle homeostasis requires ESCRTs.

Tsan-Wen Lu, Adam Frost, Frank R Moss.

The endosomal sorting complexes required for transport (ESCRT) catalyze membrane shape transformations throughout the cell. Canonical functions of the ESCRTs include endosomal multivesicular body biogenesis, enveloped virus budding, and abscission of daughter cell plasma membranes. The ESCRT machinery is also required for membranous organelle homeostasis generally, including by facilitating lipid transport at membrane contact sites, repairing membrane damage, driving lysosomal catabolism, and maintaining nuclear envelope integrity, among other roles. Here, we review a subset of recent discoveries and highlight opportunities to better understand how ESCRT activities support cell health.

DOI: https://doi.org/10.1016/j.ceb.2025.102481
Cell Commun Signal. 2025 Feb 15. 23(1): 89

Targeting membrane contact sites to mediate lipid dynamics: innovative cancer therapies.

Jie Wang, Meifeng Wang, Xueni Zeng, Yanhan Li, Lingzhi Lei, Changan Chen, Xi Lin, Peiyuan Fang, Yuxuan Guo, Xianjie Jiang, Yian Wang, Lihong Chen, Jun Long.

  Membrane contact sites (MCS) are specialized regions where organelles are closely interconnected through membrane structures, facilitating the transfer and exchange of ions, lipids, and other molecules. This proximity enables a synergistic regulation of cellular homeostasis and functions. The formation and maintenance of these contact sites are governed by specific proteins that bring organelle membranes into close apposition, thereby enabling functional crosstalk between cellular compartments. In eukaryotic cells, lipids are primarily synthesized and metabolized within distinct organelles and must be transported through MCS to ensure proper cellular function. Consequently, MCS act as pivotal platforms for lipid synthesis and trafficking, particularly in cancer cells and immune cells within the tumor microenvironment, where dynamic alterations are critical for maintaining lipid homeostasis. This article provides a comprehensive analysis of how these cells exploit membrane contact sites to modulate lipid synthesis, metabolism, and transport, with a specific focus on how MCS-mediated lipid dynamics influence tumor progression. We also examine the differences in MCS and associated molecules across various cancer types, exploring novel therapeutic strategies targeting MCS-related lipid metabolism for the development of anticancer drugs, while also addressing the challenges involved.

Keywords:  Anticancer therapy; Cancer metabolism; Lipid metabolism; Membrane contact sites; Organelle interactions

DOI:  https://doi.org/10.1186/s12964-025-02089-z
Cell. 2025 Feb 20. pii: S0092-8674(24)01376-X. [Epub ahead of print]188(4): 958-977.e23

Plasmodesmata act as unconventional membrane contact sites regulating intercellular molecular exchange in plants.

Jessica Pérez-Sancho, Marija Smokvarska, Gwennogan Dubois, Marie Glavier, Sujith Sritharan, Tatiana S Moraes, Hortense Moreau, Victor Dietrich, Matthieu P Platre, Andrea Paterlini, Ziqiang P Li, Laetitia Fouillen, Magali S Grison, Pepe Cana-Quijada, Françoise Immel, Valerie Wattelet, Mathieu Ducros, Lysiane Brocard, Clément Chambaud, Yongming Luo, Priya Ramakrishna, Vincent Bayle, Linnka Lefebvre-Legendre, Stéphane Claverol, Matej Zabrady, Pascal G P Martin, Wolfgang Busch, Marie Barberon, Jens Tilsner, Yrjö Helariutta, Eugenia Russinova, Antoine Taly, Yvon Jaillais, Emmanuelle M Bayer.

  Membrane contact sites (MCSs) are fundamental for intracellular communication, but their role in intercellular communication remains unexplored. We show that in plants, plasmodesmata communication bridges function as atypical endoplasmic reticulum (ER)-plasma membrane (PM) tubular MCSs, operating at cell-cell interfaces. Similar to other MCSs, ER-PM apposition is controlled by a protein-lipid tethering complex, but uniquely, this serves intercellular communication. Combining high-resolution microscopy, molecular dynamics, and pharmacological and genetic approaches, we show that cell-cell trafficking is modulated through the combined action of multiple C2 domains transmembrane domain proteins (MCTPs) 3, 4, and 6 ER-PM tethers and phosphatidylinositol-4-phosphate (PI4P) lipid. Graded PI4P amounts regulate MCTP docking to the PM, their plasmodesmata localization, and cell-cell permeability. SAC7, an ER-localized PI4P-phosphatase, regulates MCTP4 accumulation at plasmodesmata and modulates cell-cell trafficking capacity in a cell-type-specific manner. Our findings expand MCS functions in information transmission from intracellular to intercellular cellular activities.

Keywords:  MCTP; endoplasmic reticulum plasma membrane; intercellular communication; membrane contact sites; phosphoinositide; plant biology; plasmodesmata

DOI:  https://doi.org/10.1016/j.cell.2024.11.034
Mol Neurobiol. 2025 Feb 18.

Visual Analysis of Research Hotspots and Trends on Mitochondria-Associated Membranes in the Past 20 Years-Focused on Neurodegenerative Diseases.

Yihang Du, Chenglin Duan, Xueping Zhu, Meng Lyu, Jiafan Chen, Yi Wei, Yuanhui Hu.

  The interaction between mitochondria and the endoplasmic reticulum is mediated by mitochondria-associated endoplasmic reticulum membranes (MAMs), which play a crucial role in regulating intracellular signal transduction and molecular interactions. This study employs bibliometric analysis to examine the research progress on MAMS and identify research hotspots and trends. A total of 1406 publications on MAMs were collected from the Web of Science Core Collection. Software such as CiteSpace, VOSviewer, and Scimago Graphica were utilized in the bibliometric analysis process. This study conducted a bibliometric analysis of over 20 years of MAM research, identifying the countries, institutions, authors, journals, and publications involved in the field. The number of publications on MAMs has been increasing annually since 2010, exhibiting a steady upward trend. The main contributors to this field are the USA, China, and Italy, with the journal Frontiers in Cell and Developmental Biology publishing the most publications. Common keywords include "endoplasmic reticulum stress," "Ca2 + ," "mitofusin2," "oxidative stress," "apoptosis," "autophagy," and "Alzheimer's disease." We found that the role of MAMs in neurodegenerative diseases has aroused great interest among researchers. The associations between calcium homeostasis, autophagy, mitochondrial dysfunction, and cell death with MAMs are also considered research hotspots and show broad research prospects. In addition, changes in MAM-resident proteins, including the mitochondria-ER tethering complex, Mfn2, and Sig-1R, have been highlighted as prominent research directions. The findings provide a comprehensive overview of research on MAMs and valuable insights for researchers, which is helpful for exploring future directions and trends in this field.

Keywords:  CiteSpace; Hotspots and trends; Mitochondria-associated membranes; Neurodegenerative diseases; VOSviewer; Visual analysis

DOI:  https://doi.org/10.1007/s12035-025-04722-x
Int Immunopharmacol. 2025 Feb 16. pii: S1567-5769(25)00256-5. [Epub ahead of print]150 114266

Lipin1 ameliorates cognitive ability of diabetic encephalopathy via regulating Ca2+ transfer through mitochondria-associated endoplasmic reticulum membranes.

Ziyun Zhuang, Shan Huang, Xiaochen Zhang, Xiaolin Han, Mengyu Hua, Zhonghao Liang, Nengjun Lou, Li Lv, Fengjie Zheng, Liang Zhang, Xiaojing Liu, Shuyan Yu, Shihong Chen, Xianghua Zhuang.

  Diabetic encephalopathy (DE) is a common central nervous system complication resulting from diabetes mellitus (DM). While the exact pathogenesis remains unclear, a homeostatic imbalance of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) within neurons has been shown to be closely associated with the dysfunctional cognitive pathology of this condition. Our previous work has revealed that phosphatidate phosphatase Lipin1 plays a critical role in the cognitive processes of DE via regulating mitochondrial function. In this study, we reported that the integrity of neuronal MAMs was disrupted in DE mice, which was accompanied by a decrease in the expression of hippocampal Lipin1. With a knock-down of hippocampal Lipin1 in normal mice, ER stress was induced, MAMs structures were impaired and Ca2+ transfer was suppressed. Such effects resulted in mitochondrial dysfunction, synaptic plasticity impairments, and finally cognitive dysfunctions. In contrast, an up-regulation of hippocampal Lipin1 in the DE model partially alleviated these dysfunctions. These results suggest that Lipin1 may ameliorate the cognitive dysfunctions associated with DE via regulating Ca2+ transfers through MAMs. Therefore, targeting Lipin1 may serve as a therapeutic strategy for the clinical treatment of DE.

Keywords:  Ca(2+) transfer; Cognitive dysfunction; Diabetic encephalopathy; Lipin1; Mitochondria-associated endoplasmic reticulum membranes

DOI:  https://doi.org/10.1016/j.intimp.2025.114266
J Cell Sci. 2025 Feb 15. pii: JCS263503. [Epub ahead of print]138(4):

The emerging roles of the endoplasmic reticulum in mechanosensing and mechanotransduction.

Jonathan Townson, Cinzia Progida.

  Cells are continuously subjected to physical and chemical cues from the extracellular environment, and sense and respond to mechanical cues via mechanosensation and mechanotransduction. Although the role of the cytoskeleton in these processes is well known, the contribution of intracellular membranes has been long neglected. Recently, it has become evident that various organelles play active roles in both mechanosensing and mechanotransduction. In this Review, we focus on mechanosensitive roles of the endoplasmic reticulum (ER), the functions of which are crucial for maintaining cell homeostasis. We discuss the effects of mechanical stimuli on interactions between the ER, the cytoskeleton and other organelles; the role of the ER in intracellular Ca2+ signalling via mechanosensitive channels; and how the unfolded protein response and lipid homeostasis contribute to mechanosensing. The expansive structure of the ER positions it as a key intracellular communication hub, and we additionally explore how this may be leveraged to transduce mechanical signals around the cell. By synthesising current knowledge, we aim to shed light on the emerging roles of the ER in cellular mechanosensing and mechanotransduction.

Keywords:  Endoplasmic reticulum; Mechanosensing; Mechanotransduction; Membrane contact sites

DOI:  https://doi.org/10.1242/jcs.263503
bioRxiv. 2025 Feb 08. pii: 2025.02.07.637094. [Epub ahead of print]

Multiple interactions mediate the localization of BLTP2 at ER-PM contacts to control plasma membrane dynamics.

Anbang Dai, Peng Xu, Chase Amos, Kenshiro Fujise, Yumei Wu, Han Yang, Julia N Eisen, Andrés Guillén-Samander, Pietro De Camilli.

BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the endoplasmic reticulum (ER) with either the plasma membrane (PM) or recycling tubular endosomes depending on the cell type. Our findings suggest that mediating bulk lipid transport between the ER and the PM is a key function of this protein as BLTP2 tethers the ER to tubular endosomes only after they become continuous with the PM and that it also tethers the ER to macropinosomes in the process of fusing with the PM. We further identify interactions underlying binding of BLTP2 to the PM, including phosphoinositides, the adaptor proteins FAM102A and FAM102B, and also N-BAR domain proteins at membrane-connected tubules. The absence of BLTP2 results in the accumulation of intracellular vacuoles, many of which are connected to the plasma membrane, pointing to a role of the lipid transport function of BLTP2 in the control of PM dynamics.

DOI: https://doi.org/10.1101/2025.02.07.637094
NPJ Aging. 2025 Feb 21. 11(1): 11

Calcium (Ca2+) fluxes at mitochondria-ER contact sites (MERCS) are a new target of senolysis in therapy-induced senescence (TIS).

Andrea Puebla-Huerta, Hernán Huerta, Camila Quezada-Gutierez, Pablo Morgado-Cáceres, César Casanova-Canelo, Sandra A Niño, Sergio Linsambarth, Osman Díaz-Rivera, José Alberto López-Domínguez, Sandra Rodríguez-López, José Antonio González-Reyes, Galdo Bustos, Eduardo Silva-Pavez, Alenka Lovy, Gabriel Quiroz, Catalina González-Seguel, Edison Salas-Huenuleo, Marcelo J Kogan, Jordi Molgó, Armen Zakarian, José M Villalba, Christian Gonzalez-Billault, Tito Cali, Ulises Ahumada-Castro, J César Cárdenas.

Therapy-induced senescence (TIS) alters calcium (Ca²⁺) flux and Mitochondria-ER Contact Sites (MERCS), revealing critical vulnerabilities in senescent cells. In this study, TIS was induced using Doxorubicin and Etoposide, resulting in an increased MERCS contact surface but a significant reduction in ER-mitochondria Ca²⁺ flux. Mechanistically, TIS cells exhibit decreased expression of IP3R isoforms and reduced interaction between type 1 IP3R and VDAC1, impairing Ca²⁺ transfer. This flux is crucial for maintaining the viability of senescent cells, highlighting its potential as a therapeutic target. Inhibition of ER-mitochondria Ca²⁺ flux demonstrates senolytic effects both in vitro and in vivo, offering a novel strategy for targeting senescent cells.

DOI: https://doi.org/10.1038/s41514-025-00197-1
Cell Prolif. 2025 Feb 21. e70002

Mitochondrial Mutation Leads to Cardiomyocyte Hypertrophy by Disruption of Mitochondria-Associated ER Membrane.

Miao Yu, Min Song, Manna Zhang, Shuangshuang Chen, Baoqiang Ni, Xuechun Li, Wei Lei, Zhenya Shen, Yong Fan, Jianyi Zhang, Shijun Hu.

  m.3243A>G is the most common pathogenic mtDNA mutation. High energy-demanding organs, such as heart, are usually involved in mitochondria diseases. However, whether and how m.3243A>G affects cardiomyocytes remain unknown. We have established patient-specific iPSCs carrying m.3243A>G and induced cardiac differentiation. Cardiomyocytes with high m.3243A>G burden exhibited hypertrophic phenotype. This point mutation is localised in MT-TL1 encoding tRNALeu (UUR). m.3243A>G altered tRNALeu (UUR) conformation and decreased its stability. mtDNA is essential for mitochondrial function. Mitochondria dysfunction occurred and tended to become round. Its interaction with ER, mitochondria-associated ER membrane (MAM), was disrupted with decreased contact number and length. MAM is a central hub for calcium trafficking. Disrupted MAM disturbed calcium homeostasis, which may be the direct and leading cause of cardiomyocyte hypertrophy, as MAM enforcement reversed this pathological state. Considering the threshold effect of mitochondrial disease, mito-TALENs were introduced to eliminate mutant mitochondria and release mutation load. Mutation reduction partially reversed the cellular behaviour and made it approach to that of control one. These findings reveal the pathogenesis underlying m.3243A>G from perspective of organelle interaction, rather than organelle. Beyond mitochondria quality control, its proper interaction with other organelles, such as ER, matters for mitochondria disease. This study may provide inspiration for mitochondria disease intervention.

Keywords:  cardiomyocyte hypertrophy; induced pluripotent stem cell; mitochondrial mutation; mitochondria‐associated ER membrane

DOI:  https://doi.org/10.1111/cpr.70002
bioRxiv. 2025 Feb 05. pii: 2025.01.14.633043. [Epub ahead of print]

Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.

Ryan J Allen, Ana Kronemberger, Qian Shi, Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira, Vitor A Lira.

Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice we reveal that aging slows muscle relaxation leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We reveal that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are also affected early in aging and are closely associated with rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca 2+ homeostasis, cytoskeleton integrity and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.

DOI: https://doi.org/10.1101/2025.01.14.633043
Cell Prolif. 2025 Feb 21. e70009

SIRT1 Alleviates Oxidative Stress-Induced Mitochondrial Dysfunction and Mitochondria-Associated Membrane Dysregulation in Stress Urinary Incontinence.

Liying Chen, Jianming Tang, Xiaohu Zuo, Bingshu Li, Cheng Liu, Shasha Hong, Jie Min, Ming Hu, Suting Li, Min Zhou, Mao Chen, Yong He, Ya Xiao, Xiaoyu Huang, Li Hong.

  The pathogenesis of stress urinary incontinence (SUI), a condition common in women, remains to be fully elucidated. This study revealed that the incidence of SUI is associated with mitochondrial homeostasis dysregulation following oxidative stress in the fibrous connective tissue of the pelvic floor. SIRT1 is an essential factor for maintaining mitochondrial homeostasis; however, its potential role and mechanism of action in SUI pathogenesis remain unclear. Both in vitro and in vivo, we observed that oxidative stress reduced SIRT1 expression to inhibit the PGC-1α/NRF1/TFAM and PINK1/Parkin signalling pathways, eliciting impairment of mitochondrial biogenesis and mitophagy in L929 cells and SUI mice. Decreased SIRT1 levels induced endoplasmic reticulum (ER) stress and altered the structure of mitochondria-associated membranes (MAMs), disrupting ER-mitochondrial calcium homeostasis and exacerbting ROS accumulation. SIRT1 activation can restore mitochondrial function and the structure of MAMs and alleviate ER stress in fibroblasts, promoting anterior vaginal wall repair and improving urodynamic parameters in the SUI model. Our findings provide novel insights into the role and associated mechanism of SIRT1 in ameliorating oxidative stress-induced mitochondrial dysfunction in fibroblasts of the anterior vaginal wall and propose SIRT1 as a potential therapeutic target for SUI.

Keywords:  SIRT1; mitochondrial biogenesis; mitochondria‐associated membranes; mitophagy; stress urinary incontinence

DOI:  https://doi.org/10.1111/cpr.70009
Curr Biol. 2025 Feb 14. pii: S0960-9822(25)00125-3. [Epub ahead of print]

Compositionally unique mitochondria in filopodia support cellular migration.

Madeleine Marlar-Pavey, Daniel Tapias-Gomez, Marcel Mettlen, Jonathan R Friedman.

  Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca2+ uniporter MCU, suggesting a functional specialization. METEORs are also enriched for the myosin MYO19, which promotes their trafficking to a small subset of filopodia. We identify a positive correlation between the length of filopodia and the presence of METEORs and show that elimination of mitochondria from filopodia impairs cellular motility. Our data reveal a novel type of mitochondrial heterogeneity and suggest compositionally specialized mitochondria support cell migration.

Keywords:  MCU; MICOS; MYO19; calcium; cristae; filopodia; migration; mitochondria; organelle

DOI:  https://doi.org/10.1016/j.cub.2025.01.062