bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–02–02
ten papers selected by
Verena Kohler, Umeå University
  1. You better keep an eye on your contacts.
  2. Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
  3. Mitochondria-plasma membrane contact sites regulate the ER-mitochondria encounter structure.
  4. Mitochondria-Associated Endoplasmic Reticulum Membranes in Microglia: One Contact Site to Rule Them all.
  5. Remodeling of ER Membrane Contact Sites During Cell Division.
  6. Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.
  7. A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.
  8. Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD).
  9. Remodeling of Mitochondria-Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation.
  10. Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling.
  1. Cell Calcium. 2025 Jan 22. pii: S0143-4160(25)00008-9. [Epub ahead of print]126 102999
    You better keep an eye on your contacts.
    Tamas Balla, Gergo Gulyas.
      Membrane contact sites (MCS) are specialized compartments found in all eukaryotic cells that are formed between membranes of different organelles that are in close proximity. MCS have important functions as they are sites of efficient transfer of molecules between neighboring organelles. Two recent articles have used the splitFAST system to mark and follow the dynamics of membrane contact sites and used the method to highlight the importance of MCS between the endoplasmic reticulum (ER) and lipid droplets in metabolic adaptation and MCS between the ER and mitochondria in Ca2+ signal propagation.
    Keywords:  Calcium signaling; Lipid droplets; Lipid transfer; Membrane contact sites; Mitochondria
    DOI:  https://doi.org/10.1016/j.ceca.2025.102999
  2. Front Mol Neurosci. 2024 ;17 1527013
    Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases.
    Yinyin Xie, Wenlin Sun, Aoya Han, Xinru Zhou, Shijie Zhang, Changchang Shen, Yi Xie, Cui Wang, Nanchang Xie.
      Mitochondria and lysosomes are critical for neuronal homeostasis, as highlighted by their dysfunction in various neurological diseases. Recent studies have identified dynamic membrane contact sites between mitochondria and lysosomes, independent of mitophagy and the lysosomal degradation of mitochondrial-derived vesicles (MDVs), allowing bidirectional crosstalk between these cell compartments, the dynamic regulation of organelle networks, and substance exchanges. Emerging evidence suggests that abnormalities in mitochondria-lysosome contact sites (MLCSs) contribute to neurological diseases, including Parkinson's disease, Charcot-Marie-Tooth (CMT) disease, lysosomal storage diseases, and epilepsy. This article reviews recent research advances regarding the tethering processes, regulation, and function of MLCSs and their role in neurological diseases.
    Keywords:  lysosomal dynamics; mitochondria-lysosome contact sites; mitochondrial network; mitophagy; neurological diseases; substance exchanges
    DOI:  https://doi.org/10.3389/fnmol.2024.1527013
  3. J Cell Sci. 2025 Jan 29. pii: jcs.263685. [Epub ahead of print]
    Mitochondria-plasma membrane contact sites regulate the ER-mitochondria encounter structure.
    Jason C Casler, Clare S Harper, Laura L Lackner.
      Cells form multiple, molecularly distinct membrane contact sites (MCSs) between organelles. Despite knowing the molecular identity of several of these complexes, little is known about how MCSs are coordinately regulated in space and time to promote organelle function. Here, we examined two well-characterized mitochondria-ER MCSs - the ER-Mitochondria encounter structure (ERMES) and the mitochondria-ER-cortex anchor (MECA). We report that loss of MECA results in a substantial reduction in the number of ERMES contacts. Rather than reducing ERMES protein levels, loss of MECA results in an increase in the size of ERMES contacts. Using live cell microscopy, we demonstrate that ERMES contacts display several dynamic behaviors, such as de novo formation, fusion, and fission, that are altered in the absence of MECA or by changes in growth conditions. Unexpectedly, we find that the mitochondria-PM tethering, not the mitochondria-ER tethering, function of MECA regulates ERMES contacts. Remarkably, synthetic tethering of mitochondria to the PM in the absence of MECA is sufficient to rescue the distribution of ERMES foci. Overall, our work reveals how one MCS can influence the regulation and function of another.
    Keywords:  Membrane contact sites; Mitochondria; Mitochondrial positioning
    DOI:  https://doi.org/10.1242/jcs.263685
  4. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564241312807
    Mitochondria-Associated Endoplasmic Reticulum Membranes in Microglia: One Contact Site to Rule Them all.
    Elisa Navarro, Jorge Montesinos.
      Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining tissue homeostasis by monitoring and responding to environmental changes through processes such as phagocytosis, cytokine production or synapse remodeling. Their dynamic nature and diverse functions are supported by the regulation of multiple metabolic pathways, enabling microglia to efficiently adapt to fluctuating signals. A key aspect of this regulation occurs at mitochondria-associated ER membranes (MAM), specialized contact sites between the ER and mitochondria. These structures facilitate the exchange of calcium, lipids, and metabolites and serve as metabolic and signaling hubs. This review synthesizes current research on how MAM influence microglial physiology, with an emphasis on their role in immunometabolism, offering new insights into the integration of metabolic and immune functions in the CNS and its impact in the context of neurodegeneration.
    Keywords:  ER-mitochondria contact sites; inflammation; metabolism; microglia; mitochondria-associated ER membranes (MAM); neurodegeneration
    DOI:  https://doi.org/10.1177/25152564241312807
  5. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564241309207
    Remodeling of ER Membrane Contact Sites During Cell Division.
    Fang Yu, Khaled Machaca.
      Membrane contact sites (MCS) provide specialized conduits for inter-organelle communications to maintain cellular homeostasis. Most organelles are interconnected, which supports their coordination and function. M-phase (mitosis or meiosis) is associated with dramatic cellular remodeling to support cell division, including the equal distribution of organelles to the two daughter cells. However, the fate of MCS in M-phase is poorly understood. Here we review recent advances arguing for differential remodeling of endoplasmic reticulum (ER) MCS with the plasma membrane (PM, ERPMCS) and the mitochondria (MERCS) during cell division.
    Keywords:  ERPMCS; MERCS; cell division; endoplasmic reticulum; meiosis; membrane contact sites; mitochondrion (mitochondria); mitosis
    DOI:  https://doi.org/10.1177/25152564241309207
  6. J Cell Sci. 2025 Jan 30. pii: jcs.263637. [Epub ahead of print]
    Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.
    Samruddhi S Shembekar, Petra Nikolaus, Ulrike Honnert, Marcus Höring, Aya Attia, Karin Topp, Birgit Lohmann, Gerhard Liebisch, Martin Bähler.
      The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The Mitochondrial Intermembrane Bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the MICOS system. However, the interaction between Myo19, Miro1/2, and the MIB/MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB/MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex, but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for Myo19 and Miro1/2's connection to MIB/MICOS. Deleting Miro1/2 mimics Myo19 deficiency effects on ER-mitochondria contacts and cristae structure, while Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites.
    Keywords:  Cristae organization; Lipid transfer; Mitochondria; Myosin; Rho GTPases
    DOI:  https://doi.org/10.1242/jcs.263637
  7. Life Sci Alliance. 2025 Apr;pii: e202402907. [Epub ahead of print]8(4):
    A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.
    Cathal Wilson, Laura Giaquinto, Michele Santoro, Giuseppe Di Tullio, Valentina Morra, Wanda Kukulski, Rossella Venditti, Francesca Navone, Nica Borgese, Maria Antonietta De Matteis.
      Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear. A yeast model, expressing human mutant and WT-VAPB under the control of the orthologous yeast promoter in haploid and diploid cells, was developed to mimic the disease situation. Inclusion formation was found to be a developmentally regulated process linked to mitochondrial damage that could be attenuated by reducing ER-mitochondrial contacts. The co-expression of the WT protein retarded P56S-VAPB inclusion formation. Importantly, we validated these results in mammalian motoneuron cells. Our findings indicate that (age-related) damage to mitochondria influences the propensity of the mutant VAPB to form aggregates via ER-mitochondrial contacts, initiating a series of events leading to disease progression.
    DOI:  https://doi.org/10.26508/lsa.202402907
  8. J Vis Exp. 2025 Jan 10.
    Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD).
    Jacob C Zellmer, Selene Lomoio, Rudolph E Tanzi, Raja Bhattacharyya.
      A method to quantitate the stabilization of Mitochondria-Associated endoplasmic reticulum Membranes (MAMs) in a 3-dimensional (3D) neural model of Alzheimer's disease (AD) is presented here. To begin, fresh human neuro progenitor ReN cells expressing β-amyloid precursor protein (APP) containing familial Alzheimer's disease (FAD) or naïve ReN cells are grown in thin (1:100) Matrigel-coated tissue culture plates. After the cells reach confluency, these are electroporated with expression plasmids encoding red fluorescence protein (RFP)-conjugated mitochondria-binding sequence of AKAP1(34-63) (Mito-RFP) that detects mitochondria or constitutive MAM stabilizers MAM 1X or MAM 9X that stabilize tight (6 nm ± 1 nm gap width) or loose (24 nm ± 3 nm gap width) MAMs, respectively. After 16-24 h, the cells are harvested and enriched by a fluorescence-activated cell sorter (FACS). An equal number of FACS-enriched cells are seeded in the 3-dimensional matrix (1:1 Matrigel) and allowed to differentiate into mature neurons for 10 days. Live cell images of the 10-day differentiated cells expressing the RFP-conjugated MAM stabilizers are captured under a fluorescent microscope equipped with a live-cell imaging culture chamber maintaining the CO2 (5%), temperature (37 °C), and humidity (~90%). Toward this end, we performed live-cell imaging and kymographic analyses to measure the motility of free mitochondria labeled with Mito-RFP or ER-bound mitochondria of tight or loose gap widths stabilized by MAM 1X or MAM 9X, respectively, in the most extended neuronal process of each ReN GA neuron which is at least 500 nm long, considering these as axons.
    DOI:  https://doi.org/10.3791/66129
  9. Biomolecules. 2025 Jan 14. pii: 126. [Epub ahead of print]15(1):
    Remodeling of Mitochondria-Endoplasmic Reticulum Contact Sites Accompanies LUHMES Differentiation.
    Emad Norouzi Esfahani, Tomas Knedlik, Sang Hun Shin, Ana Paula Magalhães Rebelo, Agnese De Mario, Caterina Vianello, Luca Persano, Elena Rampazzo, Paolo Edomi, Camilla Bean, Dario Brunetti, Luca Scorrano, Samuele Greco, Marco Gerdol, Marta Giacomello.
      Neural progenitor cells (NPCs) are often used to study the subcellular mechanisms underlying differentiation into neurons in vitro. Works published to date have focused on the pathways that distinguish undifferentiated NPCs from mature neurons, neglecting the earlier and intermediate stages of this process. Current evidence suggests that mitochondria interaction with the ER is fundamental to a wide range of intracellular processes. However, it is not clear whether and how the mitochondria-ER interactions differ between NPCs and their differentiated counterparts. Here we take advantage of the widely used NPC line LUHMES to provide hints on the mitochondrial dynamic trait changes that occur during the first stage of their maturation into dopaminergic-like neurons. We observed that the morphology of mitochondria, their interaction with the ER, and the expression of several mitochondria-ER contact site resident proteins change, which suggests the potential contribution of mitochondria dynamics to NPC differentiation. Further studies will be needed to explore in depth these changes, and their functional outcomes, which may be relevant to the scientific community focusing on embryonic neurogenesis and developmental neurotoxicity.
    Keywords:  LUHMES; MERCs; Neural precursor cells; differentially expressed genes; mitochondria; mitochondria–ER contact sites
    DOI:  https://doi.org/10.3390/biom15010126
  10. Mol Cell Neurosci. 2025 Jan 23. pii: S1044-7431(25)00002-8. [Epub ahead of print]132 103992
    Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling.
    Xuan Liu, Tianjiao Li, Xinya Tu, Mengying Xu, Jianwu Wang.
      Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca2+ signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca2+ signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca2+ signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca2+ signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.
    Keywords:  Ca(2+) signaling; Mitochondrial fusion and fission; Mitochondrial-associated membranes (MAMs); Mitochondrial–ER contact sites (MERCs); Neurodegenerative diseases; Potential drugs
    DOI:  https://doi.org/10.1016/j.mcn.2025.103992
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