bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–03–30
twelve papers selected by
Verena Kohler, Umeå University
  1. Beyond Static Tethering at Membrane Contact Sites: Structural Dynamics and Functional Implications of VAP Proteins.
  2. Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
  3. Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2.
  4. S-palmitoylation modulates ATG2-dependent non-vesicular lipid transport during starvation-induced autophagy.
  5. Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
  6. MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.
  7. Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis.
  8. The perspective of modern transplant science -transplant arteriosclerosis: Inspiration derived from mitochondria associated endoplasmic reticulum membrane dysfunction in arterial diseases (review article).
  9. Patient-specific mutation of a contact site protein Tomm70 causes neurodegeneration in a zebrafish model.
  10. Identification and validation of mitochondrial endoplasmic reticulum membrane-related genes in atherosclerosis.
  11. Pannexin-2 deficiency disrupts visual pathways and leads to ocular defects in zebrafish.
  12. PINK1 link mitochondria-ER contacts controls deposition of intramuscular fat in pigs.
  1. Molecules. 2025 Mar 08. pii: 1220. [Epub ahead of print]30(6):
    Beyond Static Tethering at Membrane Contact Sites: Structural Dynamics and Functional Implications of VAP Proteins.
    Takashi S Kodama, Kyoko Furuita, Chojiro Kojima.
      The membranes surrounding the eukaryotic cell and its organelles are continuously invaginating, budding, and undergoing membrane fusion-fission events, which enable them to perform functions not found in prokaryotic cells. In addition, organelles come into close contact with each other at membrane contact sites (MCSs), which involve many types of proteins, and which regulate the signaling and transport of various molecules. Vesicle-associated membrane protein (VAMP)-associated protein (VAP) is an important factor involved in the tethering and contact of various organelles at MCSs in almost all eukaryotes and has attracted attention for its association with various diseases, mainly neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, the detailed mechanism of its functional expression remains unclear. In this review, we quantitatively discuss the structural dynamics of the entire molecule, including intrinsically disordered regions and intramolecular and intermolecular interactions, focusing on the vertebrate VAP paralogs VAPA and VAPB. Molecular phylogenetic and biophysical considerations are the basis of the work.
    Keywords:  IDR; MCS; MSP; VAP; WGD; coiled coil; transmembrane
    DOI:  https://doi.org/10.3390/molecules30061220
  2. Cell Death Dis. 2025 Mar 27. 16(1): 214
    Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
    Lucia Barazzuol, Tetiana Tykhonenko, Tia L Griffiths, Alessio Vagnoni, Marisa Brini, Tito Calì.
      Organelle contact sites are crucial for cellular function, enabling the exchange of lipids, ions, and other molecules between different organelles. The ability to track these contact sites in vivo has been significantly advanced by the development of SPLICS (Split-GFP-based Contact Site Sensors) reporters, which have provided unprecedented insights into the intricate network of organelle communication. This innovative and powerful tool allows the real-time visualization of different organelle interactions in living cells and in vivo thus unraveling the complexity of their dynamic in the context of cellular homeostasis. Recent studies highlighted the dynamic nature of organelle contact sites either in terms of tethering/untethering and of movement of the contact itself in time and space: whether unique temporal behaviors and contact site-specific dynamics of different organelle interactions exist is currently unknown. In this study, we investigated the spatiotemporal distribution of various organelle contact sites using time-lapse in vitro and in vivo imaging and discovered an evolutionarily conserved dynamic pattern among different contact sites, influenced by the specific partner organelles involved. These findings highlight the importance of spatial and temporal regulation at organelle contact sites, which may underlie their diverse physiological functions. The discovery of contact site-specific dynamics opens new avenues for understanding the regulation of organelle interactions in health and disease, with potential implications for developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-025-07511-5
  3. Mov Disord. 2025 Mar 28.
    Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2.
    Sarah D Neuman, Rajan S Thakur, Scott J Gratz, Kate M O'Connor-Giles, Arash Bashirullah.
       BACKGROUND: Bridge-like lipid transfer proteins (BLTPs) mediate bulk lipid transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity and temporal requirements of BLTPs in disease pathogenesis remain poorly understood.
    OBJECTIVE: The objective of this study was to determine tissue-specific and aging-dependent roles for VPS13A and BLTP2 using Drosophila models.
    METHODS: We generated tissue-specific knockdowns of the VPS13A ortholog (Vps13) and the BLTP2 ortholog (hobbit) in neurons and muscles of Drosophila. We analyzed age-dependent locomotor behavior, neurodegeneration, and synapse development and function.
    RESULTS: Neuron-specific loss of the VPS13A ortholog caused neurodegeneration followed by aging-dependent movement deficits and reduced lifespan, whereas muscle-specific loss affected only lifespan. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, whereas muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction.
    CONCLUSIONS: VPS13A maintains neuronal survival, whereas BLTP2 orchestrates synaptic development. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  VPS13A; lipid transfer proteins; lipids; membrane contact sites; parkinsonism
    DOI:  https://doi.org/10.1002/mds.30178
  4. EMBO J. 2025 Mar 24.
    S-palmitoylation modulates ATG2-dependent non-vesicular lipid transport during starvation-induced autophagy.
    Wenhui Zheng, Maomao Pu, Sai Zeng, Hongtao Zhang, Qian Wang, Tao Chen, Tianhua Zhou, Chunmei Chang, Dante Neculai, Wei Liu.
      Lipid transfer proteins mediate the non-vesicular transport of lipids at membrane contact sites to regulate the lipid composition of organelle membranes. Despite significant recent advances in our understanding of the structural basis for lipid transfer, its functional regulation remains unclear. In this study, we report that S-palmitoylation modulates the cellular function of ATG2, a rod-like lipid transfer protein responsible for transporting phospholipids from the endoplasmic reticulum (ER) to phagophores during autophagosome formation. During starvation-induced autophagy, ATG2A undergoes depalmitoylation as the balance between ZDHHC11-mediated palmitoylation and APT1-mediated depalmitoylation. Inhibition of ATG2A depalmitoylation leads to impaired autophagosome formation and disrupted autophagic flux. Further, in cell and in vitro analyses demonstrate that S-palmitoylation at the C-terminus of ATG2A anchors the C-terminus to the ER. Depalmitoylation detaches the C-terminus from the ER membrane, enabling it to interact with phagophores and promoting their growth. These findings elucidate a S-palmitoylation-dependent regulatory mechanism of cellular ATG2, which may represent a broad regulatory strategy for lipid transport mediated by bridge-like transporters within cells.
    Keywords:  ATG2; Autophagy; Lipid Transfer Protein; S-palmitoylation
    DOI:  https://doi.org/10.1038/s44318-025-00410-7
  5. J Transl Med. 2025 Mar 24. 23(1): 366
    Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
    Rui Wang, Jie Wang, Jing Yu, Zhiqiang Li, Minfang Zhang, Yuhu Chen, Fen Liu, Dongmei Jiang, Jingfei Guo, Xiaomei Li, Yun Wu.
       BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Recent studies indicate that Mitochondrial fusion protein 2 (Mfn2) maintains intracellular calcium (Ca2+) homeostasis via the mitochondria-associated endoplasmic reticulum membranes (MAMs) pathway, thereby inhibiting PASMCs proliferation and reducing pulmonary artery pressure. However, the precise mechanisms remain unclear.
    METHODS: This study explored the roles of Mfn2 and IP3R3 in PAH progression by assessing their expression in lung tissues of a monocrotaline (MCT)-induced PAH rat model. Immunoprecipitation assays were performed to confirm the interaction between Mfn2 and IP3R3. PASMCs were treated with either silenced or overexpressed Mfn2 and exposed to TNF-ɑ to observe effects on ER stress, IP3R3 expression, mitochondrial Ca2+ transport, and mitochondrial integrity. We also evaluated the effects of 4-phenylbutyric acid (4-PBA) and cistanche phenylethanol glycosides (CPGs) on the Mfn2-IP3R3 interaction in a TNF-α-induced PAH cell model, focusing on Ca2+ transport and mitochondrial structure.
    RESULTS: Mfn2 expression was significantly down-regulated in the MCT-induced PAH rat model. Inhibition of ER stress upregulated Mfn2 expression, downregulated IP3R3 expression, increased mitochondrial Ca2+ concentration, and reduced autophagy, improving pulmonary hemodynamics and vascular remodeling. Overexpression of Mfn2 reduced ER stress, decreased IP3R3 expression, decreased mitochondrial Ca2+ transport, and restored mitochondrial integrity. Immunoprecipitation assays confirmed the interaction between Mfn2 and IP3R3. Inhibition of IP3R3 elevated Mfn2 levels, yielding similar beneficial effects as Mfn2 overexpression. 4-PBA and CPGs modulated the Mfn2-IP3R3 signaling axis, effectively inhibiting PAH progression.
    CONCLUSIONS: Mfn2 mediates mitochondrial Ca2+ transport via IP3R3, suppressing PASMCs proliferation and pulmonary vascular remodeling, underscoring Mfn2's potential in regulating metabolic processes and vascular remodeling in PAH. These findings provide new insights for developing PAH-targeted therapeutics and establish a theoretical basis for traditional Chinese medicine in PAH prevention and treatment.
    Keywords:  Ca2+ homeostasis; Endoplasmic reticulum stress; Mfn2 interact with IP3R3; Mitochondrial autophagy; Pulmonary artery hypertension
    DOI:  https://doi.org/10.1186/s12967-025-06384-8
  6. Cell Mol Biol Lett. 2025 Mar 28. 30(1): 35
    MAM kinases: physiological roles, related diseases, and therapeutic perspectives-a systematic review.
    A Anjana Mohan, Priti Talwar.
      Mitochondria-associated membranes (MAMs) are tethering regions amid the membranes of the endoplasmic reticulum (ER) and mitochondria. They are a lipid raft-like structure occupied by various proteins that facilitates signal transduction between the two organelles. The MAM proteome participates in cellular functions such as calcium (Ca2+) homeostasis, lipid synthesis, ER stress, inflammation, autophagy, mitophagy, and apoptosis. The human kinome is a superfamily of homologous proteins consisting of 538 kinases. MAM-associated kinases participate in the aforementioned cellular functions and act as cell fate executors. Studies have proved the dysregulated kinase interactions in MAM as an etiology for various diseases including cancer, diabetes mellitus, neurodegenerative diseases, cardiovascular diseases (CVDs), and obesity. Several small kinase inhibitory molecules have been well explored as promising drug candidates in clinical trials with an accelerating impact in the field of precision medicine. This review narrates the physiological actions, pathophysiology, and therapeutic potential of MAM-associated kinases with recent updates in the field.
    Keywords:  Cancer; Diabetes; ER stress; Kinases; MAM; Mitophagy; Neurodegenerative disease; Therapeutics
    DOI:  https://doi.org/10.1186/s11658-025-00714-w
  7. iScience. 2025 Mar 21. 28(3): 112096
    Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis.
    Modesto Berraquero, Víctor A Tallada, Juan Jimenez.
      The EMC complex, a highly conserved transmembrane chaperone in the endoplasmic reticulum (ER), has been associated in humans with sterol homeostasis and a myriad of different cellular activities, rendering the mechanism of EMC functionality enigmatic. Using fission yeast, we demonstrate that the EMC complex facilitates the biogenesis of the sterol transfer protein Lam6/Ltc1 at ER-plasma membrane and ER-mitochondria contact sites. Cells that lose EMC function sequester unfolded Lam6/Ltc1 and other proteins at the mitochondrial matrix, leading to surplus ergosterol, cold-sensitive growth, and mitochondrial dysfunctions. Remarkably, inhibition of ergosterol biosynthesis, but also fluidization of cell membranes to counteract their rigidizing effects, reduce the ER-unfolded protein response and rescue growth and mitochondrial defects in EMC-deficient cells. These results suggest that EMC-assisted biogenesis of Lam6/Ltc1 may provide, through ergosterol homeostasis, optimal membrane fluidity to facilitate biogenesis of other ER-membrane proteins.
    Keywords:  Biochemistry; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112096
  8. Int J Surg. 2025 Mar 28.
    The perspective of modern transplant science -transplant arteriosclerosis: Inspiration derived from mitochondria associated endoplasmic reticulum membrane dysfunction in arterial diseases (review article).
    Jingyi Li, Qian Lin, Chao Ren, Xiaodong Li, Xiaowei Li, Haofeng Li, Shadan Li.
      The mitochondria-associated endoplasmic reticulum membrane (MAM) is a crucial structure connecting mitochondria and the endoplasmic reticulum (ER), regulating intracellular calcium homeostasis, lipid metabolism, and various signaling pathways essential for arterial health. Recent studies highlight MAM's significant role in modulating vascular endothelial cells (EC) and vascular smooth muscle cells (VSMC), establishing it as a key regulator of arterial health and a contributor to vascular disease pathogenesis. Organ transplantation is the preferred treatment for end-stage organ failure, but transplant arteriosclerosis (TA) can lead to chronic transplant dysfunction (CTD), significantly impacting patient survival. TA, like other vascular diseases, features endothelial dysfunction and abnormal proliferation and migration of VSMC. Previous research on TA has focused on immune factors, the pathological and physiological changes in grafts following immune system attacks have garnered insufficient attention. For example, the potential roles of MAM in TA has not been thoroughly investigated. Investigating the relationship between MAM and TA, as well as the mechanisms behind TA progression, is essential. This review aims to outline the fundamental structure and the primary functions of MAM, summarize its key molecular regulators of vascular health, and explore future prospects for MAM in the context of TA research, providing insights for both basic research and clinical management of TA.
    DOI:  https://doi.org/10.1097/JS9.0000000000002362
  9. Dis Model Mech. 2025 Mar 28. pii: dmm.052029. [Epub ahead of print]
    Patient-specific mutation of a contact site protein Tomm70 causes neurodegeneration in a zebrafish model.
    Vranda Garg, Ralf Heinrich, Roshan Priyarangana Perera, Till Ischebeck, Wiebke Möbius, Torben Ruhwedel, Patricia Scholz, Gabriela Salinas, Christian Dullin, Martin C Göpfert, Jacob Engelmann, Roland Dosch, Bart R H Geurten.
      Tomm70 is a receptor at the contact site between mitochondria and the endoplasmic reticulum, and has been identified as a risk gene for hereditary spastic paraplegia. Furthermore, de novo missense mutations in TOMM70 have been identified to cause neurological impairments in two unrelated patients. Here, we show that mutant zebrafish ruehreip25ca also harbor a missense mutation in tomm70, affecting the same conserved isoleucine residue as in one of the human patients. Using this model, we demonstrate how loss of Tomm70 function leads to impairment. At the molecular level, the mutation affects the interaction of Tomm70 with the endoplasmic reticulum protein Lam6, a known sterol transporter. At the neuronal level, the mutation impairs mitochondrial transport to the axons and dendrites, leading to demyelination of large calibre axons in the spinal cord. These neurodegenerative defects in zebrafish are associated with reduced endurance, swimming efficiency, and alterations in the C-start escape response, which correlate with decreased spiking in giant Mauthner neurons. Thus, in zebrafish, a mutation in the endoplasmic reticulum-mitochondria contact site protein Tomm70 recreates some of the neurodegenerative phenotypes characteristic of hereditary spastic paraplegia.
    Keywords:  Endoplasmic reticulum-mitochondria contact site (ER-MCS); Neurodegeneration; Tomm70; Zebrafish
    DOI:  https://doi.org/10.1242/dmm.052029
  10. Mamm Genome. 2025 Mar 28.
    Identification and validation of mitochondrial endoplasmic reticulum membrane-related genes in atherosclerosis.
    Li-Rong Wang, Chun-Xi Zhang, Lv-Bo Tian, Jie Huang, Li-Jun Jia, Hao Tao, Neng-Wei Yu, Bing-Hu Li.
      The mitochondria-associated endoplasmic reticulum membrane is implicated in atherosclerosis (AS). However, its precise molecular mechanisms remain undefined. This study identified KLRC1 and SOCS2 as key protective genes against AS through transcriptomic analysis integrated with Mendelian randomization. Both genes exhibited significantly reduced expression in the AS group. Immune infiltration analysis revealed a strong positive correlation between activated CD8+ T cells and these genes, while eosinophils displayed the most pronounced negative correlation with KLRC1, and regulatory T cells exhibited the strongest negative association with SOCS2. Notably, SOCS2 emerged as a pivotal protective factor, offering novel insights into AS pathogenesis and providing a robust theoretical foundation for early diagnosis and potential therapeutic strategies.
    DOI:  https://doi.org/10.1007/s00335-025-10124-0
  11. Biochim Biophys Acta Mol Basis Dis. 2025 Mar 21. pii: S0925-4439(25)00152-8. [Epub ahead of print] 167807
    Pannexin-2 deficiency disrupts visual pathways and leads to ocular defects in zebrafish.
    Riya Shanbhag, Georg S O Zoidl, Fatema Nakhuda, Shiva Sabour, Heike Nauman, Christiane Zoidl, Armin Bahl, Nima Tabatabaei, Georg R Zoidl.
      Pannexin-2 (Panx2) is a unique ion channel localized to ER-mitochondria contact sites. These specialized microdomains are abundant in neurons and glia and essential for cellular signaling and metabolism. While synaptic interactions are well-studied, the role of intracellular contacts, such as those of ER-mitochondrial junctions, in neuronal function and neurodegeneration remains largely unexplored. To investigate the roles of Panx2 in neuronal communication, we examined its expression pattern in the zebrafish brain and used TALEN technology to generate homozygous Panx2 knockout (Panx2Δ11) zebrafish. Our results demonstrate that panx2 mRNA is present in several brain regions, notably in visual centers such as the optic tectum and the thalamus. In 6 days post fertilization TL (Panx2+/+) larvae, Panx2 expression was observed in the retina and the arborization fields of the optic tract. Transcriptome profiling of Panx2Δ11 larvae by RNA-seq analysis revealed down-regulation of genes involved in visual perception and lens development. Behavioral tests showed that loss of Panx2 leads to an altered ability to interpret visual information, such as changes in ambient illuminations, and respond with the characteristic motor action. Additionally, the knockout larvae displayed significantly impaired optomotor response. Lastly, when we tested the retinal structure of adult zebrafish eyes using optical coherence tomography, Panx2Δ11 fish revealed a longer mean axial length and a negative shift in retinal refractive error (RRE) values. Our findings highlight a distinct, novel function of Panx2 in sensory perception and ocular health, beyond its recognized roles in neurodevelopment and cancer.
    Keywords:  Ocular health; Pannexins; Sensory-motor; Transcriptomics; Visual system; Zebrafish
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167807
  12. Biochem Biophys Res Commun. 2025 Mar 21. pii: S0006-291X(25)00386-9. [Epub ahead of print]759 151672
    PINK1 link mitochondria-ER contacts controls deposition of intramuscular fat in pigs.
    Jiaxin Cao, Nana Li, Ruolan Huang, Fengjuan Jia, Ziyi He, Wenlong Han, Wenzhang Liu, Songqiao Li, Weiye Wang, Weiyuan Ren, Bo Xia.
      Intramuscular fat (IMF) is a key determinant of meat quality in pigs, influencing characteristics such as tenderness, flavor, and marbling. The regulation of IMF deposition involves complex metabolic processes, with mitochondrial function playing a central role. PTEN-induced kinase 1 (PINK1), a protein involved in mitophagy and mitochondrial quality control, has recently been implicated in regulating fat deposition, although its role in IMF deposition in pigs remains unclear. This study investigates how PINK1 regulates IMF deposition by modulating mitochondrial-endoplasmic reticulum (ER) interactions. We utilized single-cell RNA sequencing to demonstrate that PINK1 is predominantly expressed in fibro-adipogenic progenitors (FAPs) and adipocytes, and its expression is negatively correlated with IMF content in multiple pig breeds. Knockdown of PINK1 in vivo led to increased intramuscular triglyceride content and enhanced adipogenic differentiation in primary porcine IMF cells. Additionally, PINK1 depletion resulted in impaired mitochondrial respiration, increased mitochondrial biogenesis, and disruption of mitochondria-ER contacts, further suggesting that PINK1 mediated of mitochondrial function and communication between mitochondria and ER is essential for controlling lipid deposition. These findings provide novel insights into the molecular mechanisms governing IMF accumulation and highlight PINK1 as a potential target for manipulating fat deposition in both agricultural and biomedical contexts.
    Keywords:  Intramuscular fat; Mitochondria-ER contacts; Mitophagy; PINK1; Pig
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151672
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