bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–04–06
nine papers selected by
Verena Kohler, Umeå University
  1. PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth.
  2. STIM1 and Endoplasmic Reticulum-Plasma Membrane Contact Sites Oscillate Independently of Calcium-Induced Calcium Release.
  3. Three's company: Membrane waltz among organelles.
  4. Mitochondria associated membranes in dilated cardiomyopathy: connecting pathogenesis and cellular dysfunction.
  5. VAP27-1 interacts with KCS6 and CER2 to facilitate the biosynthesis of very- long-chain fatty acids.
  6. Remodelling of Cellular Protein Homeostasis by Enhanced ER-Mitochondrial Tethering.
  7. ER nests are specialized ER subdomains in Arabidopsis where peroxisomes and lipid droplets form.
  8. Current research on mitochondria‑associated membranes in cardiovascular diseases (Review).
  9. Editorial: Lipids and membrane contacts - structure, functional aspects and implications on ageing, cell death and autophagy, volume II.
  1. Cell Rep. 2025 Mar 28. pii: S2211-1247(25)00254-2. [Epub ahead of print]44(4): 115483
    PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth.
    Rajan S Thakur, Kate M O'Connor-Giles.
      Building synaptic connections requires coordinating a host of cellular activities from cell signaling to protein turnover, placing a high demand on intracellular communication. Membrane contact sites (MCSs) formed between organelles have emerged as key signaling hubs for coordinating diverse cellular activities, yet their roles in the developing nervous system remain obscure. We investigate the in vivo function of the endoplasmic reticulum (ER) MCS tethering and lipid-transfer protein PDZD8, which was recently linked to intellectual disability, in the nervous system. We find that PDZD8 is required for activity-dependent synaptic bouton formation in multiple paradigms. PDZD8 is sufficient to drive excess synaptic bouton formation through an autophagy-dependent mechanism and required for synapse development when autophagy is limited. PDZD8 accelerates autophagic flux by promoting lysosome maturation at ER-late endosome/lysosome MCSs. We propose that PDZD8 functions in the nervous system to increase autophagy during periods of high demand, including activity-dependent synaptic growth.
    Keywords:  CP: Cell biology; CP: Neuroscience; Drosophila; autophagy; lipid transfer protein; lysosomes; membrane contact sites; neurodevelopment; synapse
    DOI:  https://doi.org/10.1016/j.celrep.2025.115483
  2. bioRxiv. 2025 Mar 17. pii: 2025.03.16.643575. [Epub ahead of print]
    STIM1 and Endoplasmic Reticulum-Plasma Membrane Contact Sites Oscillate Independently of Calcium-Induced Calcium Release.
    Ding Xiong, Cheesan Tong, Yang Yang, Jeffery Yong, Min Wu.
      Calcium (Ca²⁺) release from intracellular stores, Ca²⁺ entry across the plasma membrane, and their coordination via store-operated Ca²⁺ entry (SOCE) are critical for receptor-activated Ca²⁺ oscillations. However, the precise mechanism of Ca²⁺ oscillations and whether their control loop resides at the plasma membrane or intracellularly remain unresolved. By examining the dynamics of stromal interaction molecule 1 (STIM1)-an endoplasmic reticulum (ER)-localized Ca²⁺ sensor that activates the Orai1 channel on the plasma membrane for SOCE-and in mast cells, we found that a significant proportion of cells exhibited STIM1 oscillations with the same periodicity as Ca²⁺ oscillations. These cortical oscillations, occurring in the cell's cortical region and shared with ER-plasma membrane (ER-PM) contact sites proteins, were only detectable using total internal reflection fluorescence microscopy (TIRFM). Notably, STIM1 oscillations could occur independently of Ca²⁺ oscillations. Simultaneous imaging of cytoplasmic Ca²⁺ and ER Ca²⁺ with SEPIA-ER revealed that receptor activation does not deplete ER Ca²⁺, whereas receptor activation without extracellular Ca²⁺ influx induces cyclic ER Ca²⁺ depletion. However, under such nonphysiological conditions, cyclic ER Ca²⁺ oscillations lead to sustained STIM1 recruitment, indicating that oscillatory Ca²⁺ release is neither necessary nor sufficient for STIM1 oscillations. Using optogenetic tools to manipulate ER-PM contact site dynamics, we found that persistent ER-PM contact sites reduced the amplitude of Ca²⁺ oscillations without alteration of oscillation frequency. Together, these findings suggest an active cortical mechanism governs the rapid dissociation of ER-PM contact sites, thereby control amplitude of oscillatory Ca²⁺ dynamics during receptor-induced Ca²⁺ oscillations.
    DOI:  https://doi.org/10.1101/2025.03.16.643575
  3. Biochim Biophys Acta Bioenerg. 2025 Apr 01. pii: S0005-2728(25)00021-0. [Epub ahead of print] 149555
    Three's company: Membrane waltz among organelles.
    Valentin Guyard, Francesca Giordano.
      The study of membrane contact sites (MCS) has profoundly transformed our understanding of inter-organelle communication. These sites, where the membranes of two organelles are closely apposed, facilitate the transfer of small molecules such as lipids and ions. They are especially crucial for the maintenance of the structure and function of organelles like mitochondria and lipid droplets, which are largely excluded from vesicular trafficking. The significant advancements in imaging techniques, and molecular and cell biology research have shown that MCS are more complex than what originally thought and can involve more than two organelles. This has revealed the intricate nature and critical importance of these subcellular connections. Here, we provide an overview of newly described three-way inter-organelles associations, and the proteins involved in these MCS. We highlight the roles these contacts play in key cellular processes such as lipid droplet biogenesis and mitochondrial division. Additionally, we discuss the latest advances in super-resolution imaging that enable the study of these complex three-way interactions. Ongoing research, driven by technological innovations, promises to uncover further insights into their roles in fundamental cellular processes and their implications for health and disease.
    Keywords:  Lipid droplet biogenesis; Membrane contact sites; Mitochondria; Mitochondria dynamics
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149555
  4. Front Cardiovasc Med. 2025 ;12 1571998
    Mitochondria associated membranes in dilated cardiomyopathy: connecting pathogenesis and cellular dysfunction.
    Pingge He, Hongbo Chang, Yueqing Qiu, Zhentao Wang.
      Dilated cardiomyopathy (DCM) is a leading cause of heart failure, yet therapeutic options remain limited. While traditional research has focused on mechanisms such as energy deficits and calcium dysregulation, increasing evidence suggests that mitochondria-associated membranes (MAMs) could provide new insights into understanding and treating DCM. In this narrative review, we summarize the key role of MAMs, crucial endoplasmic reticulum (ER)-mitochondria interfaces, in regulating cellular processes such as calcium homeostasis, lipid metabolism, and mitochondrial dynamics. Disruption of MAMs function may initiate pathological cascades, including ER stress, inflammation, and cell death. These disruptions in MAM function lead to further destabilization of cellular homeostasis. Identifying MAMs as key modulators of cardiac health may provide novel insights for early diagnosis and targeted therapies in DCM.
    Keywords:  DCM; MAMS; MAMs-associated proteins; cardiomyocytes; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fcvm.2025.1571998
  5. Plant Sci. 2025 Mar 31. pii: S0168-9452(25)00107-4. [Epub ahead of print]355 112489
    VAP27-1 interacts with KCS6 and CER2 to facilitate the biosynthesis of very- long-chain fatty acids.
    Haiyan Wang, Yifan Li, Qinyao Wang, Mengxia Wu, Ruiyuan Wang, Xinran Han, Lin Liu, Ting Liu, Chunmei Shi, Linlin Zhong, Hongyan Zhang, Yunjiang Cheng, Pengwei Wang, Xiaolu Qu.
      Cuticular wax is primarily composed of very-long-chain fatty acids (VLCFAs) and their derivatives. It forms a critical hydrophobic layer on plant surfaces, acting as a protective barrier against biotic and abiotic stress. The biosynthesis of VLCFAs and their derivative wax occurs in endoplasmic reticulum (ER) and is subsequently transported to the plant surface. While substantial research has focused on cuticular wax biosynthesis enzymes and their transcriptional regulation, the mechanisms by which these enzymes are modulated by proteins within cytosol organelles remain poorly understood. In this study, we identified that β-ketoacyl-CoA synthase 6 (KCS6), an ER-localized rate-limiting enzyme in VLCFAs biosynthesis, also localized at ER-plasma membrane contact sites (EPCS). We further demonstrated that KCS6 and its cofactor ECERIFERUM 2 (CER2) interact with vesicle-associated membrane protein-associated protein 27-1 (VAP27-1), a key regulator of EPCS formation and stabilization. Overexpression of VAP27-1 in Arabidopsis thaliana resulted in a significant increase in almost all cuticular wax components compared to WT. Additionally, firefly luciferase complementation imaging assays (LCI) and yeast heterologous expression analysis revealed that VAP27-1 strengthens the interaction between the KCS6-CER2 complex, resulting in increased accumulation of VLCFAs. In conclusion, this study emphasized the critical role of VAP27-1 in regulating the biosynthesis of cuticular wax mediated by KCS6-CER2, providing new insights into the fine-tuning mechanisms of cuticular wax biosynthesis within the ER. Furthermore, the identification of VAP27-1 as a novel modulator of VLCFA synthases offers a potential target for enhancing plant resilience to environmental stresses.
    Keywords:  CER2; Cuticular wax; EPCS; Endoplasmic reticulum; KCS6; VAP27-1; Very-long-chain fatty acids
    DOI:  https://doi.org/10.1016/j.plantsci.2025.112489
  6. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251329704
    Remodelling of Cellular Protein Homeostasis by Enhanced ER-Mitochondrial Tethering.
    Elisa Tonelli, Justyna Malecka, Elettra Barberis, Camilla Romano, Emanuela Pessolano, Maria Talmon, Armando A Genazzani, Claudio Casali, Marco Biggiogera, Marcello Manfredi, Laura Tapella, Dmitry Lim, Giulia Dematteis.
      Alterations of endoplasmic reticulum (ER)-mitochondrial interaction have been associated with different pathological conditions, including neurodegenerative diseases, characterized by dysregulation of protein homeostasis. However, little is known about how enhanced ER-mitochondrial tethering affects cellular proteostatic machinery. Here, we transiently overexpressed synthetic ER-mitochondrial linkers (EMLs), stabilizing the ER-mitochondrial distance at ≤5 nm (denominated as 5 nm-EML) and ∼10 nm (10 nm-EML), in HeLa cells. No alterations were found in cell growth, although metabolic activity and total ATP were significantly reduced. In EML-expressing cells, global protein synthesis was significantly reduced, accompanied by a reduction of total PERK and eIF2α protein levels, but increased p-eIF2α. Unfolded protein response (UPR) markers ATF4 and ATF6 were upregulated, suggesting that enhanced ER-mitochondrial tethering deranges protein synthesis and induces a low-grade ER stress/UPR. To further investigate ER-mitochondrial tethering-induced protein dyshomeostasis, we performed shotgun mass spectrometry proteomics followed by bioinformatic analysis. Analysis of highly changed proteins and the most significantly overrepresented gene ontology (GO) terms revealed that ≤5 nm tethering preferentially affected the expression of proteins involved in RNA processing and splicing and proteasomal protein degradation, while ∼10 nm tethering preferentially affected protein translation. Both EMLs affected expression of proteins involved in mitochondrial bioenergetics and metabolism, defense against oxidative stress, ER protein homeostasis, signaling and secretion. Finally, lipidomic analysis suggests that 5 nm-EML and 10 nm-EML differentially affect lipid homeostasis. Altogether, our results suggest that enhanced ER-mitochondrial tethering leads to a profound remodeling of cellular protein homeostasis, which may play a key role in pathogenesis of Alzheimer's and other neurodegenerative diseases.
    Keywords:  MAMs; MERCS; mitochondria-ER contact sites; proteostasis
    DOI:  https://doi.org/10.1177/25152564251329704
  7. Dev Cell. 2025 Mar 25. pii: S1534-5807(25)00152-2. [Epub ahead of print]
    ER nests are specialized ER subdomains in Arabidopsis where peroxisomes and lipid droplets form.
    Zachary J Wright, Nathan E Tharp, Bonnie Bartel.
      Organelles are defining features of eukaryotic cells, yet much remains to be learned about organelle biogenesis. Lipid droplets and peroxisomes, which play opposing roles in storing and catabolizing fats, form from a mysterious domain in the endoplasmic reticulum (ER). We used live-cell fluorescence microscopy to visualize peroxisome and lipid droplet biogenesis in young Arabidopsis seedlings, where lipid catabolism is active, and peroxisomes can be unusually large. We found that the ER domains where these organelles are born, which we term ER nests, are complex, dynamic structures that exclude general ER proteins but accumulate other proteins, including lipid biosynthetic enzymes and the COPII component SAR1. Furthermore, ER nests appear to define peroxisome-lipid droplet contact sites. Our findings provide a framework for understanding how these domains form and sort their protein components, illuminate eukaryotic lipid biosynthesis, and elucidate how distinct organelles arise from the ER.
    Keywords:  Arabidopsis cell biology; RHD3/atlastin; SAR1; endomembrane trafficking; lipid droplet; organelle biogenesis; peroxisome
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.005
  8. Mol Med Rep. 2025 Jun;pii: 141. [Epub ahead of print]31(6):
    Current research on mitochondria‑associated membranes in cardiovascular diseases (Review).
    Jiaheng Zhang, Jing Tao, Zijuan Zhou, Wanjuan Pei, Yili Xiao, Yanghongxu Guo, Jian Gao, Chenyv Jiang, Ling Dai, Guomin Zhang, Chao Tan.
      The present study aimed to explore the role of mitochondria‑associated membranes (MAMs) as a key interface between mitochondria and the endoplasmic reticulum (ER) and to evaluate their importance in maintaining the physiological functions of these two organelles. MAMs not only act as a structural bridge between mitochondria and the ER but also widely participate in the regulation of mitochondrial biosynthesis and function, Ca2+ signal transduction, lipid metabolism, oxidative stress response and autophagy. In addition, the specific protein composition of MAMs is increasingly being recognized as having a profound impact on their function, and these proteins play a central role in regulating intercellular communication. Recently, the scientific community has accumulated a large amount of evidence supporting MAMs as potential targets for cardiovascular disease treatment. The present review focuses on the fine structure and multifunctional properties of MAMs and their mechanisms in the occurrence and development of cardiovascular diseases. The goal is to explore the mechanism of MAMs, therapeutic intervention points directly related to cardiovascular diseases, and feasibility of incorporating MAMs into the diagnostic strategy and treatment plan of cardiovascular diseases to provide novel insights and theoretical support for clinical practice in this field. MAMs have great potential as therapeutic targets for various cardiovascular diseases. This finding not only deepens the understanding of the interaction between organelles but also opens up a promising research path for the development of new therapeutic strategies for cardiovascular diseases.
    Keywords:  atherosclerosis; diabetic cardiomyopathy; mitochondria‑associated endoplasmic reticulum membrane; myocardial infarction; myocardial ischemia reperfusion
    DOI:  https://doi.org/10.3892/mmr.2025.13506
  9. Front Cell Dev Biol. 2025 ;13 1589044
    Editorial: Lipids and membrane contacts - structure, functional aspects and implications on ageing, cell death and autophagy, volume II.
    Christopher T Beh, Alexandre Toulmay, Patrick Rockenfeller.
      
    Keywords:  autophagy; lipid exchange and transport; membrane contact sites (MCSs); membrane homoeostasis; membrane signaling; membrane-related diseases
    DOI:  https://doi.org/10.3389/fcell.2025.1589044
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