bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–02–16
eight papers selected by
Verena Kohler, Umeå University
  1. Cytosolic companionship: Rickettsia connects with the endoplasmic reticulum.
  2. The fundamental role of mitochondria-endoplasmic reticulum contacts in ageing and declining healthspan.
  3. Binary division of plastids involves ER-mediation.
  4. Fluoride induces spermatocyte apoptosis by IP3R1/MCU-mediated mitochondrial calcium overload through MAMs.
  5. The Pathophysiological Role of Mitochondria-associated Membranes in Coronary Artery Disease and Atherosclerosis.
  6. Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage.
  7. ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress.
  8. Endoplasmic Reticulum-Mitochondria Crosstalk in Fuchs Endothelial Corneal Dystrophy: Current Status and Future Prospects.
  1. J Cell Biol. 2025 Mar 03. pii: e202412181. [Epub ahead of print]224(3):
    Cytosolic companionship: Rickettsia connects with the endoplasmic reticulum.
    Stacey D Gilk.
      Rickettsia are bacterial pathogens known for their actin-based motility in the host cell cytoplasm. In this issue, Acevedo-Sánchez and colleagues (https://doi.org/10.1083/jcb.202406122) discover non-motile Rickettsia bacteria hijack host machinery to form stable membrane contact sites with the host endoplasmic reticulum.
    DOI:  https://doi.org/10.1083/jcb.202412181
  2. Open Biol. 2025 Feb;15(2): 240287
    The fundamental role of mitochondria-endoplasmic reticulum contacts in ageing and declining healthspan.
    Richard M Monaghan.
      This open question research article highlights mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), which have emerged as crucial cellular structures that challenge our traditional understanding of organelle function. This review highlights the critical importance of MAMs as a frontier in cell biology with far-reaching implications for health, disease and ageing. MAMs serve as dynamic communication hubs between the ER and mitochondria, orchestrating essential processes such as calcium signalling, lipid metabolism and cellular stress responses. Recent research has implicated MAM dysfunction in a wide array of conditions, including neurodegenerative diseases, metabolic disorders, cardiovascular diseases and cancer. The significant lack of biological knowledge behind MAM function emphasizes the need to study these enigmatic subcellular sites in greater detail. Key open questions include the mechanisms controlling MAM formation and disassembly, the full complement of MAM-associated proteins and how MAMs contribute to cellular decision-making and ageing processes. Advancing our understanding of MAMs through interdisciplinary approaches and cutting-edge technologies promises to reveal new insights into fundamental cellular signalling pathways and potentially lead to innovative therapeutic strategies for a range of diseases. As such, MAM research represents a critical open question in biology with the potential to transform our understanding of cellular life and human health.
    Keywords:  ageing; endoplasmic reticulum; healthspan; membrane contact sites; metabolism; mitochondria
    DOI:  https://doi.org/10.1098/rsob.240287
  3. J Exp Bot. 2025 Feb 13. pii: eraf064. [Epub ahead of print]
    Binary division of plastids involves ER-mediation.
    Puja Puspa Ghosh, Thomas Kadanthottu Kunjumon, Jaideep Mathur.
      Plastids divide through binary division, involving the cytosolic protein Accumulation and Replication of Chloroplast 5 (ARC5), suggested to constrict and sever the plastid envelope membrane. However, the mechanisms involved in ARC5 recruitment to the mid-plastid division site and the final separation of daughter plastids are not fully understood. Using time-lapse imaging of Arabidopsis thaliana stable transgenics expressing fluorescently tagged endoplasmic reticulum (ER) and ARC5 proteins, we investigated the role played by the ER in the late stages of plastid division. Our observations establish that prior to its mid-plastid localization at the division-plane, ARC5 associates with ER membranes. ARC5-ER association generates an ER band around the plastid mid-plane that persists throughout division. Progressive tightening of the ER-band narrows the plastid middle to form an isthmus. Concomitantly, tandem plastid - ER dynamics facilitated by membrane contact sites (MCSs) move and rotate the dividing plastid and ultimately lead to the separation of daughter plastids. Our findings strongly indicate a pivotal role for the ER in facilitating plastid division.
    Keywords:  ARC5/DRP5B; ER; Fluorescent proteins; Plastid-division
    DOI:  https://doi.org/10.1093/jxb/eraf064
  4. J Hazard Mater. 2025 Feb 05. pii: S0304-3894(25)00426-1. [Epub ahead of print]489 137514
    Fluoride induces spermatocyte apoptosis by IP3R1/MCU-mediated mitochondrial calcium overload through MAMs.
    Xin Guo, Linyuan Wang, Jingyan Xuan, Tong Chen, Yu Du, Hanxing Qiao, Shaosan Zhang, Zilong Sun, Jundong Wang, Ruiyan Niu.
      Excessive fluoride exposure has been shown to induce diminished sperm quality and mitochondrial dysfunction. The interaction between mitochondria and the endoplasmic reticulum (ER) is critical for regulating mitochondrial function in spermatogenic cells. Therefore, this study was designed to investigate the molecular events involved in mitochondria-associated ER membranes (MAMs) in mice exposed to 25, 50, and 100 mg/L NaF for 60 days, and in GC-2spd treated with 1.5, 2.0, and 2.5 mM NaF for 24 hours. Mitochondrial stress tests revealed a significant reduction in basal respiration, maximal respiration, and ATP production, suggesting mitochondrial dysfunction following fluoride exposure. Results further indicated that fluoride exposure significantly enhanced ER-mitochondria contacts, mitochondrial Ca2+ levels, and the expressions of IP3R1, GRP75, VDAC1, and MCU, while reduced the levels of MFN1, MFN2, VAPB, and PTPIP51, along with an increase in Cytochrome C and Caspase-3. Treatment with the Ru360 and IP3R1 siRNA restored mitochondrial membrane potential, while reduced mitochondrial Ca2+ levels and apoptosis rates, indicating that both MCU and IP3R1 play a role in regulating fluoride-induced the formation of MAMs. Collectively, these findings proved that fluoride promoted Ca2+ transfer through MAMs in spermatocytes via the IP3R1-GRP75-VDAC1-MCU axis, and inhibiting IP3R1/MCU might be a potential therapeutic target in fluorosis.
    Keywords:  Apoptosis; Fluoride; MAMs; Mitochondrial Ca(2+); Spermatocytes
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.137514
  5. Curr Med Chem. 2025 Feb 12.
    The Pathophysiological Role of Mitochondria-associated Membranes in Coronary Artery Disease and Atherosclerosis.
    Junyan Zhang, Zhongxiu Chen, Li Rao, Yong He.
      Mitochondria-associated membranes (MAMs) are pivotal in cellular homeostasis, mediating communication between the endoplasmic reticulum and mitochondria. They are increasingly recognized for their role in atherosclerosis and coronary artery disease (CAD). This review delves into the cellular perspective of MAMs' impact on atherosclerosis and CAD, highlighting their influence on disease progression and the potential for therapeutic intervention. MAMs are implicated in key pathophysiological processes such as the generation of reactive oxygen species, calcium homeostasis, myocardial ischemia-reperfusion injury, autophagy, lipid synthesis and transport, and energy metabolism-fundamental to the development and progression of atherosclerosis and CAD. The complex interplay of MAMs with these pathological processes underscores their potential as therapeutic targets. This review synthesizes current understanding and emphasizes the need for further research to elucidate the multifaceted roles of MAMs in atherosclerosis and CAD, offering avenues for developing novel strategies aimed at improving mitochondrial health and mitigating the impact of these conditions.
    Keywords:  Mitochondria-associated membranes (MAMs); atherosclerosis; autophagy; calcium homeostasis; coronary artery disease (CAD); ischemia-reperfusion injury; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.2174/0109298673343245250128093845
  6. Cells. 2025 Jan 28. pii: 195. [Epub ahead of print]14(3):
    Pharmacological Targeting of the NMDAR/TRPM4 Death Signaling Complex with a TwinF Interface Inhibitor Prevents Excitotoxicity-Associated Dendritic Blebbing and Organelle Damage.
    Omar A Ramírez, Andrea Hellwig, Zihong Zhang, Hilmar Bading.
      Focal swellings of dendrites ("dendritic blebbing") together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called "overactivation" of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein-protein complex with TRPM4, drives these pathological traits. In contrast, strong activation of synaptic NMDARs fails to induce cell damage despite evoking plateau-type calcium signals that are comparable to those generated by activation of the NMDAR/TRPM4 complex, indicating that high intracellular calcium levels per se are not toxic to neurons. Using confocal laser scanning microscopy and transmission electron microscopy, we show that disrupting the NMDAR/TRPM4 complex using the recently discovered small-molecule TwinF interface inhibitor FP802 inhibits the NMDA-induced neurotoxicity-associated dendritic blebbing and structural damage to mitochondria and the ER. It also prevents, at least in part, the disruption of ER-mitochondria contact sites. These findings establish the NMDAR/TRPM4 complex as the trigger for the structural damage of dendrites and intracellular organelles associated with excitotoxicity. They also suggest that activation of the NMDAR/TRPM4 complex, in addition to inducing high-amplitude, plateau-type calcium signals, generates a second signal required for glutamate neurotoxicity ("two-hit hypothesis"). As structural damage to organelles, particularly mitochondria, is a common feature of many human neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS), TwinF interface inhibitors have the potential to provide neuroprotection across a broad spectrum of these diseases.
    Keywords:  ER–mitochondria contact sites; NMDAR/TRPM4 complex; TwinF interface inhibitor; endoplasmic reticulum; glutamate neurotoxicity; mitochondria; organelle damage
    DOI:  https://doi.org/10.3390/cells14030195
  7. Nat Commun. 2025 Feb 10. 16(1): 1508
    ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress.
    Isshin Shiiba, Naoki Ito, Hijiri Oshio, Yuto Ishikawa, Takahiro Nagao, Hiroki Shimura, Kyu-Wan Oh, Eiki Takasaki, Fuya Yamaguchi, Ryoan Konagaya, Hisae Kadowaki, Hideki Nishitoh, Takehito Tanzawa, Shun Nagashima, Ayumu Sugiura, Yuuta Fujikawa, Keitaro Umezawa, Yasushi Tamura, Byung Il Lee, Yusuke Hirabayashi, Yasushi Okazaki, Tomohiro Sawa, Ryoko Inatome, Shigeru Yanagi.
      The proximal domains of mitochondria and the endoplasmic reticulum (ER) are linked by tethering factors on each membrane, allowing the efficient transport of substances, including lipids and calcium, between them. However, little is known about the regulation and function of mitochondria-ER contacts (MERCs) dynamics under mitochondrial damage. In this study, we apply NanoBiT technology to develop the MERBiT system, which enables the measurement of reversible MERCs formation in living cells. Analysis using this system suggests that induction of mitochondrial ROS increases MERCs formation via RMDN3 (also known as PTPIP51)-VAPB tethering driven by RMDN3 phosphorylation. Disruption of this tethering caused lipid radical accumulation in mitochondria, leading to cell death. The lipid radical transfer activity of the TPR domain in RMDN3, as revealed by an in vitro liposome assay, suggests that RMDN3 transfers lipid radicals from mitochondria to the ER. Our findings suggest a potential role for MERCs in cell survival strategy by facilitating the removal of mitochondrial lipid radicals under mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-025-56666-4
  8. Int J Mol Sci. 2025 Jan 22. pii: 894. [Epub ahead of print]26(3):
    Endoplasmic Reticulum-Mitochondria Crosstalk in Fuchs Endothelial Corneal Dystrophy: Current Status and Future Prospects.
    Anisha Kasi, William Steidl, Varun Kumar.
      Fuchs endothelial corneal dystrophy (FECD) is a progressive and debilitating disorder of the corneal endothelium (CE) that affects approximately 4% of individuals over the age of 40. Despite the burden of the disease, the pathogenesis of FECD remains poorly understood, and treatment options are limited, highlighting the need for deeper investigation into its underlying molecular mechanisms. Over the past decade, studies have indicated independent contributions of endoplasmic reticulum (ER) and mitochondrial stress to the pathogenesis of FECD. However, there are limited studies suggesting ER-mitochondria crosstalk in FECD. Recently, our lab established the role of chronic ER stress in inducing mitochondrial dysfunction for corneal endothelial cells (CEnCs), indicating the existence of ER-mitochondria crosstalk in FECD. This paper aims to provide a comprehensive overview of the current understanding of how ER and mitochondrial stress contribute to FECD pathogenesis. The paper also reviews the literature on the mechanisms of ER-mitochondria crosstalk in other diseases relevant to FECD.
    Keywords:  ER stress; Fuchs; MAMs; crosstalk; mitochondrial stress
    DOI:  https://doi.org/10.3390/ijms26030894
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