bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–11–09
ten papers selected by
Verena Kohler, Umeå University
  1. CNX:FAM134B-driven ERLAD of ATZ polymers proceeds via enhanced formation of VAPA:ORP1L:RAB7 contact sites between ER and endolysosomes.
  2. Membrane curvature at the ER-PM contact sites.
  3. The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts.
  4. Contact-dependent incorporation of endoplasmic reticulum into retraction fibers and migrasomes.
  5. Mitochondria Rewiring by Polyphenol-Copper Nanodots to Truncate Mitochondrial-Endoplasmic Reticulum Crosstalk for Acute Kidney Injury Therapy.
  6. The Myo2 adaptor Ldm1 and its receptor Ldo16 mediate actin-dependent lipid droplet motility.
  7. Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
  8. Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
  9. PACS-2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis.
  10. Morphological alterations of peridroplet mitochondria in human liver biopsy.
  1. Autophagy Rep. 2025 ;4(1): 2574355
    CNX:FAM134B-driven ERLAD of ATZ polymers proceeds via enhanced formation of VAPA:ORP1L:RAB7 contact sites between ER and endolysosomes.
    Elisa Fasana, Ilaria Fregno, Maurizio Molinari.
      Membrane contact sites (MCS) between organelles maintain the proximity required for controlled exchange of small molecules and ions yet preventing fusion events that would compromise organelles' identity and integrity. Here, by investigating the intracellular fate of the disease-causing Z-variant of alpha1 antitrypsin (ATZ), we report on a novel function of MCS between the endoplasmic reticulum (ER) and RAB7/LAMP1-positive endolysosomes in ER-to-lysosome-associated degradation (ERLAD). For this function, the VAPA:ORP1L:RAB7 multi-protein complex forming MCS between the ER and endolysosomes engages, in an ERLAD client-driven manner, the misfolded protein segregation complex formed by the lectin chaperone calnexin (CNX), the ER-phagy receptor FAM134B, and the ubiquitin-like protein LC3. Generation of this supramolecular complex facilitates the membrane fusion events regulated by the SNARE proteins STX17 and VAMP8 that ensure efficient delivery of ATZ polymers from their site of generation, the ER, to the site of their intracellular clearance, the degradative RAB7/LAMP1-positive endolysosomes.
    Keywords:  Calnexin (CNX); ER-phagy; ER-to-Lysosome-Associated Degradation (ERLAD); Endoplasmic Reticulum (ER); FAM134B; Membrane Contact Sites (MCS); ORP1L; RAB7; VAPA; endolysosomes
    DOI:  https://doi.org/10.1080/27694127.2025.2574355
  2. Trends Cell Biol. 2025 Nov 06. pii: S0962-8924(25)00225-9. [Epub ahead of print]
    Membrane curvature at the ER-PM contact sites.
    Yang Yang, Luis A Valencia, Bianxiao Cui.
      Membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) are essential for lipid transfer, calcium signaling, and membrane organization. While the formation and function of ER-PM contacts are increasingly well-characterized, the spatiotemporal regulation of their localization remains elusive. Emerging evidence using nanopatterned substrates, ultrastructural imaging, and protein localization analyses indicates that membrane curvature can act as a spatial cue for the recruitment of specific tethering proteins, influencing where contact sites form. This opinion article synthesizes recent advances linking membrane topography ER-PM contact organization and highlights systems where curvature actively orchestrates contact position through curvature-sensing proteins. It also outlines key unanswered questions about how membrane curvature integrates into broader signaling networks that govern organelle contact communication.
    Keywords:  ER–PM contact; RyR2; calcium signaling; junctophilin; membrane curvature
    DOI:  https://doi.org/10.1016/j.tcb.2025.10.002
  3. Cell Rep. 2025 Oct 30. pii: S2211-1247(25)01257-4. [Epub ahead of print]44(11): 116486
    The ER thioredoxin-related transmembrane protein TMX2 controls redox-mediated tethering of ER-mitochondria contacts.
    Junsheng Chen, Megan C Yap, Arthur Bassot, Danielle M Pascual, Tadashi Makio, Jannik Zimmermann, Heather Mast, Rakesh Bhat, Samuel G Fleury, Yuxiang Fan, Adriana Zardini Buzatto, Jack Moore, Klaus Ballanyi, Liang Li, Michael Overduin, M Joanne Lemieux, Hélène Lemieux, Grazia M S Mancini, Bruce Morgan, Paul C Marcogliese, Thomas Simmen.
      Thioredoxin-related transmembrane proteins (TMXs) of the endoplasmic reticulum (ER) determine not only redox conditions within the ER lumen but also the formation and function of ER-mitochondria membrane contact sites (ERMCS). The presence of cytosolic, reactive oxygen species (ROS)-derived redox nanodomains at ERMCS suggests TMXs could also control these. The prime candidate for such a function is TMX2, the sole TMX family protein with a cytosolic thioredoxin domain. Indeed, TMX2 controls the extent of ERMCS through interaction with outer mitochondrial membrane proteins, including TOM70. Assisted by cytosolic peroxiredoxins, TMX2 moderates the sulfenylation of the TOM70 C206 residue. Thereby, TMX2 reduces mitochondrial Ca2+ uptake and metabolism. Accordingly, mutation of the TMX2 gene in cells from a patient with a neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS) results in hyperactive mitochondria. In a fly in vivo NEDMCMS model, TMX2 knockdown manifests predominantly in glial cells, where it prevents seizure-like behavior.
    Keywords:  CP: Molecular biology; Ca(2+); ER; MCS; PRDX; TMX2; TOM70; endoplasmic reticulum; membrane contact sites; mitochondria; peroxiredoxin; redox
    DOI:  https://doi.org/10.1016/j.celrep.2025.116486
  4. J Cell Biol. 2025 Dec 01. pii: e202505064. [Epub ahead of print]224(12):
    Contact-dependent incorporation of endoplasmic reticulum into retraction fibers and migrasomes.
    Peiyao Fan, Rui Ji, Yiling Wen, Yaping Dang, Yong Li, Xiaojie Yan, Murong Li, Qiaoxia Zheng, Yifan Ge, Pengli Zheng, Yang Chen.
      Migrating cells form retraction fibers (RFs) at their trailing edge, where migrasomes, ranging from 0.5 to 3 μm, grow at the tips or intersections of RF. Migrasomes play crucial roles when released extracellularly, but before release, they remain physically connected to cell body via RFs, facilitating long-range signal transmission. Since many signaling molecules are highly localized, the mechanism of long-range signal transmission has not been fully understood. Here, we demonstrated that tubular ER extended into RFs and localized to migrasomes, which depended on microtubule-regulated ER extension. Tubular ER adhered to migrasome biogenesis site through ER-plasma membrane contact sites (ER-PM MCSs). Notably, tubular ER functions as cholesterol and calcium reservoir, facilitating the transfer of cholesterol and calcium to migrasomes, potentially at ER-PM MCSs that promoted membrane expansion, stability, and localized secretion of migrasome. Our findings revealed a novel dynamic of tubular ER and provided a new mechanism for long-range site-specific calcium and cholesterol transmission through RFs and migrasomes in migrating cells.
    DOI:  https://doi.org/10.1083/jcb.202505064
  5. Adv Mater. 2025 Nov 05. e08379
    Mitochondria Rewiring by Polyphenol-Copper Nanodots to Truncate Mitochondrial-Endoplasmic Reticulum Crosstalk for Acute Kidney Injury Therapy.
    Jiaojiao Zhang, Jingyi Li, Xue Jiang, Qirui Wang, Kaidi Zhang, Hao Huang, Zifan Cheng, Yang Zhu, Weijun Tong, Lie Ma, Jianghua Chen, Zhengwei Mao, Hong Jiang.
      Aberrant mitochondria-endoplasmic reticulum (ER) interactions at mitochondria-associated membranes (MAMs) drive renal tubular cell injury in acute kidney injury (AKI), exacerbating oxidative stress, calcium dysregulation, and homeostasis disruption. However, targeted intervention remains challenging. To address this challenge, this study employs gallic acid-modified polyphenol-copper nanodots (GA-Cu) to target tubular mitochondria and ameliorate AKI by rewiring organelle communication. Following systemic administration, the ultrasmall GA-Cu nanodots readily traverse the renal filtration barrier and are internalized by tubular cells. Their surface polyphenol composition enables precise enrichment around mitochondria, where they not only scavenge reactive oxygen species but also disrupt the core MAM tethering complex-the IP3R-GRP75-VDAC1 axis. In vitro and in vivo studies demonstrate that GA-Cu remodels mitochondria-ER interfaces, significantly suppressing pathological MAM formation. This intervention attenuates ER-to-mitochondria calcium transfer and restores mitochondrial function, resulting in remarkable renal protection. Hence, this refined cellular regulation is expected to offer substantial prospects for activating new subcellular compartment-specific homeostatic effects.
    Keywords:  acute kidney injury; calcium overload; mitochondrial‐associated membranes; oxidative stress; polyphenol‐copper nanoparticles
    DOI:  https://doi.org/10.1002/adma.202508379
  6. Cell Rep. 2025 Oct 25. pii: S2211-1247(25)01246-X. [Epub ahead of print]44(11): 116475
    The Myo2 adaptor Ldm1 and its receptor Ldo16 mediate actin-dependent lipid droplet motility.
    Xue-Tong Zhao, Duy Trong Vien Diep, Louis Percifull, Rebecca Martina Fausten, Marie Hugenroth, Pascal Höhne, Beatriz Leite, Bianca Marie Esch, Javier Collado, Jenny Keller, Stephan Wilmes, Meryem Aysenur Turhan, Mike Wälte, Thomas Becker, Daniel Kümmel, Christian Schuberth, Rubén Fernández-Busnadiego, Florian Fröhlich, Roland Wedlich-Söldner, Maria Bohnert.
      Organelle motility enables strategic cellular reorganizations. In yeast, this process depends on the actin cytoskeleton, type V myosin motor proteins, and organelle-specific myosin adaptor proteins. While the myosin adaptors for most organelles are known, the coupling of myosin to lipid droplets (LDs), the cellular lipid storage organelles, remained enigmatic. Using genome-wide screening, we identified Ldm1 (lipid droplet motility 1/Yer085c) as a myosin adaptor. Ldm1 binds to the globular tail domain of the myosin Myo2 and to the LD surface protein Ldo16 to enable actin-dependent LD motility. Ldo16 has additional roles in LD contact sites to the vacuole and the endoplasmic reticulum, suggesting a coordination of LD motility and organelle tethering. Ldm1 has a second role in mitochondrial transport, and elevated Ldm1 levels rescue defects of the mitochondrial Myo2-adaptors Mmr1/Ypt11. Our work identifies the molecular machinery for LD motility and contributes to a comprehensive understanding of acto-myosin-based cellular reorganization.
    Keywords:  CP: Cell biology; CP: Metabolism; Ldm1; Ldo16; actin cytoskeleton; acto-myosin; lipid droplet; lipid droplet motility protein 1; lipid droplet organization protein of 16 kDa; mitochondria; organelle motility; type V myosin motor protein Myo2
    DOI:  https://doi.org/10.1016/j.celrep.2025.116475
  7. Cell Death Differ. 2025 Nov 01.
    Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
    Jose C Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh.
      The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPRER) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPRER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans, increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPRER activation were dependent on PERK signalling and its interaction with the UPRmt. The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.
    DOI:  https://doi.org/10.1038/s41418-025-01603-7
  8. J Cell Sci. 2025 Nov 03. pii: jcs.263920. [Epub ahead of print]
    Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
    Sebabrata Maity, Anwesha Dutta Gupta, Izaz Monir Kamal, Rajdeep Das, Rupsha Mondal, Arpit Tyagi, Deepak Sharma, Joy Chakraborty, Saikat Chakrabarti, Oishee Chakrabarti.
      The endoplasmic reticulum (ER) and mitochondria are known to affect myriad cellular mechanisms. More recently, dynamic association between them has been identified in different eukaryotes; these interactions vary in their composition and involvement in regulation of intracellular machineries. FAM134B or RETREG1, originally identified as an oncogene, regulates ER membrane shape and curvature. It is a key ER-phagy or reticulophagy receptor, which promotes autophagy of not only the ER but also simultaneous dual autophagy of ER and mitochondria. While it is known that FAM134B can potentiate contact with mitochondria, its direct involvement in affecting mitochondrial dynamics remains unexplored. Here we show that FAM134B can interact with the canonical fission-promoting protein, DRP1. Functional depletion of FAM134B leads to local Actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in hyperfusion. A decrease in FAM134B levels is observed with aging in rat brains, cell and mouse models of Parkinson's disease and patient-derived samples. Our study establishes FAM134B as the ER partner that helps in maintaining mitochondrial morphology and dynamics.
    Keywords:  DRP1; FAM134B; Fission; Mitochondrial hyperfusion
    DOI:  https://doi.org/10.1242/jcs.263920
  9. Adv Sci (Weinh). 2025 Nov 05. e11781
    PACS-2 Mitigates NPSC Apoptosis and Intervertebral Disc Degeneration by Preserving MAM Integrity via the SP1/LRRK2/Mfn2 Axis.
    Liang Kang, Jiaqi Wang, Chenhao Zhao, Qiuwei Li, Zhigang Zhang, Huaqing Zhang, Chongyu Jia, Luping Zhou, Yanxin Wang, Yu Chen, Kaixuan Li, Xu Yan, Jie Fang, Haibao Wang, Dandan Wang, Pingping Su, Jingyu Zhang, Zhiwei Chen, Renjie Zhang, Cailiang Shen.
      Intervertebral disc (IVD) degeneration (IDD) is a leading cause of lower back pain, and the application of nucleus pulposus-derived stem cells (NPSCs) holds promise for regenerative treatment. However, the harsh microenvironment of degenerative IVDs increases apoptosis in endogenous and transplanted NPSCs, limiting the effectiveness of NPSC-based therapies. Mitochondria-associated ER membrane (MAM) facilitates communication between mitochondria and ER and is critical for cellular homeostasis. PACS-2 is a central regulator of MAM homeostasis. It is found that MAM structure is disrupted in degenerative human and rat IVDs and in NPSCs exposed to an acidic environment, coinciding with reduced PACS-2 expression and increased apoptosis. In addition, Pacs-2 knockout mice with IDD displayed accelerated degeneration, accompanied by the exacerbation of ER stress, mitochondrial dysfunction, and apoptosis. Mechanistically, PACS-2 suppresses phosphorylation and nuclear translocation of the transcription factor SP1, thereby downregulating its downstream target LRRK2. This reduces LRRK2-mediated ubiquitination and degradation of Mfn2 through the JNK pathway, preserving MAM integrity and promoting NPSC survival. In vivo, transplantation of Pacs-2-overexpressing NPSCs improved cell survival and enhanced IVD repair in a degenerative model. These findings demonstrate that PACS-2 supports NPSC-mediated IVD regeneration by maintaining MAM integrity via the SP1/LRRK2/Mfn2 axis, offering potential therapeutic targets for IDD.
    Keywords:  apoptosis; intervertebral disc degeneration; mitochondria‐associated endoplasmic reticulum membrane; nucleus pulposus–derived stem cells; phosphofurin acidic cluster sorting protein 2
    DOI:  https://doi.org/10.1002/advs.202511781
  10. Sci Rep. 2025 Nov 04. 15(1): 38650
    Morphological alterations of peridroplet mitochondria in human liver biopsy.
    Hanna Kawecka, Norihiro Imai, Yuki Ohsaki, Jinglei Cheng, Dongming Liu, Jingjing Zhang, Fumitaka Mizuno, Taku Tanaka, Shinya Yokoyama, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Michał Woźniak, Hiroaki Wake, Hiroki Kawashima.
      Mitochondrial dysfunction and the accumulation of lipid droplets (LD) contribute to the pathogenesis of liver diseases. Mitochondria bound to LD, termed peridroplet mitochondria (PDM), form a subpopulation with distinct functions compared to cytoplasmic mitochondria (CM). In this first in vivo human liver study, we aimed to investigate the morphological differences between PDM and CM and to assess their associations with clinical parameters. Our analysis of mitochondrial ultrastructure using transmission electron microscopy images of human liver biopsies showed that CM were significantly smaller, more spherical, and solid, whereas PDM were larger and more elongated. Overall, PDM exhibited more uniform morphology, while CM displayed disease-specific morphological alterations. CM were associated with serum liver enzyme levels and high-density lipoprotein cholesterol, suggesting sensitivity to liver stress and a potential role in liver cholesterol transport. In contrast, PDM were associated with serum triglyceride levels, indicating a role in lipid metabolism. Total PDM and LD counts showed a positive correlation, reinforcing their close functional relationship. These findings show that PDM and CM represent distinct mitochondrial subpopulations with unique morphologies and differing associations with hepatic pathophysiological pathways, which highlights the significance of LD interactions in contributing to mitochondrial heterogeneity.
    Keywords:  Deep learning model; Lipid droplets; Lipid metabolism; Mitochondrial contact sites; Mitochondrial dynamics; Transmission electron microscopy
    DOI:  https://doi.org/10.1038/s41598-025-22496-z
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