bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–03–23
ten papers selected by
Verena Kohler, Umeå University
  1. Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
  2. Comparative Analysis of SPLICS and MCS-DETECT for Detecting Mitochondria-ER Contact Sites (MERCs).
  3. STIM1/2 maintain signaling competence at ER-PM contact sites during neutrophil spreading.
  4. Lipid juggling: Any1 scrambles membranes for endosome biogenesis.
  5. ZDHHC9-Mediated PKG1 Affects Osteogenesis by Regulating MAMs in T2DM.
  6. Pharmacological landscape of endoplasmic reticulum stress: Uncovering therapeutic avenues for metabolic diseases.
  7. Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane.
  8. Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors.
  9. Inhibition of Endoplasmic Reticulum Oxidoreductin 1 modulates neuronal excitability and nociceptive sensitivity in mice.
  10. The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.
  1. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251329250
    Mitochondria-Lysosome Contact Sites: Emerging Players in Cellular Homeostasis and Disease.
    Francesca Rizzollo, Patrizia Agostinis.
      Mitochondria and lysosomes regulate a multitude of biological processes that are essential for the maintenance of nutrient and metabolic homeostasis and overall cell viability. Recent evidence reveals that these pivotal organelles, similarly to others previously studied, communicate through specialized membrane contact sites (MCSs), hereafter referred to as mitochondria-lysosome contacts (or MLCs), which promote their dynamic interaction without involving membrane fusion. Signal integration through MLCs is implicated in key processes, including mitochondrial fission and dynamics, and the exchange of calcium, cholesterol, and amino acids. Impairments in the formation and function of MLCs are increasingly associated with age-related diseases, specifically neurodegenerative disorders and lysosomal storage diseases. However, MLCs may play roles in other pathological contexts where lysosomes and mitochondria are crucial. In this review, we introduce the methodologies used to study MLCs and discuss known molecular players and key factors involved in their regulation in mammalian cells. We also argue other potential regulatory mechanisms depending on the acidic lysosomal pH and their impact on MLC's function. Finally, we explore the emerging implications of dysfunctional mitochondria-lysosome interactions in disease, highlighting their potential as therapeutic targets in cancer.
    Keywords:  lysosome; membrane contact sites; mitochondria; mitochondria-lysosome contacts
    DOI:  https://doi.org/10.1177/25152564251329250
  2. Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251313721
    Comparative Analysis of SPLICS and MCS-DETECT for Detecting Mitochondria-ER Contact Sites (MERCs).
    Jieyi Zheng, Ben Cardoen, Milene Ortiz-Silva, Ghassan Hamarneh, Ivan R Nabi.
      Detection of mitochondria-ER contacts (MERCs) from diffraction limited confocal images commonly uses fluorescence colocalization analysis of mitochondria and endoplasmic reticulum (ER) as well as split fluorescent probes, such as the split-GFP-based contact site sensor (SPLICS). However, inter-organelle distances (∼10-60 nm) for MERCs are lower than the 200-250 nm diffraction limited resolution obtained by standard confocal microscopy. Super-resolution microscopy of 3D volume analysis provides a two-fold resolution improvement (∼120 nm XY; 250 nm Z), which remains unable to resolve MERCs. MCS-DETECT, a membrane contact site (MCS) detection algorithm faithfully detects elongated ribosome-studded riboMERCs when applied to 3D STED super-resolution image volumes. Here, we expressed the SPLICSL reporter in HeLa cells co-transfected with the ER reporter RFP-KDEL and label fixed cells with antibodies to RFP and the mitochondrial protein TOM20. MCS-DETECT analysis of 3D STED volumes was compared to contacts determined by co-occurrence colocalization analysis of mitochondria and ER or the SPLICSL probe. Percent mitochondria coverage by MCS-DETECT derived contacts was significantly smaller than those obtained for colocalization analysis or SPLICSL, and more closely matched contact site metrics obtained by 3D electron microscopy. Further, STED analysis localized a subset of the SPLICSL label to mitochondria with some SPLICSL puncta observed to be completely enveloped by mitochondria in 3D views. These data suggest that MCS-DETECT reports on a limited set of MERCs that more closely corresponds to those observed by EM.
    Keywords:  MCS-DETECT; SPLICS; mitochondria-ER contact sites; stimulated emission depletion microscopy; super-resolution microscopy
    DOI:  https://doi.org/10.1177/25152564251313721
  3. J Cell Biol. 2025 May 05. pii: e202406053. [Epub ahead of print]224(5):
    STIM1/2 maintain signaling competence at ER-PM contact sites during neutrophil spreading.
    Camille Rabesahala de Meritens, Amado Carreras-Sureda, Nicolas Rosa, Robert Pick, Christoph Scheiermann, Nicolas Demaurex.
      Neutrophils are highly motile leukocytes that migrate inside tissues to destroy invading pathogens. Ca2+ signals coordinate leukocytes migration, but whether Ca2+ fluxes mediated by Stim proteins at ER-PM contact sites regulate neutrophil actin-based motility is unclear. Here, we show that myeloid-specific Stim1/2 ablation decreases basal cytosolic Ca2+ levels and prevents adhesion-induced Ca2+ elevations in mouse neutrophils, reducing actin fiber formation and impairing spreading. Unexpectedly, more ER-PM contact sites were detected on the actin-poor adhesive membranes of Stim1/2-deficient neutrophils, which had reduced inositol-1,4,5-trisphosphate receptor (IP3R) immunoreactivity on confocal and immunogold micrographs despite preserved IP3R levels on western blots. Remarkably, Stim1/2-deficient neutrophils regained signaling and spreading competence in Ca2+-rich solutions and were recruited more effectively in mouse inflamed cremaster muscles in vivo. Our findings indicate that Stim1/2 preserve IP3R functionality in neutrophils, generating adhesion-dependent Ca2+ signals that control actin dynamics during neutrophil spreading. Stim proteins thus maintain IP3R signaling competence at adhesive membranes, enabling Ca2+-dependent actin remodeling during spreading in mouse neutrophils.
    DOI:  https://doi.org/10.1083/jcb.202406053
  4. J Cell Biol. 2025 Apr 07. pii: e202502158. [Epub ahead of print]224(4):
    Lipid juggling: Any1 scrambles membranes for endosome biogenesis.
    Sinead Iduna Schwabl, Konstantin Adrian Siegmann, David Teis.
      Multivesicular bodies (MVBs) are crucial for membrane protein degradation and lipid homeostasis. A recent study by Gao and colleagues (https://doi.org/10.1083/jcb.202410013) identifies Any1 as a phospholipid scramblase that plays an important role in MVB biogenesis by coordinating membrane remodeling with lipid transfer through Vps13 at organelle contact sites.
    DOI:  https://doi.org/10.1083/jcb.202502158
  5. J Dent Res. 2025 Mar 18. 220345251321776
    ZDHHC9-Mediated PKG1 Affects Osteogenesis by Regulating MAMs in T2DM.
    B Y Li, G Q Ma, H D Gui, S J Zhou, Y X Liu, A L Wu, Q X He, J Y Chen, J Y Diao, D N Wu, X Xu, D J Zhang.
      Palmitoylation is recognized as a prevalent posttranslational modification of proteins, which is highlighted in recent studies as a key player in regulating protein stability, subcellular localization, membrane transport, and other cellular biological processes. However, its role in peri-implant osteogenesis under type 2 diabetes mellitus (T2DM) remains unclear. During this study, the in vitro high-glucose model based on MC3T3-E1 cells demonstrated that a high-glucose environment in vitro markedly inhibited osteoblasts proliferation and osteogenesis; meanwhile, ZDHHC9 emerged as a significantly upregulated protein. Then, Zdhhc9 knockdown improved the dysfunction of osteoblasts and peri-implant osteogenesis of T2DM mice. In addition, co-immunoprecipitation and fluorescence co-localization analysis revealed an interaction between ZDHHC9 and cyclic guanosine monophosphate (GMP)-dependent protein kinase G 1 (PKG1), and silencing of Prkg1 prevented the improvement in osteoblasts with Zdhhc9 knockdown. Furthermore, we verified that Zdhhc9 knockdown and Prkg1 silencing altered the distance between the endoplasmic reticulum and mitochondria and the expression of mitochondria-associated endoplasmic reticulum membranes (MAMs)-related proteins in osteoblasts. Collectively, our data show that ZDHHC9 could regulate MAMs through palmitoylation of PKG1 to induce osteoblast dysfunction in T2DM. ZDHHC9 might become a novel therapeutic target for peri-implant osteogenesis in diabetes patients.
    Keywords:  bone remodeling/regeneration; cell differentiation; dental implant(s); diabetes; osteoblast(s); palmitoylation
    DOI:  https://doi.org/10.1177/00220345251321776
  6. Eur J Pharmacol. 2025 Mar 13. pii: S0014-2999(25)00263-8. [Epub ahead of print]998 177509
    Pharmacological landscape of endoplasmic reticulum stress: Uncovering therapeutic avenues for metabolic diseases.
    Ghallab Alotaibi, Abdullah Alkhammash.
      The endoplasmic reticulum (ER) plays a fundamental role in maintaining cellular homeostasis by ensuring proper protein folding, lipid metabolism, and calcium regulation. However, disruptions to ER function, known as ER stress, activate the unfolded protein response (UPR) to restore balance. Chronic or unresolved ER stress contributes to metabolic dysfunctions, including insulin resistance, non-alcoholic fatty liver disease (NAFLD), and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Recent studies have also highlighted the importance of mitochondria-ER contact sites (MERCs) and ER-associated inflammation in disease progression. This review explores the current pharmacological landscape targeting ER stress, focusing on therapeutic strategies for rare metabolic and neurodegenerative diseases. It examines small molecules such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA), repurposed drugs like 17-AAG (17-N-allylamino-17demethoxygeldanamycin (tanespimycin)) and berberine, and phytochemicals such as resveratrol and hesperidin. Additionally, it discusses emerging therapeutic areas, including soluble epoxide hydrolase (sEH) inhibitors for metabolic disorders and MERCs modulation for neurological diseases. The review emphasizes challenges in translating these therapies to clinical applications, such as toxicity, off-target effects, limited bioavailability, and the lack of large-scale randomized controlled trials (RCTs). It also highlights the potential of personalized medicine approaches and pharmacogenomics in optimizing ER stress-targeting therapies.
    Keywords:  Endoplasmic reticulum (ER) stress; Mitochondria-ER contact sites (MERCs); Protein folding disorders; Tauroursodeoxycholic acid (TUDCA); Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177509
  7. Nat Commun. 2025 Mar 19. 16(1): 2725
    Septin5 deletion enhances β-cell exocytosis by releasing microtubule-tethered insulin granules onto plasma membrane.
    Li Xie, Fei Kang, Tairan Qin, Youhou Kang, Tao Liang, Huanli Xie, Carol D Froese, Hong Xie, Aaron Au, Christopher M Yip, William S Trimble, Herbert Y Gaisano.
      Septin5 interacts with SNARE proteins to regulate exocytosis in neurons, but its role in pancreatic β-cells is unknown. Here, we report that Septin5 is abundant in rodent and human β-cells, deletion of which dramatically enhances biphasic glucose-stimulated insulin secretion, including in type 2 diabetes (T2D). Super-resolution imaging shows that Septin5 is preferentially assembled in microtubule-plasma membrane contact sites in a microtubule-dependent manner, which provides discrete harbor for secretory granule anchoring. By decreasing the stability of the cortical microtubule meshwork, Septin5 depletion increases insulin granule dynamics and access to the plasma membrane. Analysis of spatiotemporal coupling of fusion events and localized Ca2+ influx through L-type Ca2+ channels show that Septin5 depletion increases releasable granule pool clustering on Ca2+ channels, previously shown to be impaired in T2D, thus rectifying this T2D defect. Hence, inhibition of Septin5 can improve insulin secretion.
    DOI:  https://doi.org/10.1038/s41467-025-57421-5
  8. J Inherit Metab Dis. 2025 Mar;48(2): e70019
    Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors.
    Foudil Lamari, Francis Rossignol, Grant A Mitchell.
      Glycerophospholipids (GPLs) are the main lipid components of cellular membranes. They are implicated in membrane structure, vesicle trafficking, neurotransmission, and cell signalling. GPL molecules are amphiphilic, organized around the three carbons of glycerol. Positions sn-1 and sn-2 are each esterified to a fatty acid (FA). At position sn-3, a phosphate group is linked, which in turn can bind a polar head group, the most prevalent classes being phosphatidic acid (PA, phosphate alone as head group), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and cardiolipin (CL). Pathways of GPL biosynthesis span several cell compartments (endoplasmic reticulum (ER), Golgi mitochondria). Particularly important are mitochondria-associated membranes (MAMs), where the ER and mitochondrial outer membrane are in proximity. After synthesis, GPLs continuously undergo remodelling by FA hydrolysis and re-esterification. Esterification with different FAs alters membrane properties. Many steps in GPL synthesis and remodelling can be mediated by more than one enzyme, suggesting complexity that requires further exploration. The 38 known GPL-related inborn errors are clinically diverse. 23 (61%) have neurologic features, sometimes progressive and severe, particularly developmental delay/encephalopathy in 16 (42%) and spastic paraplegia in 12 (32%). Photoreceptor/neuroretinal disease occurs in 14 (37%). Three present skeletal dysplasias (8%). Most GPL inborn errors have been diagnosed by broad molecular testing. Lipidomics holds promise for diagnostic testing and for the discovery of functionally relevant metabolite profiles for monitoring natural history and treatment response.
    Keywords:  Glycerophospholipid; biosynthesis; cell trafficking; inborn errors of metabolism; remodelling
    DOI:  https://doi.org/10.1002/jimd.70019
  9. Anesthesiology. 2025 Mar 19.
    Inhibition of Endoplasmic Reticulum Oxidoreductin 1 modulates neuronal excitability and nociceptive sensitivity in mice.
    Aislinn D Maguire, Shawn M Lamothe, Muhammad Saad Yousuf, Kree Goss, Jayadeep Rao, Gustavo Tenorio, Sridhar R Kaulagari, Lori Hazlehurst, Jason R Plemel, Anna Mw Taylor, Harley T Kurata, Thomas Simmen, Bradley J Kerr.
       BACKGROUND: In the peripheral nervous system, nociceptors become hyperexcitable in both acute and chronic pain conditions. This phenotype can be mediated by dysregulated calcium, which occurs if the endoplasmic reticulum (ER) and mitochondria fail to buffer it appropriately. The redox enzyme endoplasmic reticulum oxidoreductin 1 (ERO1) regulates calcium transfer at ER-mitochondria contact sites (ERMCS). In this study we hypothesized that inhibiting ERO1 and thereby dampening ERMCS calcium transfer might lower nociceptor hyperexcitability in sensory neurons and pain-like behaviours in mice.
    METHODS: C57BL/6 mice were used for histology, behaviour, and cell culture experiments. Behaviour included thermal tail flick, the formalin hind paw injection model of acute inflammatory pain, and hind paw incision post-surgical pain. Post-mortem human dorsal root ganglia (DRGs) were used for immunohistochemistry and in vitro calcium imaging.
    RESULTS: Here we demonstrate that the α isoform of ERO1 is expressed in mouse dorsal root ganglia (DRGs) across multiple subtypes of mouse sensory neurons. This led us to peripherally administer an ERO1 inhibitor in mice, which acutely reversed nociception in acute inflammatory and post-surgical pain models. We hypothesized that this may be due to reduced excitability of DRG neurons, and tested ERO1 inhibition in vitro. In cultured DRGs, ERO1 inhibition dampened nociceptor excitability and mitochondrial function, suggesting that reduced calcium transfer through ERMCS could be responsible for the behaviour we observed in vivo. We also found ERO1 α expression in human DRGs using immunohistochemistry and previously published single cell RNA sequencing data. Finally, we showed that ERO1 inhibition modulates human sensory neuronal excitability in cultured post-mortem DRGs.
    CONCLUSIONS: We found that ERO1 inhibition dampens mitochondrial function, sensory neuron excitability, and acute pain-like behaviour in mice. Additionally, ERO1 inhibition decreases sensory neuron excitability in post-mortem human sensory neurons in vitro. We propose that targeting ERO1 may be a viable strategy for non-narcotic acute pain relief.
    DOI:  https://doi.org/10.1097/ALN.0000000000005453
  10. J Cell Sci. 2025 Mar 17. pii: jcs.263661. [Epub ahead of print]
    The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.
    Moritz Resch, Johanna S Frickel, Korbinian Dischinger, Rachel Choo Shen Wen, Kai Hell, Max E Harner.
      Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.
    Keywords:  CHCHD10; Mia40; Mic14; Mix17; Protein import; Tom40
    DOI:  https://doi.org/10.1242/jcs.263661
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