bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–01–12
seven papers selected by
Verena Kohler, Umeå University
  1. Rickettsia parkeri forms extensive, stable contacts with the rough endoplasmic reticulum.
  2. Elevating VAPB-PTPIP51 integration repairs damaged mitochondria-associated endoplasmic reticulum membranes and inhibits lung fibroblasts activation.
  3. Biological Basis of Cell Trafficking: A General Overview.
  4. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  5. Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.
  6. Intranasal insulin administration affecting perioperative neurocognitive dysfunction by regulating calcium transport protein complex IP3R/GRP75/VDAC1 on MAMs.
  7. Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM.
  1. J Cell Biol. 2025 Mar 03. pii: e202406122. [Epub ahead of print]224(3):
    Rickettsia parkeri forms extensive, stable contacts with the rough endoplasmic reticulum.
    Yamilex Acevedo-Sánchez, Patrick J Woida, Caroline Anderson, Stephan Kraemer, Rebecca L Lamason.
      Upon invasion into the host cell, a subset of bacterial pathogens resides exclusively in the cytosol. While previous research revealed how they reshape the plasma membrane during invasion, subvert the immune response, and hijack cytoskeletal dynamics to promote their motility, it was unclear if these pathogens also interacted with the organelles in this crowded intracellular space. Here, we examined if the obligate intracellular pathogen Rickettsia parkeri interacts with the endoplasmic reticulum (ER), a large and dynamic organelle spread throughout the cell. Using live-cell microscopy and transmission and focused-ion-beam scanning electron microscopy, we show that R. parkeri forms extensive contacts with the rough ER that are ∼55 nm apart and cover more than half the bacterial surface. Depletion of the ER-specific tethers VAPA and VAPB reduced rickettsia-ER contacts, and VAPA and VAPB were localized around intracellular rickettsiae. Overall, our findings illuminate an interkingdom ER contact uniquely mediated by rickettsiae that mimics some characteristics of traditional host membrane contact sites.
    DOI:  https://doi.org/10.1083/jcb.202406122
  2. Int Immunopharmacol. 2025 Jan 03. pii: S1567-5769(24)02504-9. [Epub ahead of print]147 113982
    Elevating VAPB-PTPIP51 integration repairs damaged mitochondria-associated endoplasmic reticulum membranes and inhibits lung fibroblasts activation.
    Jiaqi Ban, Hongru Tian, Yungeng Wei, Lihong Ao, Hequn Gu, Jiamin Zeng, Xiao Peng, Chunyan Ao, Yanzi Zhang, Xiu He, Hua Zhao, Jun Li.
      Long-term silica exposure to silica dust leads to irreversible pulmonary fibrosis, during which lung fibroblast activation plays an essential role. Mitochondria-associated endoplasmic reticulum membranes (MAMs) is a structural interface for communication between the outer mitochondrial membrane and the endoplasmic reticulum. VAPB-PTPIP51 is a key complex on MAMs. However, the role of VAPB-PTPIP51-linked MAMs in lung fibroblast activation remains under investigation. In this study, we observed mitochondrial damage and endoplasmic reticulum stress in a SiO2-induced lung fibrosis model using C57BL/6J mice. In the model of TGF-β1-induced mouse lung fibroblast (MLG) activation, interventions with Dioscin and TUDCA reduced mitochondrial damage and alleviated endoplasmic reticulum stress by repairing damaged MAMs. Additionally, TUDCA may restore the MAMs structure by enhancing the interaction between VAPB and PTPIP51. Our findings indicate that MAMs may play a crucial role in linking mitochondrial damage and endoplasmic reticulum stress, suggesting their potential involvement in fibroblast activation.
    Keywords:  Endoplasmic reticulum stress; Lung fibroblast; Mitochondria-associated endoplasmic reticulum membranes; Mitochondrial damage; VAPB-PTPIP51
    DOI:  https://doi.org/10.1016/j.intimp.2024.113982
  3. J Inherit Metab Dis. 2025 Jan;48(1): e12839
    Biological Basis of Cell Trafficking: A General Overview.
    Helena Gimeno-Agud, Yaiza Díaz-Osorio, Alfonso Oyarzábal.
      Cell trafficking is a tightly regulated biological process for the exchange of signals and metabolites between cell compartments, including four main processes: membrane trafficking (transport of membrane-bound vesicles), autophagy, transport along the cytoskeleton, and membrane contact sites. These processes are cross-sectional to cellular functions, ranging from the transportation of membrane proteins, membranes, and organelles to the elimination of damaged proteins and organelles. In consequence, cell trafficking is crucial for cell survival and homeostasis, serving as a cornerstone for cellular communication and facilitating interactions both with the surrounding environment and between different organelles. Disorders of cell trafficking are clinically and pathophysiological diverse and complex and form the largest group in the recent International Classification of Inherited Metabolic Disorders (ICIMD). In this review, we explore the four categories of cell trafficking and the biological principles that drive these processes. Instead of delving profoundly into each pathway, as comprehensive reviews on those topics already exist, we offer a broad overview of the molecular mechanisms behind cell trafficking, providing a foundational understanding to ease their entry into this subject and enhance comprehension of the other articles featured in this Special Issue.
    Keywords:  autophagy; cell trafficking; cytoskeleton; endocytosis; exocytosis; membrane contact sites; membrane trafficking
    DOI:  https://doi.org/10.1002/jimd.12839
  4. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  5. J Med Chem. 2025 Jan 08.
    Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.
    Mikel Etxebeste-Mitxeltorena, Hector Flores-Romero, Sandra Ramos-Inza, Esther Masiá, Maria Nenchova, Jorge Montesinos, Loreto Martinez-Gonzalez, Gracia Porras, Mar Orzáez, María J Vicent, Carmen Gil, Estela Area-Gomez, Ana J Garcia-Saez, Ana Martinez.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control. Using the MERLIN biosensor in a high-throughput screening within the EU-OPENSCREEN ERIC, we discovered small molecules that increase MERCs in HCT116 cells, enhancing their ability to uptake cholesterol. We demonstrated that cholesterol trafficking is decreased in an ALS patient-derived cell model, and this trafficking is restored after treatment with the discovered MERC modulator 24. Electron microscopy revealed that treatment with compound 24 increases MERCs, promotes lipid droplet formation, and restores mitochondrial cristae. Overall, the brain-permeable MERC modulator, compound 24, may serve as a valuable pharmacological tool for studying MAM function and holds potential for in vivo studies in ALS and other MAM dysfunction diseases.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01368
  6. Free Radic Biol Med. 2025 Jan 04. pii: S0891-5849(25)00006-1. [Epub ahead of print]228 240-250
    Intranasal insulin administration affecting perioperative neurocognitive dysfunction by regulating calcium transport protein complex IP3R/GRP75/VDAC1 on MAMs.
    Huiqin Liu, Yanhua Jiang, Lianhui Cong, Xinyue Zhang, Yongjian Zhou, Xue Pan, Sidan Liu, Renyi Wang, Xuezhao Cao.
      Perioperative neurocognitive disorders (PND) are common complications following surgery and anesthesia, especially in the elderly. These disorders are associated with disruptions in neuronal energy metabolism and mitochondrial function. This study explores the potential of intranasal insulin administration as a therapeutic strategy to prevent PND by targeting the calcium transport protein complex IP3R/GRP75/VDAC1 on mitochondria-associated endoplasmic reticulum membranes (MAMs).
    METHODS: Male C57BL/6J mice underwent partial hepatectomy to induce PND and were subsequently treated with either intranasal insulin or saline. Cognitive function was evaluated using the Morris water maze test, and hippocampal tissue was analyzed for calcium transport protein complex IP3R/GRP75/VDAC1 expression and apoptosis markers. In vitro, HT22 and BV2 cell co-cultures were utilized to simulate surgical injury, with IP3R knockdown employed to assess its effects on oxidative stress and apoptosis.
    RESULTS: Intranasal insulin effectively alleviated cognitive impairment as demonstrated by improved performance in the Morris water maze. It significantly reduced neuronal apoptosis and modulated the expression of the IP3R/GRP75/VDAC1 complex, enhancing mitochondrial ATP production and stabilizing MAMs. Furthermore, insulin administration also increased PI3K/AKT signaling, counteracting the impact of surgical stress. In vitro experiments confirmed that IP3R knockdown mitigated inflammation-induced oxidative stress and neuronal apoptosis, while insulin's beneficial effects were blocked by inhibition of the PI3K/AKT pathway.
    CONCLUSION: Intranasal insulin mitigates PND by modulating the IP3R/GRP75/VDAC1 complex and enhancing mitochondrial function through the PI3K/AKT signaling pathway. This study supports the potential of intranasal insulin as a promising therapeutic strategy for preventing and managing PND, potentially leading to improved surgical outcomes for elderly patients.
    Keywords:  Calcium transport protein complex; Intranasal insulin; Mitochondria-associated ER membranes; Mitochondrial dysfunction; Perioperative neurocognitive disorders
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.006
  7. Biomolecules. 2024 Nov 26. pii: 1505. [Epub ahead of print]14(12):
    Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM.
    Gayoung Ryu, Minjeong Ko, Sooyeon Lee, Se In Park, Jin-Woong Choi, Ju Yeon Lee, Jin Young Kim, Ho Jeong Kwon.
      An ellagitannin-derived metabolite, Urolithin A (UA), has emerged as a potential therapeutic agent for metabolic disorders due to its antioxidant, anti-inflammatory, and mitochondrial function-improving properties, but its efficacy in protecting against ER stress remains underexplored. The endoplasmic reticulum (ER) is a cellular organelle involved in protein folding, lipid synthesis, and calcium regulation. Perturbations in these functions can lead to ER stress, which contributes to the development and progression of metabolic disorders such as metabolic-associated fatty liver disease (MAFLD). In this study, we identified a novel target protein of UA and elucidated its mechanism for alleviating palmitic acid (PA)-induced ER stress. Cellular thermal shift assay (CETSA)-LC-MS/MS analysis revealed that UA binds directly to the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), an important regulator of calcium homeostasis in mitochondria-associated ER membranes (MAMs). As an agonist of SERCA, UA attenuates abnormal calcium fluctuations and ER stress in PA-treated liver cells, thereby contributing to cell survival. The lack of UA activity in SERCA knockdown cells suggests that UA regulates cellular homeostasis through its interaction with SERCA. Collectively, our results demonstrate that UA protects against PA-induced ER stress and enhances cell survival by regulating calcium homeostasis in MAMs through SERCA. This study highlights the potential of UA as a therapeutic agent for metabolic disorders associated with ER stress.
    Keywords:  CETSA-LC-MS/MS; ER stress; MAFLD; MAM; SERCA; Urolithin A
    DOI:  https://doi.org/10.3390/biom14121505
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