bims-mecosi 2026-07-05 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–07–05
eleven papers selected by
Verena Kohler, Umeå University

Cadherin regulation of endoplasmic reticulum-plasma membrane contact sites.
GDAP1 orchestrates redox signaling at membrane contact sites to preserve axonal integrity in Charcot-Marie-Tooth disease.
Advancing the monitoring of organelle contact sites in vitro and in vivo.
The nucleus-vacuole junction at a glance.
[Functions and measurement methods of organelle contact sites].
CHCHD3(MIC19): mitochondrial cristae structure regulation and disease associations.
Crosstalk collapse: mitochondria-centric organelle network disruption in ovarian aging.
Syntabulin promotes heart failure by enhancing SR-mitochondria tethering and impairing mitofission.
Targeting Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs): A Novel Therapeutic Strategy for Diabetic Complications.
Mitochondria in the middle of inter- organellar cross talk: insights from yeast to humans.
The ER-Resident Protein PDZD8 Inhibits Virus Production of West Nile Virus.

Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00686-8. [Epub ahead of print]45(7): 117608

Cadherin regulation of endoplasmic reticulum-plasma membrane contact sites.

Sonam Lhamo, Navaneetha Krishnan Bharathan, William Giang, Kandice R Levental, Cory L Simpson, Stephanie E Zimmer, Thomas Saba, Julie Beaucousin, Mélina L Heuzé, Andrew P Kowalczyk.

  The spatial organization and dynamics of the endoplasmic reticulum (ER) govern when and where ER tubules engage with other organelles and the plasma membrane. We previously found that ER tubules are closely associated with desmosomes, but the mechanisms of ER recruitment to these adhesive intercellular junctions were unclear. Here, we demonstrate that recruitment of ER tubules to intercellular junctions is dependent upon E-cadherin association with α-catenin. During junction formation, adherens junctions and ER tubules appear nearly simultaneously at nascent cell-cell contacts, followed by desmosome formation. ER recruitment allows the formation of ER-plasma membrane contact sites (ER-PMCSs) and an assembly comprising adherens junctions, ER-PMCS, and desmosomes. Ablating adherens junctions disrupts this tripartite assembly and perturbs global lipid levels. Collectively, our findings identify cadherins as key organizers of ER-PMCS positioning and suggest that the cell-cell adhesion-organelle unit integrates cellular mechanical elements with plasma membrane homeostasis.

Keywords:  CP: cell biology; ER-plasma membrane contact sites; adherens junctions; desmosomes; endoplasmic reticulum

DOI:  https://doi.org/10.1016/j.celrep.2026.117608
Neurobiol Dis. 2026 Jun 28. pii: S0969-9961(26)00257-3. [Epub ahead of print]227 107512

GDAP1 orchestrates redox signaling at membrane contact sites to preserve axonal integrity in Charcot-Marie-Tooth disease.

Lara Cantarero, Mònica Roldán, María Rodríguez-Sanz, Angela J Mathison, Montserrat Olivares-Fuentes, Yaiza Díaz-Osorio, Jordi Pijuan, Marcos Frías, Raul Urrutia, Janet Hoenicka, Francesc Palau.

  Pathogenic variants in GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy characterized by progressive axonal degeneration. Although GDAP1 is an atypical glutathione S-transferase localized to the outer mitochondrial membrane, it has been proposed to function as a redox sensor that likely maintains inter-organelle communication in neurons. However, the mechanisms by which GDAP1 performs these functions remain unclear. To address this question, we here used a robust multi-tier approach that combines high-resolution and live-cell imaging with pH-sensitive probes, membrane contact sites (MCSs) analysis, lipid studies, transcriptomics, and nerve ultrastructural studies in both patient-derived fibroblasts and Gdap1-/- mice. We find that deletion of the GDAP1 gene induces localized pH and redox imbalances at mitochondria-lysosomes contact sites, which propagate to defective mitochondria-peroxisome interactions, impaired peroxisome biogenesis and morphology, leading to altered lipid homeostasis. These defects are accompanied by axonal organelle mislocalization, disruption of nodes of Ranvier, and structural abnormalities in peripheral nerves. Investigations on the potential reversibility of these processes, reveal that restoration of redox balance rescues MCS organization, identifying a therapeutically tractable MCS-peroxisome axis downstream of GDAP1. Together, our findings position GDAP1 as a redox-sensing organizer of mitochondrial membrane contact sites whose dysfunction triggers a cascade of organelle and axonal defects underlying CMT pathogenesis. Thus, this new knowledge should be taken into consideration in the future design of therapeutic interventions that can ameliorate the symptoms of this dismal disease.

Keywords:  Charcot-Marie-tooth disease; GDAP1; Lysosome; Membrane contact sites; Mitochondria; Node of Ranvier; Peroxisome

DOI:  https://doi.org/10.1016/j.nbd.2026.107512
Biochem Soc Trans. 2026 Jul 29. 54(7): 887-899

Advancing the monitoring of organelle contact sites in vitro and in vivo.

Lucia Barazzuol, Caterina Peggion, Marisa Brini, Yusuke Nasu, Tito Calì.

  Organelle contact sites are highly dynamic and specialized regions where distinct organelles come into proximity, enabling direct inter-organelle communication. These structures play fundamental roles in cellular homeostasis by coordinating the exchange of lipids, metabolites, and ions, as well as regulating key processes such as organelle dynamics, mitochondrial fission, autophagy, and metabolic integration. Alterations in contact site architecture and function have been increasingly associated with a wide range of human diseases, including neurodegeneration, metabolic disorders, and cancer. Despite their biological relevance, the nanoscale nature and dynamic behaviour of contact sites have historically posed significant challenges for their accurate detection and functional characterization. Here, we provide a comprehensive overview of the methodologies currently available to study organelle contact sites, ranging from classical approaches such as electron microscopy and biochemical fractionation to advanced imaging techniques and genetically encoded reporters. We discuss recent developments in high-resolution and live-cell microscopy that have improved the spatial and temporal resolution of contact site analysis, as well as emerging tools designed to selectively label, quantify, and manipulate these interfaces. Attention is given to the next generation of engineered reporters capable of sensing molecular and ionic exchanges at contact sites, thereby moving beyond structural description toward functional interrogation. By critically evaluating the strengths and limitations of existing approaches, we aim to provide a framework for selecting appropriate tools and to highlight future directions in the field. Ultimately, advancing our ability to monitor and dissect organelle contact sites will be essential for understanding their contribution to cellular physiology and disease.

Keywords:  Organelle contact sites; SPLICS; genetically encoded reporters

DOI:  https://doi.org/10.1042/BST20250371
J Cell Sci. 2026 Jun 15. pii: jcs264845. [Epub ahead of print]139(12):

The nucleus-vacuole junction at a glance.

Pascal Höhne, Marie Hugenroth, Maria Bohnert.

  The nucleus-vacuole junction (NVJ) is a central membrane contact site in yeast that connects the nuclear endoplasmic reticulum and the vacuole. This organelle interface is heavily involved in the handling of lipids: it houses numerous lipid metabolism enzymes and lipid transfer proteins, and acts as a hotspot for lipid droplet biogenesis. The NVJ shows plastic responses to metabolic cues, adapting both its architecture and its proteome. Many NVJ-resident proteins display alternative, metabolically controlled localizations at other contact sites. This close-knit communication with diverse cellular structures makes the NVJ an important model for understanding general principles of contact site regulation. In this Cell Science at a Glance article and the accompanying poster, we highlight the multifunctionality and metabolic plasticity of the NVJ, as well as its integration into the cellular contact site network.

Keywords:  Contact site; Lipid droplet; Lipid transfer protein; NVJ; Nvj1; Vac8

DOI:  https://doi.org/10.1242/jcs.264845
Nihon Yakurigaku Zasshi. 2026 ;161(4): 222-225

[Functions and measurement methods of organelle contact sites].

Isshin Shiiba.

Intracellular organelles do not function in isolation but instead cooperate through organelle contact sites, where membranes closely appose without fusion to exchange information and metabolites. Among these interfaces, mitochondria-endoplasmic reticulum contact sites (MERCs) have emerged as central regulatory hubs involved not only in calcium and lipid exchange but also in mitochondrial dynamics, autophagy, stress responses, cell death, and metabolic regulation. In this review, the molecular basis of MERC formation is first organized from the perspectives of tethering, molecular transfer, and contact-site regulation, emphasizing that MERCs represent dynamic functional domains that are reorganized according to cellular conditions rather than static structures. Our recent findings are then introduced demonstrating that the mitochondrial outer membrane E3 ubiquitin ligase MITOL (also known as MARCHF5) selectively modulates substrate activity at MERCs and may contribute to mitochondrial iron supply and respiratory maintenance through regulation of the heme-degrading enzyme HMOX2. Because MERCs undergo rapid and reversible remodeling, quantitative analysis in living cells is essential. A split-luciferase-based reversible assay is presented as an example of an approach for real-time monitoring of MERC dynamics, revealing a stress-responsive increase in MERCs triggered by mitochondrial reactive oxygen species that is linked to the handling of lipid radicals. Finally, current methodologies for MERC analysis, including electron microscopy, super-resolution imaging, proximity sensors, and proximity labeling, are overviewed.

DOI: https://doi.org/10.1254/fpj.26004
Front Mol Biosci. 2026 ;13 1861303

CHCHD3(MIC19): mitochondrial cristae structure regulation and disease associations.

Zheng Tai Kuai, Xiao Min Zheng, Yue Yue Li, Tian Qi Wang.

  Mitochondrial bioenergetic competence critically depends on cristae architecture, which is organized and stabilized by the mitochondrial contact site and cristae organizing system (MICOS) complex. As a core MICOS subunit, CHCHD3 (also known as MIC19) contributes to assembly of the mitochondrial intermembrane space bridging (MIB) supercomplex and regulates cristae morphology, endoplasmic reticulum-mitochondria contact sites, and cellular metabolic homeostasis. Aberrant CHCHD3 expression or functional deficiency is implicated in the pathogenesis of neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and cancers. Notably, CHCHD3 function is governed by a dose-dependent "Goldilocks" principle, wherein both insufficient and excessive expression-as well as preserved abundance with impaired functional integrity-can compromise mitochondrial homeostasis, underscoring the need for context-specific therapeutic modulation. Here, we systematically summarize CHCHD3 molecular characteristics and post-translational modification networks, with emphasis on its roles in energy metabolism, organelle crosstalk, and apoptosis. We further examine the mechanistic links between CHCHD3 dysregulation and disease pathogenesis, evaluate current targeting strategies and their pharmacological limitations, and identify remaining controversies and knowledge gaps to guide future research toward clinical translation.

Keywords:  CHCHD3; MIC19; MICOS complex; apoptosis; energy metabolism; mitochondrial contact sites; mitochondrial cristae

DOI:  https://doi.org/10.3389/fmolb.2026.1861303
Cell Commun Signal. 2026 Jul 02. pii: 389. [Epub ahead of print]24(1):

Crosstalk collapse: mitochondria-centric organelle network disruption in ovarian aging.

Wenhan Ju, Binghan Yan, Danping Li, Fang Lian, Shan Xiang.

  Ovarian aging defines the reproductive lifespan of females and exerts profound systemic effects on metabolism and overall health. However, its molecular basis remains incompletely understood. Traditional research has focused primarily on mitochondrial dysfunction, whereas emerging evidence indicates that ovarian aging involves a progressive collapse of a mitochondria-centered organelle interaction network. Mitochondria dynamically communicate with the endoplasmic reticulum, lysosomes, peroxisomes, lipid droplets, and the nucleus through membrane contact sites, coordinating energy metabolism, lipid trafficking, calcium signaling, redox balance, and epigenetic regulation. The disruption of these interactions results in excessive reactive oxygen species generation, defective steroidogenesis, impaired quality control, and transcriptional dysregulation, ultimately driving oocyte deterioration and follicular failure. Here, we propose the "Organelle Interaction Network Disruption Model" of ovarian aging, which integrates recent mechanistic insights into a unifying conceptual framework. This model elucidates the dynamic breakdown of inter-organelle communication and highlights potential diagnostic and therapeutic opportunities to mitigate ovarian functional decline. Together, this perspective provides a mitochondria-centric paradigm for understanding ovarian aging and guiding strategies to preserve female reproductive longevity.

Keywords:  Membrane contact sites; Mitochondrial function; Organelle crosstalk; Ovarian aging; Oxidative stress

DOI:  https://doi.org/10.1186/s12964-026-02860-w
Cardiovasc Res. 2026 Jun 29. pii: cvag139. [Epub ahead of print]

Syntabulin promotes heart failure by enhancing SR-mitochondria tethering and impairing mitofission.

Ying Li, Ziquan Sun, Haixia Duan, Mingyue Wu, Jing Yi, Gang Wang, Wenjuan Liu, Chenglin Zhang, Wanwen Cheng, Jicheng Li, Weixuan Chen, Kunfu Ouyang, Hui Tan, Yueheng Wu, Jie Liu.

   AIMS: Mitochondrial dysfunction is a critical driver of heart failure (HF). Syntabulin (SYBU), known for its role as a motor linker at the outer mitochondrial membrane in neuronal system, has recently been suggested as a heart failure-associated gene. However, the role of SYBU in regulating cardiac function remains unclear.
METHODS AND RESULTS: Pressure overload-induced cardiac hypertrophy and HF was produced by transverse aortic constriction (TAC) in mice and phenylephrine (PE) stimulation in neonatal rat ventricular myocytes (NRVMs). SYBU expression was significantly increased in hypertrophic mouse hearts and patient hearts with dilated cardiomyopathy. The cardiac-specific upregulating SYBU expression, achieved via recombinant adeno-associated virus driven by cardiac troponin T promoter, led to increased cardiomyocyte death and worsened heart failure under hypertrophic conditions. In contrast, SYBU knockdown mitigated PE-induced cardiomyocyte injury. Structured illumination microscopy (SIM) and analysis of mitochondria-associated endoplasmic reticulum membrane (MAM) fractions revealed that SYBU localizes to ER-mitochondria contact sites. SYBU enhances sarcoplasmic reticulum (SR)-mitochondria tethering through interactions with RyR2 and SERCA2, leading to mitochondrial Ca2+ overload and impaired mitochondrial respiratory capacity. Furthermore, excessive mitochondrial Ca2+ triggered ER stress and PKA activation, inducing phosphorylation of Drp1 at Ser637, and ultimately disrupting mitochondrial fission and mitophagy.
CONCLUSION: Our findings established a critical role of SYBU in promoting HF by inducing cardiomyocyte injury via increasing SR-mitochondria tethering and impairing mitochondrial fission and mitophagy. Therefore, targeting SYBU and its downstream signaling pathways could be a promising therapeutic strategy to restrain HF in pressure overload - induced cardiac hypertrophy.

Keywords:  SR–mitochondria tethering; heart failure; mitochondrial dynamic; syntabulin

DOI:  https://doi.org/10.1093/cvr/cvag139
Diabetes Metab Syndr Obes. 2026 ;19 599670

Targeting Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs): A Novel Therapeutic Strategy for Diabetic Complications.

Jianmei Shi, Xiaohan Sun, Jiajun You, Xiaoxu Ji, Juanmei Xie, Yuxuan Li, Kailei Gu, Xiaojie Wei.

  The pathogenesis of diabetes mellitus and its complications involves multiple factors and complex mechanisms. Currently, clinical treatment options remain limited, posing an ongoing and severe challenge to global public health. Therefore, in-depth research and understanding are urgently needed to advance the development of therapeutic strategies. Extensive studies have indicated that the endoplasmic reticulum (ER) and mitochondria are key organelles driving the occurrence and progression of diabetes mellitus and its complications. Notably, the mitochondria-associated endoplasmic reticulum membranes (MAMs), serving as a physical and functional bridge connecting the ER and mitochondria, play a critical role in maintaining organelle functional homeostasis, which underscores the importance of inter-organelle communication. This review systematically summarizes the integrated structure and regulatory mechanisms of MAMs, as well as their physiological functions in mediating inter-organelle signal transduction and material exchange. Furthermore, it elaborates in detail on the diverse pathogenic roles of MAMs dysfunction in diabetes mellitus and its complications, with a focus on its involvement in calcium signaling, lipid synthesis and transport, mitochondrial dynamics, cellular stress, and cell death. In addition, this review specifically points out that multi-component and multi-target holistic regulatory strategies exhibit unique potential in restoring MAMs homeostasis, thereby providing novel perspectives and potential preclinical intervention approaches for the "holistic regulation" treatment of diabetes complications. In conclusion, clarifying the role of MAMs in diabetes mellitus and its complications is expected to lay an important theoretical foundation for the development of preclinical therapeutic strategies, although significant challenges remain for clinical translation, including tissue-specific targeting, safety, and the lack of validated biomarkers.

Keywords:  diabetes-related complications; endoplasmic reticulum stress; holistic regulation; multi-target therapy; organelle homeostasis

DOI:  https://doi.org/10.2147/DMSO.S599670
Front Cell Dev Biol. 2026 ;14 1820168

Mitochondria in the middle of inter- organellar cross talk: insights from yeast to humans.

Nicoletta Guaragnella, Maria Antonietta Di Noia, Giampaolo Morciano, Angela Primavera.

  Mitochondria are multifaceted organelles acting as energy, metabolic and signaling hubs in the cells. Their role as sensors, integrators and transducers of intra and extracellular inputs can drive many processes of stress response. Mitochondrial signal integration can occur at different levels involving functional and physical interactions. An example of functional interaction is the mitochondria-cytosol-nucleus cross talk, named retrograde pathway, which is evolutionary conserved from yeast to humans and allows metabolic rewiring in the presence of. mitochondrial dysfunction. On the other hand, Physical Interactions, such as mitochondria associated membranes (MAMs), specialized contact sites between mitochondria and the endoplasmic reticulum (ER), play pivotal roles in calcium signaling and stress response. Calcium is tightly regulated at MAMs and functions both as stress sensor and mediator. Impaired mitochondrial function can lead to dysregulated calcium flux, particularly from the ER to mitochondria, triggering retrograde signaling pathways that alter nuclear gene expression and support cell adaptation. In yeast, the ER-mitochondria encounter structure (ERMES) complex exemplifies conserved mechanisms facilitating organelle tethering and metabolic cross talk. Dysfunctional mitochondria have significant repercussion on MAMs architecture, and viceversa, which impact on cell stress response particularly in, but not limited to, neurodegenerative disorders and cancer. In this review, we provide an overview of mitochondria-centered inter-organellar cross talk underpinning stress adaptation across eukaryotes, from yeast to humans. This comparative approach allows us to focus on key regulatory nodes, which are emerging as potential therapeutic targets. Components, such as calcium-dependent effectors, transcription factors, tethering proteins, or mitochondrial carriers could enable selective modulation of stress responses.

Keywords:  ERMES complex; MAMS; inter-organellar cross talk; mitochondria; retrograde signaling pathway

DOI:  https://doi.org/10.3389/fcell.2026.1820168
Microbiol Immunol. 2026 Jun 29.

The ER-Resident Protein PDZD8 Inhibits Virus Production of West Nile Virus.

Shiori Abe, Akari Sato, Haruto Eguchi, Keisuke Maezono, Passawat Thammahakin, Duong Thi Ngoc Thuy, Hiroaki Kariwa, Shintaro Kobayashi.

  West Nile virus (WNV) remodels the endoplasmic reticulum (ER) membrane in cells to aid virus production. However, the molecular mechanisms underlying this process remain unclear. PDZD8 is an ER-resident protein that mediates ER-mitochondria contact and lipid transfer, both of which are associated with membrane remodeling. In this study, we found that WNV infection suppressed the expression of PDZD8, leading to a reduction in ER-mitochondria contact sites. By contrast, PDZD8 suppressed WNV production by inhibiting the processes of viral particle assembly and release. These findings suggest that WNV suppresses PDZD8 expression to partially counteract its inhibitory effect on WNV production.

Keywords:  ER–mitochondria contact; PDZD8; West Nile virus; membrane remodeling; viral production

DOI:  https://doi.org/10.1111/1348-0421.70072