bims-mecosi Biomed News
on Membrane contact sites
Issue of 2026–05–03
eight papers selected by
Verena Kohler, Umeå University
  1. Mechanistic dissection of BLTP2 targeting to ER-PM contact sites.
  2. Structural and Functional Alterations of MAMs and Their Immunomodulatory Roles in Sepsis-Induced Lung Injury.
  3. Mitochondria-lipid droplet communication remodels bioenergetic metabolism in cardiovascular diseases.
  4. Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
  5. Regulation of the Cell Wall Integrity pathway at the contact site between mating partners in yeast.
  6. Pro- and anti-viral functions of lipid droplets in infection at a glance.
  7. Diel remodeling and cellular integration of the nitroplast.
  8. Bone marrow mesenchymal stem cell-derived exosomes deliver miR-21a-5p to alleviate paraquat-induced acute lung injury by regulating endoplasmic reticulum-mitochondria contacts and pyroptosis in alveolar macrophages.
  1. bioRxiv. 2026 Apr 13. pii: 2026.04.12.718032. [Epub ahead of print]
    Mechanistic dissection of BLTP2 targeting to ER-PM contact sites.
    Sarah D Neuman, Amy T Cavanagh, Nicole Sheffels, Elizabeth Conibear, Arash Bashirullah.
      The bridge-like lipid transfer proteins (BLTPs) are a novel superfamily of rod-shaped lipid transporters that engage in bulk non-vesicular movement of lipids at organelle membrane contact sites. The molecular and cellular functions of these proteins are still emerging; however, it is clear that one key aspect that regulates BLTP function is targeting to the appropriate membrane contact site(s). Here, we use Drosophila as a model system to dissect the mechanisms that drive targeting of BLTP2 ( hobbit in Drosophila ) to endoplasmic reticulum-plasma membrane (ER-PM) contact sites. We demonstrate that a conserved adapter protein, which we name bilbobaggins ( bbo ), is required for targeting of Hobbit to ER-PM contacts; importantly, loss of bbo phenocopies loss of hobbit , indicating that bbo is required for hobbit function. Additionally, our structure-function analyses show that cis -acting sequences in the C-terminal tail of Hobbit are also required for ER-PM targeting. Crucially, our data indicates that that these cis -acting sequences and Bbo binding are independent and likely sequential mechanisms that we propose function like a "hook" and "latch" to govern Hobbit targeting. Thus, we define a new regulatory paradigm governing targeting of BLTPs to membrane contact sites.
    DOI:  https://doi.org/10.64898/2026.04.12.718032
  2. J Immunol Res. 2026 ;2026(1): e9888339
    Structural and Functional Alterations of MAMs and Their Immunomodulatory Roles in Sepsis-Induced Lung Injury.
    Yihao Wang, Jingran Yang, Xia Li.
       BACKGROUND: Sepsis-induced acute lung injury (SI-ALI) is a major cause of morbidity and mortality among septic patients. Recent evidence highlights the role of mitochondria-associated membranes (MAMs)-specialized contact sites between the endoplasmic reticulum (ER) and mitochondria-in regulating calcium signaling, lipid metabolism, energy homeostasis, and immune responses. Structural and functional alterations of MAMs are increasingly recognized as critical contributors to the pathogenesis of SI-ALI.
    OBJECTIVES: This review aims to summarize the structural and functional characteristics of MAMs, elucidate their alterations and immunoregulatory roles in sepsis-induced lung injury, and discuss potential therapeutic strategies targeting MAMs to mitigate pulmonary damage.
    METHODS: A comprehensive literature review was conducted using recent studies focused on the molecular structure, signaling mechanisms, and pathological changes of MAMs in sepsis and related inflammatory diseases. Emphasis was placed on calcium signaling, mitochondrial dysfunction, oxidative stress, and inflammasome activation.
    RESULTS: MAMs maintain close ER-mitochondria contacts (10-30 nm) through key proteins such as inositol 1,4,5-trisphosphate receptor (IP3R), glucose-regulated protein 75 (GRP75), voltage-dependent anion channel (VDAC), and mitofusin-2 (MFN2). During sepsis, oxidative stress and inflammatory cytokines disrupt these contacts, leading to impaired calcium transfer, mitochondrial dysfunction, and energy deficiency. Dysregulated MAMs promote NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, excessive reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) release, thereby amplifying inflammatory cascades and immune cell apoptosis. Therapeutic strategies that restore MAM integrity-such as upregulating MFN2, activating ER autophagy, or modulating calcium transport proteins-have shown potential to attenuate lung injury by improving mitochondrial metabolism and reducing oxidative stress.
    CONCLUSIONS: MAMs play essential roles in maintaining intracellular homeostasis and immune balance. Their structural and functional disruption contributes significantly to the progression of SI-ALI. Targeting MAMs offers promising therapeutic opportunities for preventing and treating sepsis-induced lung injury, although further mechanistic and clinical studies are warranted to translate these findings into practice.
    Keywords:  MAMs; endoplasmic reticulum; immune regulation; inflammatory response; mitochondria; septic lung injury; structural and functional changes
    DOI:  https://doi.org/10.1155/jimr/9888339
  3. Pharmacol Res. 2026 Apr 28. pii: S1043-6618(26)00135-0. [Epub ahead of print]228 108220
    Mitochondria-lipid droplet communication remodels bioenergetic metabolism in cardiovascular diseases.
    Zhongyang Chi, Wei Deng, Saiyang Xie.
      The heart's high energy demands are primarily fulfilled through mitochondrial fatty acid (FA) β-oxidation, with lipid droplets (LDs) being the main source of FAs. Research indicates that cardiac lipid homeostasis relies on a dynamic interaction between LDs and mitochondria, facilitated by specialized membrane contact sites (MCSs). These sites are marked by essential proteins such as the Perilipin (PLIN) family, mitochondrial dynamics proteins, and Rab GTPases, forming an efficient pathway for transferring FAs from storage to mitochondrial oxidation. This protective mechanism helps to avert the accumulation of lipotoxic intermediates while supporting lipid synthesis during periods of nutrient surplus. Conversely, the dysregulation of this mitochondria-LD axis is often implicated in various metabolic cardiovascular diseases (CVDs), including heart failure, atherosclerosis, and diabetic cardiomyopathy. Such imbalances lead to interconnected pathological processes, including cardiomyocyte lipotoxicity and mitochondrial dysfunction, which ultimately contribute to myocardial injury and pathological cardiac growth and fibrosis. This review comprehensively examines the current understanding of this intricate organelle crosstalk, emphasizing its structural and functional aspects, diverse biological roles, and significant implications for CVD pathogenesis. A deeper insight into and targeted modulation of this axis could pave the way for innovative therapeutic strategies aimed at addressing metabolic CVDs.
    Keywords:  Cardiovascular diseases; Lipid droplet; Lipid metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.phrs.2026.108220
  4. Nucleic Acids Res. 2026 Apr 23. pii: gkag233. [Epub ahead of print]54(8):
    Mitochondrial DNA replication is regulated by endoplasmic reticulum-mitochondrial contact sites, the mitochondrial calcium uniporter, and manganese.
    Amaia Lopez de Arbina, Angelica Zamudio-Ochoa, Mikel Muñoz-Oreja, Diego Perez-Rodriguez, Laura Mosqueira-Martín, Rebecca Lasalandra, Marina Villar-Fernandez, Uxoa Fernandez-Pelayo, Laura Rodriguez-Gomez, Seungtae Lee, Francisco Gil-Bea, Nerea Osinalde, Ainara Vallejo-Illaramendi, Dmitry Temiakov, Antonella Spinazzola, Ian J Holt.
      Mitochondrial DNA replication occurs at contact sites between the endoplasmic reticulum (ER) and mitochondria (ERMCS). Beyond the known role of the tubular ER protein RTN4, the factors regulating this process are poorly defined. Here, we show that repressing the ER protein ERLIN2 in human fibroblasts depletes ER-mitochondrial contact sites and inhibits mitochondrial DNA replication, as does silencing RTN4 or the ER-mitochondrial tether GRP75. GRP75 or RTN4 scarcity also decreases the level of the mitochondrial calcium uniporter (MCU), whose inhibition blocks mitochondrial DNA synthesis. Because ERMCS depletion did not diminish mitochondrial calcium, and MCU complex can transport manganese, we tested whether manganese could bypass these defects. Manganese supplementation restored mitochondrial DNA replication in cells lacking ERMCS or with inhibited MCU, identifying manganese as a critical mediator. We then considered mitochondrial transcription as a potential manganese target, since it provides both transcripts for gene expression and primers for DNA replication. In vitro, manganese inhibits transcription re-start and stimulates RNA synthesis at the light-strand origin of replication. These findings support a model in which ER-mitochondrial contact sites, in conjunction with MCU, deliver manganese from the ER to mitochondria to promote DNA replication, potentially by modulating mitochondrial RNA polymerase activity.
    DOI:  https://doi.org/10.1093/nar/gkag233
  5. J Cell Biol. 2026 Jul 06. pii: e202508068. [Epub ahead of print]225(7):
    Regulation of the Cell Wall Integrity pathway at the contact site between mating partners in yeast.
    Erin R Curtis, Aarshi Jain, Daniel J Lew.
      The fungal cell wall is constantly remodeled to allow cell growth, but any holes in the cell wall would lead to catastrophic lysis. The "Cell Wall Integrity" pathway (CWI) detects cell wall defects and promotes cell wall thickening or repair to protect cell integrity. However, cell walls must be removed at contact sites between fusing cells during mating or mycelium formation. Here, we show that in Saccharomyces cerevisiae, the CWI is downregulated specifically at the contact site between mating cells. A key component of the CWI, Pkc1, accumulated at polarity sites (shmoo tips) in cells exposed to mating pheromone, but not at contact sites. Pkc1 exclusion required a cell wall protein, Fig2, induced by pheromone. In mutants lacking Fig2, cell wall removal was delayed, blocked, or even reversed after transient fusion, leading to reduced mating. These results suggest that Fig2 designates the contact site as a "safe" spot to degrade the cell wall.
    DOI:  https://doi.org/10.1083/jcb.202508068
  6. J Cell Sci. 2026 Apr 15. pii: jcs264409. [Epub ahead of print]139(8):
    Pro- and anti-viral functions of lipid droplets in infection at a glance.
    Kim Chi Thi Vu, Laura Bierau, Eva Herker.
      Lipid droplets (LDs) were long regarded as passive storage organelles for neutral lipids as this is the most efficient way to store energy. Recently, however, they have emerged as highly dynamic and heterogenous organelles that act as central hubs of lipid metabolic pathways. LDs provide lipids for energy production, supply precursor metabolites for many lipid classes, incorporate lipids under lipotoxic insults and are interconnected with other organelles through membrane contact sites. Viruses and all other obligate intracellular pathogens rely on metabolic networks in the host cell - including lipid metabolic pathways - for replication. Enveloped viruses need lipids for viral envelope formation, and positive-sense RNA viruses require lipids for formation of the membranous compartments in which they replicate. Additionally, like all intracellular pathogens, viruses require energy for their replicative cycle. Therefore, it is not surprising that several strategies have evolved by which viruses exploit various aspects of LD biology. Furthermore, recent evidence suggests that LDs might also have a function in inflammation. Both pro- and anti-viral roles of lipid droplets are discussed in this article.
    Keywords:  Lipid droplets; Lipid metabolism; Virion morphogenesis; Virus host interaction; Virus replication
    DOI:  https://doi.org/10.1242/jcs.264409
  7. bioRxiv. 2026 Apr 14. pii: 2026.04.11.717942. [Epub ahead of print]
    Diel remodeling and cellular integration of the nitroplast.
    Ethan H Li, Tyler Coale, Gaëlle Toullec, Artur Czajkowski, Pierre Henri Jouneau, Tim M Dederichs, Chandni Bhickta, Zachary Raymond, Kyoko Hagino, Vitor Hugo Balasco Serrão, Jotham Austin, Wanda M Figueroa-Cuilan, Yannick Schwab, Francisco M Cornejo-Castillo, Jonathan Zehr, Johan Decelle, Mohammed Kaplan.
      Nitrogen-fixing eukaryotes were not believed to exist in nature until the recent discovery of a N 2 -fixing organelle, or nitroplast, in the marine microalga Braarudosphaera bigelowii . This nitroplast (formerly known as UCYN-A2) has long been recognized as key cyanobacterial contributor to global oceanic N₂ fixation. However, how this novel organelle is integrated and regulated within the architecture of a eukaryotic cell remains unclear. Here, we combine multiscale volumetric imaging with cryo-electron tomography to resolve the native architecture, cellular integration, and diel remodeling of the nitroplast in cultured and environmental cells. We find that the nitroplast occupies up to 10% of the cell volume and exhibits close interfaces with multiple host organelles through membrane contact sites, while integration of this metabolically demanding compartment does not disrupt global scaling of host organelles. Interestingly, the chloroplast-to-nitroplast volume ratio is conserved across distinct life stages. Cryo-electron tomography reveals that the nitroplast retains a reinforced four-layer cyanobacterial envelope and is additionally surrounded by two host-derived layers that remodel across the day-night cycle. During daytime N₂ fixation, these host-derived barriers become locally discontinuous and the organelle interface becomes enriched with two distinct vesicle populations. Our findings suggest that dynamic control of organelle accessibility through transient membrane gating represents a fundamental strategy by which eukaryotic cells could domesticate new endosymbiotic functions during early organellogenesis.
    DOI:  https://doi.org/10.64898/2026.04.11.717942
  8. Int Immunopharmacol. 2026 Apr 30. pii: S1567-5769(26)00497-2. [Epub ahead of print]181 116652
    Bone marrow mesenchymal stem cell-derived exosomes deliver miR-21a-5p to alleviate paraquat-induced acute lung injury by regulating endoplasmic reticulum-mitochondria contacts and pyroptosis in alveolar macrophages.
    Shiwen Liu, Yijian Chen, Yuxi Feng, Yisheng Huang, Baolin Zhong, Enjun Lei.
      Paraquat-induced acute lung injury (ALI) is characterized by a high mortality rate and the absence of effective treatment options. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) possess therapeutic potential in tissue repair and the regulation of inflammation, but the molecular pathways underlying these actions are still poorly understood. This study aimed to clarify whether BMSC-Exos protect lung tissue by delivering miR-21a-5p to modulate endoplasmic reticulum-mitochondria contact sites (ERMCSs) in alveolar macrophages. Using a mouse model of paraquat-induced ALI, we intervened with BMSC-Exos and a miR-21a-5p inhibitor and systematically evaluated inflammatory response, pyroptosis signaling, and mitochondrial homeostasis via molecular biology, ultrastructure, electrophysiology, and metabolomics. BMSC-Exos promoted the formation of ERMCSs by increasing Mfn2 and VDAC1 expression, which consequently improved mitochondrial function and restrained NLRP3-Caspase-1-GSDMD-dependent pyroptosis. Disruption of ERMCSs abolished these protective effects. This study reveals a novel mechanism through which BMSC-Exos reprogram macrophage metabolism via miR-21a-5p delivery and suggests new targets for precision therapy in acute toxic lung injury.
    Keywords:  Acute lung injury; Bone marrow mesenchymal stem cell-derived exosomes; Endoplasmic reticulum-mitochondria contact site; Mitochondrial homeostasis; Pyroptosis; miR-21a-5p
    DOI:  https://doi.org/10.1016/j.intimp.2026.116652
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