bims-mecosi 2025-09-21 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–09–21
eleven papers selected by
Verena Kohler, Umeå University

Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition.
Aurora-A inhibits hepatocellular carcinoma cell ferroptosis to mediate immune escape by disrupting phosphatidylethanolamine biosynthesis.
BLTP1 is required for survival and normal development and function of the neuromuscular junction in mice.
ATG8ylation-orchestrated vacuolar membrane remodeling facilitates plant alkaline stress tolerance.
Impaired hematopoiesis and embryonic lethality at midgestation of mice lacking both lipid transfer proteins VPS13A and VPS13C.
Construction and validation of a prognostic model based on mitochondria-associated endoplasmic reticulum membranes gene signature in LUAD patients.
Copper-mediated MAM regulation of the NF-κB signalling pathway enhances Seneca Valley virus replication in PK-15 cells.
Proximity labelling reveals VPS13C as a regulator of Salmonella-containing vacuole fission.
Calcium signalling and organelle crosstalk in cardiovascular disease: an interplay of cardiac cell death pathways.
Activity-dependent localization and dynamics of STIM1 and STIM2 at ER-PM contacts in hippocampal neurons.
Organelle activity organized by the endoplasmic reticulum-mitochondria encounter structure -ERMES- is essential for Podospora anserina development.

Metabolism. 2025 Sep 15. pii: S0026-0495(25)00262-8. [Epub ahead of print] 156393

Disruption of mitochondria-associated membranes contributes to the dysregulation of insulin secretion in undernutrition, obesity, and double burden of malnutrition.

Thiago Dos Reis Araujo, Joel Alves da Silva Junior, Bruna Lourençoni Alves, Dimitrius Santiago Passos Simões Fróes Guimarães, Lohanna Monali Barreto, Mariana Roberta Rodrigues Muniz, Jennifer Rieusset, Everardo Magalhães Carneiro.

   AIMS/HYPOTHESIS: Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM).
METHODS: Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy.
RESULTS: Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity.
CONCLUSIONS/INTERPRETATION: These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.

Keywords:  Double burden of malnutrition; Insulin secretion; Mitochondria-associated membranes; Obesity; Undernutrition

DOI:  https://doi.org/10.1016/j.metabol.2025.156393
Am J Cancer Res. 2025 ;15(8): 3693-3711

Aurora-A inhibits hepatocellular carcinoma cell ferroptosis to mediate immune escape by disrupting phosphatidylethanolamine biosynthesis.

Lei Fan, Yiqian Liu, Yucheng Cai, Xinnan Sun, Jiaxuan Li, Yiyang Xu, Changchun Sun, Shiyun Cui.

  This study aims to explore Aurora-A's role in regulating immune escape of hepatocellular carcinoma (HCC). We performed non-targeted metabolomics analysis and analyzed the impact of Aurora-A inhibitor Alisertib on anti-PD-1 therapy efficacy on xenograft tumors and co-culture models of CD8+ T cells and HCC cells. We determined reactive oxygen species (ROS) and malondialdehyde (MDA) production in HCC cells to evaluate lipid peroxidation. Confocal images of endoplasmic reticulum (ER) and mitochondria in HCC cells were taken to assess the role of Aurora-A and dynamin-related protein 1 (Drp-1) on mitochondria-associated endoplasmic reticulum membranes (MAMs) formation. The results showed that Aurora-A was upregulated in HCC cells and its knockdown significantly augmented phosphatidylethanolamine (PE) production while having no effect on phosphatidylserine decarboxylase (PSD). Further, Aurora-A inhibitor Alisertib enhanced the sensibility of HCC cells to anti-PD-1 therapy and CD45+CD8+ T cell infiltration in HCC tumors. To conclude, our work revealed that Aurora-A dysregulated PS/PE metabolism via facilitating Drp1-Ser616 phosphorylation to disrupt MAMs formation, resulting in suppressed ferroptosis in HCC cells to reduce their sensitivity to anti-PD-1.

Keywords:  Aurora-A; HCC; MAMs formation; ferroptosis; immune escape

DOI:  https://doi.org/10.62347/JTQO8098
J Neurosci. 2025 Sep 19. pii: e0029252025. [Epub ahead of print]

BLTP1 is required for survival and normal development and function of the neuromuscular junction in mice.

Yun Liu, Qiaohong Ye, Dengke K Ma, Beverly A Rothermel, Weichun Lin.

BLTP1 (Bridge-Like Lipid Transfer Protein Family Member 1), previously known as Tweek, Kiaa1109, FSA or 4932438A13Rik, is a non-vesicular lipid transport protein linked to Alkuraya-Kučinskas Syndrome (AKS), an autosomal recessive disorder with severe brain malformations and arthrogryposis in humans. Although BLTP1 is known to be involved in the transfer of phospholipids between organellar membranes at membrane contact sites, its specific role during mammalian development remains poorly defined. Here we characterized the development of the neuromuscular junction (NMJ) in Bltp1 knockout (Bltp1-/- ) mice of either sex. These mutant mice die perinatally, exhibiting reduced growth of intramuscular motor nerves and a reduction in the size of the NMJ, compared to littermate controls. Electrophysiological analysis of the diaphragm muscle in Bltp1 -/- embryos reveals defects in synaptic transmission at the NMJ. Notably, the frequency of spontaneous neurotransmitter release is markedly increased, whereas evoked neurotransmitter release and quantal content are reduced. In addition, neuromuscular synapses in Bltp1 -/- mice fail to respond to a repetitive stimulation. Remarkably, the impairment of intramuscular nerve growth in Bltp1-/- embryos is restored by supplementing pregnant dams with lecithin, a mixture of unsaturated phospholipids naturally present in foods, although lecithin supplement does not improve the overall survival of these mutant mice. Together, these results demonstrate that BLTP1 plays important roles during development for proper intramuscular nerve growth and neuromuscular synaptic function, and suggest that AKS patients may benefit from phospholipid supplementation such as lecithin.Significance Statement This paper characterizes the phenotype of mutant mice deficient in Bltp1 We show that BLTP1 is required for survival and that BLTP1 plays important roles in normal development and function of the NMJ in mice.

DOI: https://doi.org/10.1523/JNEUROSCI.0029-25.2025
Autophagy. 2025 Sep 17.

ATG8ylation-orchestrated vacuolar membrane remodeling facilitates plant alkaline stress tolerance.

Jianxiong Wu, Jun Luo, Chunya Nie, Xuanang Zheng, Caiji Gao, Jun Zhou.

  While ATG8ylation, the C-terminal lipidation of mammalian and plant Atg8 (ATG8)-family proteins, is a well-established driver of autophagosome formation, emerging evidence reveals its non-canonical role in modifying single-membrane organelles under diverse environmental stresses. In a recent study, we found that disruption of the vacuolar proton gradient by alkaline stress rapidly triggers the translocation of ATG8 to the vacuolar membrane in plants. ATG8ylation facilitates membrane invagination through a mechanism independent of both ESCRT and the cytoskeleton. Concurrently, ATG8 recruits ATG2 to endoplasmic reticulum (ER)-vacuolar membrane contact sites, a process that may contribute to damaged membrane repair. Together, these processes enable plants to rapidly recover from vacuolar pH imbalance and adapt to alkaline conditions. Our findings advance the understanding of ATG8ylation in vacuolar membrane homeostasis and damage response, highlighting its conserved role in organellar stability and stress adaptation.

Keywords:  ATG8ylation; Alkaline stress; monensin; non-canonical autophagy; vacuole

DOI:  https://doi.org/10.1080/15548627.2025.2562885
PLoS Biol. 2025 Sep 16. 23(9): e3003393

Impaired hematopoiesis and embryonic lethality at midgestation of mice lacking both lipid transfer proteins VPS13A and VPS13C.

Peng Xu, Rubia Isler Mancuso, Marianna Leonzino, Caroline J Zeiss, Diane S Krause, Pietro De Camilli.

VPS13 is the founding member of a family of proteins that mediate lipid transfer at intracellular membrane contact sites by a bridge-like mechanism. Mammalian genomes comprise 4 VPS13 genes encoding proteins with distinct localizations and function. The gene duplication resulting in VPS13A and VPS13C is the most recent in evolution and, accordingly, these two proteins are the most similar to each other. However, they have distinct subcellular localizations and their loss of function mutations in humans are compatible with life but result in two different age-dependent neurodegenerative diseases, chorea-acanthocytosis and Parkinson's disease, respectively. Thus, it remains unclear whether these two proteins have overlapping functions. Here, we show that while Vps13a KO and Vps13c KO mice are viable, embryonic development of Vps13a/Vps13c double knockout (DKO) mice is arrested at midgestation. Prior to death, DKO embryos were smaller than controls, were anemic and had a smaller liver, most likely reflecting defective embryonic erythropoiesis which at this developmental stage occurs primarily in this organ. Further analyses of erythroid precursor cells showed that their differentiation was impaired and that this defect was accompanied by activation of innate immunity as revealed by upregulation of interferon stimulated genes (ISGs). Additionally, the RIG-I and MDA5 components of dsRNA triggered innate immunity were found upregulated in the DKO fetal liver. Activation of innate immunity may result from loss of integrity of the membranes of intracellular organelles, such as mitochondria and autophagic lysosomes, or to impaired autophagy, due to the absence of these lipid transport proteins. The surprising and striking synthetic effect resulting for the combined loss of VPS13A and VPS13C suggests that despite of the different localization of these two proteins, the lipid fluxes that they mediate are partially redundant.

DOI: https://doi.org/10.1371/journal.pbio.3003393
PLoS One. 2025 ;20(9): e0330722

Construction and validation of a prognostic model based on mitochondria-associated endoplasmic reticulum membranes gene signature in LUAD patients.

Qichen Zhang, Caihong Fu, Shasha Liu, Yue Leng, Ling Duan, Na Wang, Longxia Zhang, Hui Qiao.

BACKGROUND: Mitochondrial-associated endoplasmic reticulum membranes (MAM) are implicated in various malignancies, but their prognostic value in lung adenocarcinoma (LUAD) remains underexplored.
METHODS: The Cancer Genome Atlas (TCGA) and GeneCards databases provided LUAD patient data and MAM-related genes. Differentially expressed genes (DEGs) were identified using the "Limma" package. Enrichment analyses included Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Variation Analysis (GSVA), and Gene Set Enrichment Analysis (GSEA). A prognostic risk model based on MAM genes was constructed using univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses, validated by Receiver Operating Characteristic (ROC) curve analysis. PPI explored intergene relationships, while immune infiltration analysis investigated underlying mechanisms. The Human Protein Atlas (HPA) validated key gene protein expression, and drug sensitivity was analyzed using the Gene Set Cancer Analysis (GSCA) database. Finally, we also performed immunohistochemistry (IHC) staining in the tissue samples.
RESULTS: A prognostic risk model with 3 MAM genes (ERO1A, SHC1, CCT6A) was established from 194 DEGs-MAM. Kaplan-Meier analysis showed significantly longer OS in the low-risk group. Enrichment analyses indicated MAM genes were primarily involved in immune-related pathways. TIMER analysis linked the 3 MAM genes with immune cell infiltration (CD8 + T cells, CD4 + T cells, B cells, macrophages). Expression and prognostic analyses revealed high expression of these mRNAs and proteins in LUAD tissues.
CONCLUSIONS: This study constructed a prognostic risk model for LUAD based on 3 MAM genes, revealing a potential link between MAM genes and LUAD, offering new insights into clinical treatment and prognosis.

DOI: https://doi.org/10.1371/journal.pone.0330722
Vet Res. 2025 Sep 19. 56(1): 175

Copper-mediated MAM regulation of the NF-κB signalling pathway enhances Seneca Valley virus replication in PK-15 cells.

Xiaoli Wu, Song Zhu, Min Li, Zhiwen Xu, Ling Zhu, Junliang Deng, Huidan Deng.

  Seneca Valley virus (SVV) is known to cause vesicular disease in swine, presenting new challenges to the pig industry. Recent studies have investigated the relationship between disrupted copper ion homeostasis and viral replication, suggesting that copper dysregulation has a significant impact on the replication of various viruses. Research has also shown that mitochondria-associated endoplasmic reticulum membrane (MAM) and NF-κB are involved in the innate immune response triggered by viral infections. However, the exact mechanisms by which copper (Cu), MAM, and NF-κB affect SVV replication remain unclear. In this study, it was found that SVV induces an imbalance in copper homeostasis, leading to dynamic changes in MAM while inhibiting the NF-κB pathway. This inhibition results in decreased levels of IL-6, IL-1β, TNF-α, IFN-α, and IFNλ3. Furthermore, the disruption of copper homeostasis in SVV-infected PK-15 cells regulates the NF-κB pathway through MAM, promoting SVV replication. This research provides valuable insights into the regulation of copper metabolism during SVV infection and establishes a theoretical framework for understanding the pathogenesis and immune activation mechanisms associated with SVV.

Keywords:  MAM; NF-κB pathway; SVV; copper homeostasis; innate immunity

DOI:  https://doi.org/10.1186/s13567-025-01578-w
PLoS Pathog. 2025 Sep;21(9): e1013507

Proximity labelling reveals VPS13C as a regulator of Salmonella-containing vacuole fission.

Anna K Waldmann, Dustin A Ammendolia, Andrew M Sydor, Ren Li, Jonathan St-Germain, Brian Raught, John H Brumell.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium.

DOI: https://doi.org/10.1371/journal.ppat.1013507
Mol Biol Rep. 2025 Sep 16. 52(1): 907

Calcium signalling and organelle crosstalk in cardiovascular disease: an interplay of cardiac cell death pathways.

Satinder Kaur, Gurjit Kaur Bhatti, Naina Khullar, Inderpal Singh Sidhu, Umashanker Navik, Jasvinder Singh Bhatti.

  Calcium (Ca²⁺), a fundamental intracellular second messenger, plays a pivotal role in cardiovascular physiology and pathology. While tightly regulated under normal conditions, Ca²⁺ homeostasis becomes profoundly dysregulated during myocardial infarction (MI), heart failure, ischemia-reperfusion injury, cardiac hypertrophy, and atherosclerosis, resulting in pathological signaling, organellar stress, and cardiomyocyte death. This review presents a comprehensive exploration of how intracellular Ca²⁺ orchestrates excitation-contraction coupling, mitochondrial energetics, sarcoplasmic reticulum (SR) buffering, and lysosomal signaling, while simultaneously modulating apoptosis, necrosis, pyroptosis, ferroptosis, and Clockophagy. We highlight the role of Ca²⁺ in the pathogenesis of atherosclerosis, vascular calcification, endothelial dysfunction, platelet activation, and fibroblast trans differentiation. In particular, we delineate how Ca²⁺ excitotoxicity extends across a range of organelles including mitochondria, the sarcoplasmic reticulum (SR), and lysosomes to mediate inter-organellar communication. This organellar communication, facilitated by Ca²⁺ signaling, drives the interplay of cardiac cell death mechanisms that culminate in cardiac tissue destruction. The involvement of TRPC channels in lysosome-SR-mitochondria crosstalk warrants further investigation to enable targeting of specific TRPC isoforms based on the type of cardiovascular disorder. Therapeutics targeting mitochondria-associated membranes (MAMs) and lysosomes simultaneously may offer a comprehensive and effective strategy for the treatment of cardiovascular disease.

Keywords:  Apoptosis; Calcium dysregulation; Calcium targeted therapeutics; Cardiomyocyte; Necrosis; SR mitochondria lysosome crosstalk

DOI:  https://doi.org/10.1007/s11033-025-10974-6
Cell Rep. 2025 Sep 16. pii: S2211-1247(25)01061-7. [Epub ahead of print]44(10): 116290

Activity-dependent localization and dynamics of STIM1 and STIM2 at ER-PM contacts in hippocampal neurons.

Arun Chhikara, Filip Maciąg, Nasrin Sorusch, Martin Heine.

  Stromal interaction molecules (STIMs) are Ca2+ sensors within the endoplasmic reticulum (ER) plasma membrane (PM) that contribute to homeostatic functions in neurons. Upon depletion of Ca2+ from the ER, STIMs translocate to ER-PM junctions to contact the inner leaflet of the PM. Using single-particle tracking, we characterize the dynamic properties of endogenous STIM1 and STIM2 proteins in hippocampal neurons. STIMs form clusters in the somato-dendritic compartment but only transiently visit synapses. A substantial fraction of STIM2 proteins define ER-PM contacts under resting conditions and is dependent on the constitutive activity of NMDARs. STIM1 proteins are transiently recruited to ER-PM junctions only during strong activation of NMDARs. Activity-dependent confinement of STIM proteins is not influenced by CaV1.2 channel activity. We propose that STIM proteins fulfill a dominant structural function in neurons by regulating the size and frequency of ER-PM contacts to promote ER-PM communication along dendrites.

Keywords:  CP: Cell biology; CP: Neuroscience; Ca(V)1.2; ER-PM contacts; K(V)2.1; NMDARs; SPT; STIMs; endoplasmatic reticulum; hippocampal neurons

DOI:  https://doi.org/10.1016/j.celrep.2025.116290
Microb Cell. 2025 ;12 255-273

Organelle activity organized by the endoplasmic reticulum-mitochondria encounter structure -ERMES- is essential for Podospora anserina development.

Melisa Álvarez-Sánchez, Matías Ramírez-Noguez, Beatriz Aguirre-López, Leonardo Peraza-Reyes.

  Eucaryotic cell functioning and development depend on the concerted activity of its organelles. In the model fungus Podospora anserina, sexual development involves a dynamic regulation of mitochondria, peroxisomes and the endoplasmic reticulum (ER), suggesting that their activity during this process is coordinated. The ER-Mitochondria Encounter Structure (ERMES) is a tether complex composed of the ER protein Mmm1 and the mitochondrial proteins Mdm10, Mdm12 and Mdm34, which mediates membrane contact-site formation between these organelles. This complex also mediates interactions between mitochondria and peroxisomes. Here we analyzed the role of the ERMES complex during P. anserina development. By studying a thermosensitive MDM10 mutant, we show that MDM10 is required for mitochondrial morphology and distribution, as well as for peroxisome membrane-remodeling and motility. We discovered that lipid droplets exhibit a subapical hyphal localization, which depends on MDM10. MDM10 is also required for ER shaping and dynamics, notably of the apical ER domains of the polarized-growing hyphal region, in a process that involves the activity of the protein YOP1. We also show that apical ER shaping involves a Spitzenkörper-associated membrane traffic, which implicates MDM10, and that the mycelial growth defect of mdm10 mutants is exacerbated when the ER-shaping proteins YOP1 or RTN1 are loss. Finaly, we show that MMM1 is strictly required for mycelial growth and sexual development, suggesting that its activity is essential. Our results show that the activity of distinct organelles depends on the ERMES complex, and that the function of this complex is critical for P. anserina growth and development.

Keywords:  endoplasmic reticulum; fungi; lipid droplets; mitochondria; organelle interactions; peroxisomes; sexual development

DOI:  https://doi.org/10.15698/mic2025.09.860