bims-mecosi 2026-04-26 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–04–26
eight papers selected by
Verena Kohler, Umeå University

Building bridges: BLTP2 forms ER-plasma membrane contact sites.
Alzheimer's disease: disrupted communication between the endoplasmic reticulum and mitochondria.
Organelle interactome disruption: The systemic pathological mechanisms and therapeutic prospects of mitochondria-lysosome-ER crosstalk in Alzheimer's disease.
BVDV NS5A promotes mitochondria-associated endoplasmic reticulum membrane (MAM) formation to enhance viral replication.
Localized phosphoinositide metabolism regulates STIM1/ORAI1 fast inactivation.
Oxysterol-binding protein-related protein 6 regulates neuronal morphology and migration of cerebellar granule cells during cerebellar development in vivo.
Sakuranin attenuates UVB-induced skin damage by preserving mitochondria-ER coupling and restoring redox-organelle homeostasis.
SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.

J Cell Biol. 2026 May 04. pii: e202603182. [Epub ahead of print]225(5):

Building bridges: BLTP2 forms ER-plasma membrane contact sites.

Florian Fröhlich.

Bridge-like lipid-transport protein 2 (BLTP2) transfers lipids at membrane contact sites, but its precise localization is unclear. Dziurdzik et al. and Dai et al. identify and characterize a conserved contact site between the endoplasmic reticulum and the plasma membrane mediated by BLTP2.

DOI: https://doi.org/10.1083/jcb.202603182
J Neurol. 2026 Apr 20. pii: 283. [Epub ahead of print]273(5):

Alzheimer's disease: disrupted communication between the endoplasmic reticulum and mitochondria.

Jiafu Guo, Ziying Yang, Shiyan Luo, Chenxi Li, Shijun Xu.

  Alzheimer's disease (AD) remains a major, intractable neurodegenerative disorder and a serious threat to human health, characterized by a protracted clinical course, gradual progression, and irreversible cognitive decline. The current therapeutic landscape is characterized by a lack of disease-modifying agents, making the pursuit of early, effective interventions a global priority. Endoplasmic reticulum-mitochondria contact sites (ERMCs), also termed mitochondria-associated ER membranes (MAMs), constitute critical platforms for interorganellar communication, enabling material exchange and signal transduction. Key functions regulated at these junctions include calcium (Ca2+) homeostasis, mitochondrial dynamics, and lipid synthesis/transfer. Growing evidence implicates dysregulated ERMCs in the pathogenesis of neurodegenerative diseases, including AD and Parkinson's disease (PD). Recent advances in understanding the physiological and pathological roles of ERMCs have further illuminated their multifaceted contribution to AD, spanning amyloid-β (Aβ) production, Ca2+ signaling, energy and lipid metabolism, mitochondrial integrity, and endoplasmic reticulum stress (ERs). This review synthesizes current knowledge on ERMCs as a pivotal communication hub in AD and underscores their promising potential as targets for novel therapeutic strategies. Deeper insights into this axis may inform future approaches to improve clinical outcomes.

Keywords:  Alzheimer’s disease; Ca2+ ; ERMCs; Lipid metabolism; Mitochondria

DOI:  https://doi.org/10.1007/s00415-026-13822-0
Ageing Res Rev. 2026 Apr 21. pii: S1568-1637(26)00137-6. [Epub ahead of print]118 103145

Organelle interactome disruption: The systemic pathological mechanisms and therapeutic prospects of mitochondria-lysosome-ER crosstalk in Alzheimer's disease.

Liping Xing, Annan Liu, Wei Gao, Jianhui Li, Mingyuan Yao, Jing Song, Peihan Duan, Honglin Li.

  The traditional pathological framework of Alzheimer's disease (AD) primarily focuses on the accumulation of β-amyloid (Aβ) and tau proteins. However, therapeutic strategies targeting these molecules have repeatedly encountered setbacks in clinical translation. Recent studies have progressively revealed that the dynamic interaction network among intracellular organelles plays a central role in the pathogenesis of AD. This systematic review examines the independent dysfunctions of three key organelles-mitochondria, lysosomes, and the endoplasmic reticulum (ER)-in AD, along with their physical and functional connectivity mechanisms. It emphasizes how their interaction network, formed through membrane contact sites, synergistically drives core AD pathological processes, including calcium signaling dysregulation, Aβ metabolism imbalance, mitochondrial quality control failure, lipid metabolism disorders, and neuroinflammation with apoptosis. This paper innovatively proposes that AD can be regarded as a "mitochondrial network disorder," the pathological essence of which lies in the systemic breakdown of communication between mitochondria. Building on this premise, we further discuss a therapeutic strategy centered on mitophagy enhancers to reshape the mitochondrial network and explore the translational medical prospects of achieving multi-target synergistic intervention by restoring the homeostasis of the mitochondrial network.

Keywords:  Alzheimer's disease; Endoplasmic reticulum stress; Lysosomal dysfunction; Membrane contact sites; Mitochondrial-endoplasmic reticulum connections; Organelle interaction networks

DOI:  https://doi.org/10.1016/j.arr.2026.103145
Vet Microbiol. 2026 Apr 17. pii: S0378-1135(26)00159-8. [Epub ahead of print]317 111027

BVDV NS5A promotes mitochondria-associated endoplasmic reticulum membrane (MAM) formation to enhance viral replication.

Xiangyin Zhang, Lingling Chang, Jingyi Zhang, Jiaqian Xue, Yuhan Sun, Xuelian Ma, Dewen Tong, Xiaomin Zhao.

  The nonstructural protein 5 A (NS5A) of bovine viral diarrhea virus (BVDV) is a multifunctional viral factor that coordinates BVDV RNA replication and assembly. Mitochondria-associated endoplasmic reticulum membrane (MAM) has emerged as a critical platform for lipid metabolism, Ca²⁺ signaling, and viral replication. However, whether BVDV NS5A promotes viral replication by targeting MAM remains unclear. In this study, we demonstrate that NS5A of BVDV promotes viral replication through increasing MAM formation. MAM is essential for efficient viral replication and is promoted by BVDV NS5A. NS5A directly interacts with the host MAM-tethering protein, vesicle-associated membrane protein-associated protein B (VAPB), thereby remodeling this organelle interface. We further mapped this interaction to a specific binding interface on NS5A centered around key residues (G246, K249, D259) and (D398, K400, T402, D405). Crucially, using a reverse genetics system, we show that mutations disrupting the NS5A-VAPB interaction abolish MAM expansion and severely impair viral replication. Conversely, re-establishing this interaction through complementation restores both MAM integrity and viral propagation. Taken together, our findings reveal a critical host reshaping mechanism in which BVDV NS5A interacts with VAPB to enlarge the MAM platform and create a pro-viral environment that is essential for efficient replication. Our work identifies the NS5A-VAPB interface as a promising target for host-directed antiviral strategies with potential applicability to related members of the Pestiviridae family.

Keywords:  Bovine viral diarrhea virus; Endoplasmic reticulum; Mitochondria-associated endoplasmic reticulum membrane; NS5A; Vesicle-associated membrane protein-associated protein B; Viral replication

DOI:  https://doi.org/10.1016/j.vetmic.2026.111027
iScience. 2026 May 15. 29(5): 115543

Localized phosphoinositide metabolism regulates STIM1/ORAI1 fast inactivation.

Ning Dai, Shawn M Lamothe, Jody Groenendyk, Nicolas Touret, Harley T Kurata, Marek Michalak.

  Store-operated Ca2+ entry (SOCE) is central for maintaining cellular Ca2+ homeostasis, and it is initiated by the depletion of Ca2+ in the endoplasmic reticulum (ER) and activation of stromal interaction molecule 1 (STIM1). STIM1 acts as an ER Ca2+ sensor and engages with plasma membrane ORAI1 channels to facilitate ORAI1 activation and Ca2+ influx. Here, we found that STIM1 forms a complex with myotubularin-related protein 7 (MTMR7) to regulate ORAI1 inactivation during prolonged Ca2+ entry. MTMR7 alters plasma membrane PI(3,5)P2 and PI(4,5)P2 levels, increasing ORAI1 inactivation and decreasing SOCE. Loss of catalytic phosphatase function of MTMR7 weakens ORAI1 inactivation and enhances SOCE activity, while the disruption of MTMR7 and STIM1 association retains ORAI1 inactivation. The MTMR7/STIM1 complex positions MTMR7 at ER-plasma membrane contact sites to fine-tune lipid signaling, prevent premature STIM1 activation, and modify ORAI1 inactivation. These findings provide insight into novel modes of regulation of ORAI1 inactivation by phosphoinositides (PIPs).

Keywords:  Biochemistry; Molecular biology; Pharmacology

DOI:  https://doi.org/10.1016/j.isci.2026.115543
Biochem Biophys Rep. 2026 Jun;46 102585

Oxysterol-binding protein-related protein 6 regulates neuronal morphology and migration of cerebellar granule cells during cerebellar development in vivo.

Shinya Mochizuki, Wataru Nishimura, Masanori Takahashi, Reiji Yamazaki, Ruyun Zhou, Harukata Miki, Yasuko Noda.

  Oxysterol-binding protein (OSBP)-related protein (ORP) 6, a member of subfamily III of the ORP family, localizes at endoplasmic reticulum-plasma membrane contact sites and is involved in regulating the turnover of the lipid composition of the plasma membrane through the counter-transport of phosphatidylinositol-4-phosphate and phosphatidylserine in neurons. However, the physiological functions of ORP6-mediated lipid counter-transport remain poorly understood. In the present study, we investigated the developmental expression of ORP6 protein in the mouse cerebellum and the role of ORP6 in neuronal differentiation and migration using Neuro-2A cells and primary cultured cerebellar granule cells (CGCs). The expression of the ORP6 protein increased from P7 to P21, coinciding with a key period of granule cell progenitor proliferation and immature CGC migration. Both ORP6 RNAi knockdown and overexpression of two different types of dominant-negative ORP6 constructs significantly increased the number and length of neurites in retinoic acid-induced differentiated Neuro-2A cells. Similarly, ORP6 knockdown in primary cultured CGCs increased neurite number and length and disrupted their migration in vitro. Furthermore, overexpression of a dominant-negative form of ORP6 in immature CGCs using in vivo electroporation impaired their migration into the granule layer. Taken together, these results suggest the possible involvement of lipid counter-transport by ORP6 in the regulation of neuronal morphology and migration of CGCs.

Keywords:  Cerebellar granule cells; Membrane contact site; Migration; ORP6; Oxysterol-binding protein

DOI:  https://doi.org/10.1016/j.bbrep.2026.102585
Int Immunopharmacol. 2026 Apr 22. pii: S1567-5769(26)00552-7. [Epub ahead of print]180 116706

Sakuranin attenuates UVB-induced skin damage by preserving mitochondria-ER coupling and restoring redox-organelle homeostasis.

Jayasingha Arachchige Chathuranga Chanaka Jayasingha, Wisurumuni Arachchilage Hasitha Maduranga Karunarathne, Sang Rul Park, Chang Soo Lee, Cheng-Yun Jin, Yung Hyun Choi, Kyoung Tae Lee, Gi-Young Kim.

  Ultraviolet B (UVB) irradiation elicits complex intracellular stress responses that drive keratinocyte injury and skin photoaging through coordinated disruption of redox homeostasis, mitochondrial dynamics, and endoplasmic reticulum (ER) stress signaling at mitochondria-ER contact sites. This study investigated whether sakuranin (SKR), a naturally occurring flavanone glycoside, exerts photoprotective effects by modulating mitochondria-ER networks under UVB exposure. SKR displayed no cytotoxicity at concentrations up to 100 μM, when administered as a pre-treatment, significantly reduced UVB-induced apoptotic cell death by suppressing cytosolic and mitochondrial reactive oxygen species accumulation, preserving mitochondrial membrane potential, and restoring the balance between DRP1-driven fission and OPA1-mediated fusion. In parallel, SKR markedly attenuated ER stress responses, as evidenced by reduced eIF2α phosphorylation and downregulation of GRP78 and CHOP expression, while live-cell imaging confirmed the preservation of mitochondria-ER contact integrity disrupted by UVB exposure. These protective effects were consistently reproduced in UVB-exposed zebrafish larvae, in which SKR significantly alleviated oxidative stress and ER stress responses. Collectively, these findings demonstrate that SKR provides robust photoprotection by coordinately regulating oxidative stress, mitochondrial dynamics, ER stress signaling, and mitochondria-ER communication, thereby mitigating UVB-induced apoptotic injury and supporting its potential as a natural therapeutic candidate for preventing photoaging and UVB-associated skin disorders.

Keywords:  ER stress; Mitochondrial dynamics; Mitochondria–ER coupling; Oxidative stress; Sakuranin; UVB

DOI:  https://doi.org/10.1016/j.intimp.2026.116706
Metabolism. 2026 Apr 17. pii: S0026-0495(26)00133-2. [Epub ahead of print]180 156623

SEC62 at mitochondria-associated membranes drives MASH progression by suppressing ATAD3B-mediated mitochondrial quality control.

Junchao Lin, Tong Wu, Chen Wang, Wei Zhou, Yutong Liu, Gang Yang, He Zhou, Jingyan Luo, Zhenzhen Fan, Yu Da, Jie He, Bing Xu, Mingzhuo Jiang, Daiming Fan, Kaichun Wu, Jie Liang.

   BACKGROUND: The progression of metabolic dysfunction-associated steatohepatitis (MASH) involves chronic, irreversible inflammatory responses linked to intracellular organelle dysfunction. While endoplasmic reticulum (ER) stress and mitochondrial impairment are recognized as critical drivers, the precise molecular mechanisms governing inter-organelle communication in this disease context remain incompletely understood.
AIM: This study aimed to investigate the role of the ER transmembrane protein SEC62 in MASH pathogenesis. Specifically, it sought to determine whether SEC62 expression is altered in MASH, define its functional impact on disease phenotypes, and elucidate the mechanistic pathway through which it regulates mitochondrial homeostasis and inflammation.
RESULTS: SEC62 was upregulated in both human and mouse MASH livers. Hepatocyte-specific SEC62 overexpression worsened hepatic steatosis, inflammation, and mitochondrial damage, whereas SEC62 knockout ameliorated these features. Mechanistically, SEC62 interacted directly with ATAD3B at the mitochondria-associated membranes (MAMs) interface, leading to the significant downregulation of ATAD3B expression. This SEC62-ATAD3B axis resulted in defective mitophagy, increased mitochondrial reactive oxygen species (ROS) production, and amplified inflammatory responses.
CONCLUSION: Our results demonstrate that SEC62 is a novel regulator of MAMs that drives MASH progression. By interacting with and suppressing ATAD3B, SEC62 disrupts mitochondrial quality control, leading to oxidative stress and inflammation. Together, these findings define a specific molecular mechanism of organelle interplay in MASH and position SEC62 as a potential therapeutic target for intervention.

Keywords:  ATAD3B; Endoplasmic reticulum; FOXO3a; Metabolic-associated steatohepatitis; Mitochondria; SEC62

DOI:  https://doi.org/10.1016/j.metabol.2026.156623