bims-mecosi 2026-06-14 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2026–06–14
seventeen papers selected by
Verena Kohler, Umeå University

Septins in the Middle-Makers and Breakers of Membrane Contact Sites.
VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.
Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.
Glycosphingolipids regulate phosphatidylserine transport machinery that operates at ER-PM contact sites.
Spatial architecture of immunometabolism: Mitochondrial‑organelle interfaces in immune signaling (Review).
G-quadruplex-modulated nanoplatform triggers a Ca2+ storm via the mitochondria-associated endoplasmic reticulum membrane for anti-melanoma multimodal therapy.
Mechanism of lipid transfer by bridge-like protein VPS13A and the scramblase XK.
Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
Mitochondria-ER contacts function as an iron supply hub.
A prognostic model for breast cancer based on mitochondria-associated endoplasmic reticulum membrane (MAM) signature genes.
ERO1a fosters glioblastoma aggressiveness and metabolic flexibility by regulating mitochondria-associated membrane dynamics.
Targeting AVEN Liquid-Liquid Phase Separation in Colorectal Cancer: Insights From a Raddeanin A-Based Chemical Probe.
p53 overexpression counteracts the pro-survival effect of Bcl-2 by restoring MAMs function in cutaneous squamous cell carcinoma.
HKDC1 contributes to aberrant lysosome-mitochondria contact in Niemann-Pick disease type C.
Targeting Neuroinflammation in Depression: The Integrative Role of Sigma-1 Receptor Modulation.
TMEM230 and mitochondrial regulation in Alzheimer's disease.
Mitochondria directly interact with the nuclear pore complex.

J Neurochem. 2026 Jun;170(6): e70495

Septins in the Middle-Makers and Breakers of Membrane Contact Sites.

TrishaJean J Holt, Elias T Spiliotis.

Intracellular communication in neurons requires precise coordination of signals across geometrically complex and highly compartmentalized cellular architectures. Membrane contact sites (MCS)-specialized junctions where two organelles are closely apposed without undergoing fusion-have emerged as key organizational hubs enabling efficient exchange of ions, lipids, and metabolites, yet the cytoskeletal proteins that organize and regulate these junctions remain poorly understood. Here, we review evidence that septins-a conserved family of heteromeric GTP-binding proteins that assemble into filamentous oligomers and polymers-function as integral components of MCS in neurons and beyond. Septins associate with hyperboloid, hourglass-shaped membrane curvatures and distinct membrane domains and organelles through polybasic motifs, amphipathic helices, and transmembrane domains. We review how septins establish diffusion barriers at endoplasmic reticulum (ER)-plasma membrane (PM) contacts in budding yeast and consider evidence that analogous mechanisms operate at dendritic branch points and spine necks in mammalian neurons. We examine septin roles in regulating store-operated calcium entry at ER-PM contacts and explore how septins regulate membrane contacts at presynaptic active zones. Additionally, we highlight how septins organize membrane contacts between host organelles and intracellular pathogens, scaffolding autophagic, mitochondrial, and lysosomal membranes for bacterial clearance. Collectively, these findings support the view that septins constitute a versatile and underappreciated class of MCS tethers whose paralog- and isoform-specific complex compositions may confer spatial and functional selectivity for distinct MCS, opening new avenues for understanding organelle connectivity in health and disease.

DOI: https://doi.org/10.1111/jnc.70495
Tissue Cell. 2026 Jun 10. pii: S0040-8166(26)00386-1. [Epub ahead of print]103 103692

VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.

Rabab S Hamad, Eman Hamza, Ebtehal M Abdel-Aal, Elsayed A Elmorsy, Hanan Eissa, Alshaimaa A Farrag, Ahmed Shata, Ghada M Nassar, Nesreen Elsayed Morsy, Ahmed A El-Mansy, Ahmed G Hamad, Eman R Abdellatif, Sameh Saber.

  Organelle contact sites are increasingly recognized as regulatory interfaces that coordinate lipid transfer, ion signaling, and metabolic adaptation. In neurons, communication among the endoplasmic reticulum (ER), lysosomes, and mitochondria is essential for cellular homeostasis. Recent studies have identified vacuolar protein sorting 13 homolog C (VPS13C), a lipid transport protein, as a key mediator of ER-lysosome tethering and as an important component of the response to lysosomal stress. Structural analyses show that VPS13 family proteins form elongated lipid transport channels that are proposed to facilitate phospholipid transfer between adjacent membranes. Following lysosomal damage, VPS13C is recruited to ER-lysosome contact interfaces, where it forms tethering bridges that may support membrane repair by enabling high-capacity lipid transfer from the ER to lysosomal membranes. Beyond membrane repair, these contact interfaces may also participate in broader organelle communication networks. ER-lysosome contacts can occur in proximity to ER-mitochondria junctions, potentially forming multi organelle signaling hubs that coordinate lipid redistribution, calcium signaling, and mitochondrial adaptation. These signals may influence downstream responses, including activation of TFEB and TFE3, which regulate lysosomal biogenesis and autophagy. Disruption of this contact site network has emerged as a potential contributor to Parkinson's disease. Loss of VPS13C function is associated with altered lysosomal homeostasis and intersects with pathogenic pathways involving α-synuclein aggregation, PINK1/Parkin-mediated mitophagy, and LRRK2 signaling. This review presents a framework in which ER-lysosome tethering is considered part of a staged cellular damage response linking membrane repair, metabolic coordination, and transcriptional adaptation.

Keywords:  ER-lysosome tethering; Lipid transfer; Lysosomal membrane repair; Organelle contact sites; Parkinson’s disease; VPS13C

DOI:  https://doi.org/10.1016/j.tice.2026.103692
J Cell Sci. 2026 Jun 08. pii: jcs.264795. [Epub ahead of print]

Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.

Ranran Mao, Jiaqi Zhai, Chunfang Tong, Wenfeng Fu, Dong Li, Jia-Jia Liu.

  In eukaryotic cells, organelles communicate through membrane contact sites-specialized regions where their membranes come into close apposition without fusing. Among these, contacts between the endoplasmic reticulum (ER) and the Golgi apparatus are critical for lipid trafficking and polarized sorting of protein cargoes, yet their regulation and physiological roles remain poorly understood due to limited research tools. Here, we developed genetically encoded biosensors that selectively label ER-Golgi contact sites by building upon split GFP/YFP systems. These fluorescent probes reliably detect ER-Golgi contacts whose formation depends on Golgi-enriched phosphatidylinositol 4-phosphate and the lipid transfer activity of Oxysterol-Binding Protein, and reveal the dynamic remodeling of these structures in live cells. Notably, the biosensors captured alterations in ER-Golgi contacts during cell division and ER stress, as well as their developmental loss in mammalian neurons. We propose these biosensors as powerful tools for investigating ER-Golgi interactions in response to physiological cues or pathological perturbations across diverse cell types.

Keywords:  Biosensor; Endoplasmic reticulum; Golgi; Membrane contact sites; Split GFP

DOI:  https://doi.org/10.1242/jcs.264795
Nat Commun. 2026 Jun 12.

Glycosphingolipids regulate phosphatidylserine transport machinery that operates at ER-PM contact sites.

Ritchel Gannaban, Sher Ali, Wei Chen, Melanie Nguyen, Li Lai, Travis I Moore, Yubin Zhou, John F Hancock, Junchen Liu.

Plasma membrane (PM) localization of KRAS requires specific glycosphingolipids in the outer leaflet and phosphatidylserine (PS) in the inner leaflet. PM PS content is controlled by lipid transport proteins ORP5 and ORP8, which operate at ER-PM membrane contact sites (MCSs). Using high-resolution imaging, we now show that GSLs, including GM3 and SM4, are required to maintain ORP5 and ORP8 localization to MCSs. Genetic deletion or pharmacologic inhibition of enzymes required for the biosynthesis of GM3 or SM4 displaces PI4-kinase Type IIIα (PI4KIIIα) and its adaptor EFR3A from the PM, thereby reducing PM phosphatidylinositol 4-phosphate (PI4P) content. PM interactions of ORP5 and ORP8 are also disrupted. Since ORP5 and ORP8 transport PS to the PM by counter-transporting PI4P to the ER, PM PS content is substantially reduced. We further show that GM3 and GM2 regulate the assembly of ER-PM-MCSs, such that the function of other MCS-localized macromolecular machineries including calcium release-activated calcium channels is abrogated when glycosphingolipid biosynthesis is blocked. Together, this study establishes glycosphingolipids as organizers of PS transport and ER-PM MCSs, expanding the regulators of MCSs beyond protein tethers to include glycosylated lipids and revealing how glycosphingolipids control KRAS function.

DOI: https://doi.org/10.1038/s41467-026-74252-0
Int J Mol Med. 2026 Aug;pii: 216. [Epub ahead of print]58(2):

Spatial architecture of immunometabolism: Mitochondrial‑organelle interfaces in immune signaling (Review).

Yaping Wu, Hao Yu, Ling Xia, Li Yang, Yu Zhou, Qian Yu.

  Metabolic reprogramming is fundamental to immune cell function, yet the spatial architecture that organizes these metabolic states remains incompletely defined. Rather than functioning as isolated bioenergetic units, mitochondria act as spatial hubs embedded within dynamic organelle networks that coordinate immuno‑metabolic signaling. In the present review, the structural and functional basis of mitochondrial organelle interfaces were delineated, including membrane contact sites and vesicular trafficking pathways, with the endoplasmic reticulum, lysosomes, peroxisomes, lipid droplets and the nucleus. It was discussed how these interfaces generate specialized microdomains for the localized exchange of calcium, lipids and redox signals, thereby shaping innate and adaptive effector programs. It was further highlighted how mitochondria‑derived vesicles and mitochondria‑containing extracellular vesicles extend this regulatory axis, linking intracellular organelle crosstalk directly to systemic tissue homeostasis. Crucially, maladaptive decoupling of these interface circuits emerges as a recurrent feature of infection, sepsis, cancer, autoimmunity and chronic inflammation diseases. Finally, emerging interface‑targeted therapeutic strategies were evaluated and the technical methodologies required to validate nanoscale interactions were critically assessed. By conceptualizing immunometabolism as a spatially coordinated process, the prsent review provides a comprehensive landscape for decoding immune signaling and identifies tractable avenues for precision immunotherapy.

Keywords:  cancer immunity; immunometabolism; inflammation; innate immunity; mitochondria; mitochondria-associated membrane; vesicle trafficking

DOI:  https://doi.org/10.3892/ijmm.2026.5887
Acta Biomater. 2026 Jun 11. pii: S1742-7061(26)00383-1. [Epub ahead of print]

G-quadruplex-modulated nanoplatform triggers a Ca2+ storm via the mitochondria-associated endoplasmic reticulum membrane for anti-melanoma multimodal therapy.

Li Yang, Xue Chen, Yuanhang Li, Xudong Xie, Chaolin Liu, Zhengjian Qi.

  Endoplasmic reticulum (ER)-mitochondria interplay shapes tumor fate, with Ca²⁺ homeostasis serving as a critical node linking these organelles. Here, we engineered a TTO photosensitizer (PS) that recognizes G-quadruplex (G4) in mitochondria through conformationally restricted π-π interactions, thereby potentiating photodynamic therapy (PDT)-mediated interference with Ca²⁺ homeostasis. Hemin was electrostatically co-assembled with TTO and hyaluronic acid-polyethyleneimine (HA-PEI) copolymer to generate lethal hydroxyl radicals (·OH) that magnify PDT-induced oxidative damage, while the HA-PEI component enables tumor-specific delivery. With this synergy, TTO-Hemin@HA-PEI (TH@HP) propagates PDT influence to provoke ER stress and dysregulate the inositol 1,4,5-trisphosphate receptor (IP3R)-glucose regulator protein 75 (GRP75)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter (MCU) Ca2+-transfer axis at the mitochondria-associated ER membrane (MAM), leading to MAM remodeling. This self-amplifying pathological loop is characterized by persistent ER Ca²⁺ leakage to mitochondria and cytoplasm via MAM, which impairs adenosine triphosphate (ATP) synthesis, disables energy-dependent Ca²⁺ feedback regulation, and ignites a systemic Ca²⁺ storm, thereby activating markers of immunogenic cell death (ICD) and converting mitochondrial damage into pro-immunogenic signals that drive melanoma immune infiltration. Collectively, this effort reveals a feed-forward mechanism between mitochondrial impairment and ER-driven ICD, offering a compelling paradigm for mitochondria-targeted multimodal therapies. STATEMENT OF SIGNIFICANCE: In this contribution, a multimodal anti-melanoma nanoplatform was engineered to follow the causal chain: G-quadruplex (G4) coupling and biocatalytic reactions-photodynamic therapy (PDT) amplification-Ca2+ storm-immune response activation. It has verified that existing mitochondrial-targeted immunogenic cell death (ICD) involves a mechanism where single organelle stimulus while multiple organelles execute responses. Furthermore, a functional association exists between mitochondrial damage and endoplasmic reticulum-driven ICD through mitochondria-associated endoplasmic reticulum membrane (MAM). Simultaneously, this research furnishes comprehensive theoretical and experimental evidence for PDT amplification mechanism following G4 interaction. It is the first time in our known research that rationale and advantages of G4 targeting in PDT applications have been proposed, and we believe it will carry substantial reference for subsequent studies.

Keywords:  Endogenous Ca(2+) storm; G-quadruplex target; Mitochondria-associated endoplasmic reticulum membrane; Multimodal therapy; Tumor vaccine

DOI:  https://doi.org/10.1016/j.actbio.2026.06.022
Cell. 2026 Jun 12. pii: S0092-8674(26)00586-6. [Epub ahead of print]

Mechanism of lipid transfer by bridge-like protein VPS13A and the scramblase XK.

Bodan Hu, Daniel Álvarez, Cristian Rocha-Roa, Valentin Guyard, Dazhi Li, Yara Ahmed, Xinbo Wang, Pietro De Camilli, Stefano Vanni, Karin M Reinisch.

  In eukaryotes, bridge-like lipid-transfer proteins (BLTPs) are central in mediating vesicle-independent lipid transfer between organelles. BLTPs span the cytosolic space between organelles at contact sites, featuring hydrophobic channels for lipids to travel between membranes. How BLTPs cooperate with partner proteins to orchestrate lipid delivery remains a mystery. Here, we used cryo-electron microscopy to visualize a complex comprising the prototypical BLTP VPS13A and the plasma membrane-localized scramblase XK at near-atomic resolution. VPS13A interacts with XK via its pleckstrin homology domain, priming VPS13A's bridge-like lipid-transfer domain to deliver lipids directly to the cytosolic leaflet of the acceptor membrane. In molecular dynamics simulations, this arrangement allows for robust lipid transfer. Newly delivered lipids can then be equilibrated between leaflets of the membrane bilayer by the scramblase, allowing for membrane growth. Mechanistic insights regarding lipid delivery by VPS13A are directly applicable to all VPS13 proteins and, more broadly, to all BLTP family members.

Keywords:  VPS13; XK; bridge-like lipid-transfer protein; cryo-EM; lipid transfer; membrane contact sites; molecular dynamics simulations; scramblase

DOI:  https://doi.org/10.1016/j.cell.2026.05.027
Curr Neuropharmacol. 2026 Jun 08.

Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.

Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.

Keywords:  Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.

DOI:  https://doi.org/10.2174/011570159X473929260605103158
Nat Cell Biol. 2026 Jun 10.

Mitochondria-ER contacts function as an iron supply hub.

Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.

Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.

DOI: https://doi.org/10.1038/s41556-026-01974-0
Discov Oncol. 2026 Jun 10.

A prognostic model for breast cancer based on mitochondria-associated endoplasmic reticulum membrane (MAM) signature genes.

Jintao Cui, Limin Wei, Bin Xu, Songfu Han, Chaoyanng Guo, Xinshuai Wang.

   BACKGROUND: Mitochondria-associated endoplasmic reticulum membranes (MAMs) have emerged as key regulators of breast cancer biology. Growing evidence indicates that MAM dysfunction affects tumor progression, immune regulation, and treatment response. However, their prognostic value and therapeutic relevance in breast cancer remain insufficiently clarified.
METHODS: We curated 83 MAM-related genes from the literature and used TCGA breast cancer cohorts to construct a prognostic model through univariate Cox, LASSO, and multivariate Cox regression analyses. Protein-level validation was performed using the Human Protein Atlas (HPA). Functional enrichment, immune infiltration, immunotherapy response prediction, and drug sensitivity profiling were conducted between risk groups. Single-cell RNA-seq data (GSE255068) were analyzed to map gene expression within the tumor microenvironment. Finally, qRT-PCR and western blotting validated the expression of key genes in breast cancer cell lines.
RESULTS: A four-gene signature (VDAC1, RYR2, PINK1, and TESPA1) robustly stratified breast cancer patients into high- and low-risk groups and independently predicted overall survival across multiple cohorts. A prognostic nomogram integrating the risk score with clinicopathological variables significantly improved survival prediction accuracy. Low-risk tumors were characterized by a more inflamed tumor microenvironment, with increased immune cell infiltration and enhanced immune-related pathway activity, and were predicted to respond more favorably to immune checkpoint blockade. In contrast, high-risk patients exhibited greater predicted sensitivity to multiple cytotoxic and targeted agents, a pattern that remained largely consistent across major molecular subtypes, highlighting the robustness of the signature beyond intrinsic subtype classification. Single-cell transcriptomic analyses further revealed distinct cell-type-specific expression patterns of the four genes within the tumor microenvironment. Finally, molecular experiments confirmed elevated expression of VDAC1, RYR2, and PINK1 in breast cancer cell lines, supporting their biological relevance in tumor progression.
CONCLUSIONS: This MAM-based prognostic model provides new insights into breast cancer biology and has potential utility in guiding personalized treatment, particularly regarding immunotherapy and chemotherapy sensitivity. Experimental validation highlights VDAC1 as a promising biomarker.

Keywords:  Breast cancer; Immunotherapy; Mitochondria-associated endoplasmic reticulum membrane; Prognostic model; Single-cell analysis

DOI:  https://doi.org/10.1007/s12672-026-05287-4
Nat Cell Biol. 2026 Jun 12.

ERO1a fosters glioblastoma aggressiveness and metabolic flexibility by regulating mitochondria-associated membrane dynamics.

Arthur Bassot, Lola Violy, Lucas Gorka, Lavinia Cigalotto, Balasubramaniam Namasivayam, Ivan Mikaelian, Emma St Johnston, Chao Han, Rudy Gadet, Beatrice Alpha-Bazin, Laurine Moindrot, Emilie Clement, Helena Dragic, Marine Crépin, Olivier Berdeaux, Christophe Vanbelle, Mélina Gautier, Alice Cariou, Louis Larrouquere, Chunmei Wei, Thomas Gudermann, Jann N Sarkaria, Ester Zito, Pierre-Yves Dietrich, Paul R Walker, Ivan Nemazanyy, Hubert Lincet, Jean Armengaud, Jennifer Rieusset, Paul S Mischel, Elmina Mammadova-Bach, Thomas Simmen, Denis Martinvalet, Marie Castets, Erika Cosset.

Despite the wealth of data generated in the omics era to investigate molecular drivers, glioblastoma (GBM) remains one of the most incurable cancers with a poor median of survival. Here we unravelled the dynamic crosstalk between the endoplasmic reticulum and mitochondria, known as mitochondria-associated membranes (MAMs) and define how modulation of calcium fluxes and MAM structure influences GBM cell plasticity and metabolic flexibility. We identified ERO1α, whose expression is significantly associated with poor GBM patient survival, as a critical MAM protein that regulates MAM structure, dynamics and calcium-mediated functions. Our data demonstrate that ERO1α activity and expression promotes GBM aggressiveness in vitro and in vivo and enhances mitochondrial oxidative phosphorylation. By establishing a direct link between ERO1α-mediated MAM modulation and the antitumour effects of ERO1α inhibition, this work highlights a context-dependent, druggable vulnerability that can be exploited for GBM therapy.

DOI: https://doi.org/10.1038/s41556-026-01980-2
Basic Clin Pharmacol Toxicol. 2026 Jul;139(1): e70257

Targeting AVEN Liquid-Liquid Phase Separation in Colorectal Cancer: Insights From a Raddeanin A-Based Chemical Probe.

Xichao Yu, Hui Wu, Kezhen Guo, Zihao Liu, Lianxin Zhou, Hongjie Wu, Shuyuan Wang, Jiaqi Fu, Xing Cui, Zhifei Fu, Mengjie Guo, Ye Yang.

  Mitochondrial dysfunction is a pivotal pathogenic mechanism in colorectal cancer (CRC), which is further exacerbated by dysregulated liquid-liquid phase separation (LLPS). However, the mechanisms underlying mitochondrial dysfunction and LLPS, as well as their therapeutic targeting, remain unclear. Using Raddeanin A as a probe and through multiomics analysis, we identified apoptosis and caspase activation inhibitor (AVEN) as a potential therapeutic target. AVEN was significantly upregulated in CRC tissues and localized near mitochondria-endoplasmic reticulum contact sites (MERCS). Biophysical assays confirmed that AVEN undergoes LLPS via its intrinsically disordered regions (IDRs). Critically, we found that AVEN IDRs orchestrate mitochondrial homeostasis through dual LLPS-dependent mechanisms: inhibiting apoptosis and facilitating post-damage mitochondrial transfer. Furthermore, we identified sumatriptan (SUM) as a potent inhibitor of AVEN IDRs, which demonstrated promising therapeutic efficacy in mouse models and clinical cohorts. Our study highlights the critical role of AVEN in regulating mitochondrial homeostasis via LLPS and suggests that targeting AVEN represents a promising therapeutic strategy for CRC.

Keywords:  AVEN; CRC; LLPS; mitochondrial transfer; targeted therapy

DOI:  https://doi.org/10.1111/bcpt.70257
Cell Div. 2026 Jun 11.

p53 overexpression counteracts the pro-survival effect of Bcl-2 by restoring MAMs function in cutaneous squamous cell carcinoma.

Yupeng Huang, Jing Liu, Xiao Shao, Chunyan Xu, Xianpeng Ma.

   BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is a prevalent type of skin cancer, and its development is strongly associated with impaired regulation of apoptosis. The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the tumor suppressor p53 play pivotal roles in controlling apoptotic signaling. Although Bcl-2 expression in cSCC has been reported to be heterogeneous, its role in mitochondria-associated membranes (MAMs)-mediated apoptosis remains unclear. This study aims to clarify how Bcl-2 and p53 regulate cSCC cell apoptosis by modulating the structure and function of MAMs.
METHODS: We constructed stable Bcl-2 overexpression (oe-Bcl-2) and Bcl-2/p53 co-overexpression (oe-Bcl-2 + oe-p53) A431 cell lines using lentiviral transduction. Transcriptome sequencing (RNA-seq) was performed, followed by pathway enrichment and protein-protein interaction (PPI) network analyses to screen for critical signaling routes. Cell apoptosis, growth, migratory capacity, and invasive potential were evaluated using flow cytometry, CCK-8, EdU incorporation, colony formation, and Transwell-based assays. Key MAMs functions, including Ca2+ flux, mitochondrial membrane potential (MMP), ROS, and ATP levels, were measured. Subcutaneous tumor models in nude mice were used for in vivo validation.
RESULTS: RNA-seq analysis revealed that Bcl-2 regulates multiple apoptosis- and calcium signaling-related pathways, significantly affecting key MAM-associated proteins, including VDAC2, IP3R, SERCA2, as well as the p53 signaling pathway. Bcl-2 overexpression markedly enhanced proliferation and migration of A431 cells while reducing apoptosis. It also modulated mitochondrial membrane potential, ATP production, and ROS generation, suggesting that Bcl-2 exerts anti-apoptotic effects through MAMs. In contrast, Bcl-2 knockdown significantly suppressed proliferation and invasion while inducing apoptosis in A431 cells, further supporting its oncogenic role. Notably, p53 overexpression reversed these effects and significantly inhibited tumor growth in vivo.
CONCLUSION: Our findings demonstrate that Bcl-2 promotes cSCC progression by modulating MAMs structure and function to inhibit p53-mediated mitochondrial apoptosis. The study identifies the novel Bcl-2-MAMs-p53 signaling axis that plays a pivotal role in determining cSCC cell fate, highlighting a promising target for therapeutic intervention.

Keywords:  Apoptosis; B-cell lymphoma 2; Cutaneous squamous cell carcinoma; Mitochondria-associated membranes; RNA sequencing; p53

DOI:  https://doi.org/10.1186/s13008-026-00190-4
bioRxiv. 2026 Jun 02. pii: 2026.06.01.729255. [Epub ahead of print]

HKDC1 contributes to aberrant lysosome-mitochondria contact in Niemann-Pick disease type C.

Raffaele Pastore, Jack Stanley, Szilvia Kiraly, Christelle Dubois, Jlenia Monfregola, Antonio De Luca, Germano Guerra, Mark Skehel, Andrea Ballabio, Frances M Platt, Emily R Eden.

Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder comprising two clinically indistinguishable but genetically distinct subtypes caused by mutations in NPC1 , or NPC2 . The specific impact of each deficiency on cellular homeostasis remains poorly defined due to the phenotypic heterogeneity of patient-derived models and a lack of isogenic platforms for comparative study. Here we established isogenic ARPE19 models of NPC1 and NPC2 deficiency that faithfully recapitulate hallmark pathologies, including homogeneous lysosomal expansion and lipid sequestration. Direct comparison of these isogenic lines revealed a fundamental divergence in organelle crosstalk: while both genotypes exhibit comparable lipid accumulation, expanded mitochondria-lysosome contact sites (MLCs) are observed exclusively in NPC1 -/- cells. Using StARD3-targeted proximity labelling and quantitative proteomics, we identified the mitochondrial protein HKDC1 as an MLC regulator. We demonstrate that HKDC1 is markedly upregulated in NPC1 -/- cells and that its overexpression drives MLC expansion in wild-type cells. Thus our study uncovers a homeostatic role for HKDC1-mediated organelle remodelling and demonstrates the power of isogenic modelling for identifying novel regulators of organelle architecture and potential therapeutic targets.

DOI: https://doi.org/10.64898/2026.06.01.729255
J Neurochem. 2026 Jun;170(6): e70490

Targeting Neuroinflammation in Depression: The Integrative Role of Sigma-1 Receptor Modulation.

Jing-Ya Wang, De-Yi Yang, Yun-Feng Li, Peng Ren.

  Depression is a leading cause of global disability, yet remains insufficiently treated by conventional monoaminergic antidepressants, which are limited by their delayed onset, variable efficacy, and significant side effects. Accumulating evidence positions neuroinflammation, driven by glial dysfunction, peripheral-central immune crosstalk, and associated cellular stress pathways as a pivotal upstream mechanism in the pathogenesis of depression, contributing to both neurotransmitter dysregulation and impaired synaptic plasticity. This review examines the integrative role of the Sigma-1 receptor (Sig-1R), a ligand-operated chaperone predominantly localized at the mitochondria-associated endoplasmic reticulum membrane (MAM), as a promising therapeutic target for mitigating this neuroinflammatory cascade. We systematically synthesize preclinical evidence demonstrating that pharmacological activation of Sig-1R produces broad anti-neuroinflammatory effects, including the promotion of microglial homeostasis and a shift toward an anti-inflammatory phenotype, attenuation of reactive astrogliosis, suppression of key pro-inflammatory signaling hubs such as NF-κB and the NLRP3 inflammasome, and mitigation of oligodendrocyte dysfunction. Beyond immunomodulation, Sig-1R activation alleviates endoplasmic reticulum stress, enhances autophagic and mitophagic clearance, supports mitochondrial bioenergetics, and strengthens endogenous antioxidant defenses. Together, these actions disrupt the vicious cycle linking cellular stress, inflammation, and synaptic impairment. We also evaluate advances in representative Sig-1R agonists and review available clinical trial data, including results on the novel multi-target agent AXS-05. Genetic and pharmacological loss-of-function studies further emphasize the essential role of Sig-1R in mood regulation and stress resilience. In summary, the Sigma-1 receptor serves as a key regulator of cellular homeostasis and adaptation. Its agonists represent a promising therapeutic strategy that moves beyond symptomatic monoaminergic modulation to mechanistically target the core inflammatory and proteostatic disturbances in depression, offering the potential for improved treatment efficacy.

Keywords:  antidepressant; depression; neuroinflammation; sigma‐1 receptor

DOI:  https://doi.org/10.1111/jnc.70490
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00022-X. [Epub ahead of print]186 145-185

TMEM230 and mitochondrial regulation in Alzheimer's disease.

Ileana Zucchi, Cinzia Cocola, Paride Pelucchi, Daniela Mazzaccaro, Giovanni Nano, Mira Palizban, Giovanni Porta, Rolland A Reinbold.

  Aging is associated with an attrition of cell subcellular components of the endomembrane system due to long-term exposure to environmental stresses or physical/chemical insults. Tissue morphology physiology and function are strongly dependent on the linked dynamic activities of the endomembrane of organelles of the endomembrane system (ES). This is especially true for nervous tissue and the brain where ES components must interact over long (neurite) distances for proper synapse functions. As the endoplasmic reticulum (ER) is the primary organelle responsible for generating plasma membrane and subcellular membrane components, dysregulation of the ER has a significant role in nervous tissue physiology and diseases in which membrane function is critical, such as in age associated Alzheimer's Disease (AD). Understanding why the ER fails to respond effectively to stress may provide a promising platform for developing antiaging treatments. In this review we characterizegene pathways induced by the transmembrane (TMEM) protein, TMEM230 in the ER in Alzheimer's disease (AD). TMEM230 upregulates oxidative phosphorylation and mitochondria pathways associated cell metabolism. High levels of expression of TMEM230 associated with AD, due chronic inflammation drives hyperoxidation leading to aberrant structural changes in the tethering of the mitochondria and ER membrane and consequently, intra-organelle calcium balance. Sustained elevated levels of expression of TMEM230 leads to catastrophic oxidative stress and irreversible mitochondria damage as seen in some AD patients. Our studies support that Parkinson's Disease and Huntington's Disease may be similarly driven by chronic high levels TMEM230 which results in decoupling of ER-mitochondrial regulation.

Keywords:  Alzheimer’s disease; Anti-Aging; Endoplasmic reticulum; Huntington disease; Lysosome, RNASET2; Metabolism; Mitochondria; Mitochondria-associated membrane (MAM); Oxidative phosphorylation stress; Parkinsons’s disease; REDOX; TMEM230 (C20orf30)

DOI:  https://doi.org/10.1016/bs.irn.2026.02.002
Nature. 2026 Jun 10.

Mitochondria directly interact with the nuclear pore complex.

Ivan Menendez-Montes, Consuelo Marin-Vicente, Shibani Mukherjee, Mahmoud Salama Ahmed, Manuel Jose Gomez, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Svenja Koslowski, Ashley Solmonson, Tara Tassin, Shah R Ali, Pedro Pessoa, Abdallah Elnwasany, Nicholas T Lam, Suwannee Thet, Enrique Calvo, Alisson C Cardoso, Ana Helena M Pereira, Feng Xiao, Ping Wang, Asim Mohamed, Hamed El-Feky, Ahmed Elghamry, Gonzalo Gancedo-Alonso, Ngoc Uyen Nhi Nguyen, Ching-Cheng Hsu, Aundrea K Westfall, Ralph DeBerardinis, Roger Sik-Yin Foo, Michael Kinter, Steve Pressé, Chao Xing, Luke Szweda, Asaithamby Aroumougame, Fatima Sanchez-Cabo, Jose Antonio Enriquez, Miguel Torres, Jesus Vazquez, Hesham A Sadek.

Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.

DOI: https://doi.org/10.1038/s41586-026-10588-3