bims-mecosi Biomed News
on Membrane contact sites
Issue of 2025–12–21
nine papers selected by
Verena Kohler, Umeå University
  1. RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether.
  2. Restoring metabolic flexibility: targeting organelle interaction networks in the pathogenesis and therapy of MASLD.
  3. Upregulation of MAM by C99 disrupts ACSL4 activity and phospholipid homeostasis in Alzheimer's disease models.
  4. Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.
  5. Identification and validation of biomarkers related to mitochondria-associated endoplasmic reticulum membranes in type 2 diabetes mellitus using peripheral blood transcriptomics.
  6. Jack of all trades - the lipid droplet organization (LDO) proteins are multifunctional organelle surface receptors.
  7. There and back again: a cell biologist's journey from organelles to molecules.
  8. Ribosome-binding protein 1 maintains peroxisome biogenesis.
  9. α7 Nicotinic acetylcholine receptor activation rescues mitochondrial dysfunction in gestational diabetes mellitus by competing with p66Shc for VDAC1 binding.
  1. Nat Commun. 2025 Dec 14. 16(1): 11260
    RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether.
    Zheng Yang, Shintaro Nakajima, Hsiuchen Chen, Yogaditya Chakrabarty, Huibao Feng, David C Chan.
      The mitochondria-endoplasmic reticulum contact site (MERCS) is critical for calcium exchange, phospholipid transfer, and bioenergetics. Impairment of MERCS is implicated in numerous pathological conditions, including cancer and neurodegenerative diseases. Remodeling of MERCS can affect calcium signaling or metabolism, but the mechanisms involved in dynamic MERCS remodeling are unknown. Employing a genome-wide CRISPRi screen, we uncover the ability of the small GTPase RHOA to tune the cellular MERCS level. RHOA knockdown, or increasing its degradation by CUL3 overexpression, reduces the MERCS level; conversely, upregulation of RHOA increases the MERCS level. RHOA binds to the ER protein VAPB and regulates complex formation between VAPB and mitochondrial PTPIP51, which form a tethering complex at the interface between ER and mitochondria. Furthermore, this regulatory mechanism is perturbed by disease alleles of RHOA, CUL3, and VAPB involved in cancer, hyperkalemia, and neurodegeneration, suggesting that MERCS may be affected in a range of pathological conditions. This study identifies RHOA as a regulator of mitochondria-ER communication, providing mechanistic insights into the dynamic remodeling of MERCS and potential therapeutic strategies for diseases linked to MERCS dysfunction.
    DOI:  https://doi.org/10.1038/s41467-025-66138-4
  2. Front Cell Dev Biol. 2025 ;13 1718799
    Restoring metabolic flexibility: targeting organelle interaction networks in the pathogenesis and therapy of MASLD.
    Yiming Liu, Yue Wang, Jiaying Zhou, Hong Li, Caiyun Liu, Beilei Zhong, Juan Liu, Leiming Liu, Lingling Zhang, Leimin Sun.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex and heterogeneous metabolic disorder where subcellular organelle dysfunction and disrupted inter-organelle communication are recognized as increasingly important drivers of pathogenesis, moving beyond traditional views focused solely on macroscopic metabolic regulation. This review systematically explores the functional impairments of key organelles-including mitochondria, the endoplasmic reticulum, lipid droplets, and autophagic pathways-to delineate their collective roles in fostering lipid metabolism imbalance, oxidative stress, and inflammation. A key innovation discussed is how the pathological dysregulation of membrane contact sites (MCSs) acts as a pivotal mechanism decoupling organelle function and accelerating disease progression. We conclude that therapeutic strategies aimed at restoring cellular metabolic flexibility-by precisely modulating MCSs, activating clearance pathways, and restoring energy metabolism-represent a promising new paradigm for treating MASLD, particularly in patient populations unresponsive to current therapies.
    Keywords:  autophagy; endoplasmic reticulum stress; lipid droplets; membrane contact sites; metabolic dysfunction-associated steatotic liver disease; metabolic inflexibility; mitochondria; therapeutic targets
    DOI:  https://doi.org/10.3389/fcell.2025.1718799
  3. bioRxiv. 2025 Nov 27. pii: 2025.11.25.690197. [Epub ahead of print]
    Upregulation of MAM by C99 disrupts ACSL4 activity and phospholipid homeostasis in Alzheimer's disease models.
    J Montesinos, T D Yun, I D Salomón-Cruz, S C Agudelo-Castrillón, M Uceda, A C Ferre, C Anton-Barros, N Gomez-Lopez, R R Agrawal, D Larrea, K R Velasco, A Fernàndez-Bernal, E Benitez, X Zhu, E A Schon, F Lopera, G P Cardona-Gomez, E Area-Gomez.
      The structure and function of cellular and intracellular membranes are critically governed by the fatty acid (FA) composition of phospholipids (PLs), which is dynamically regulated by a network of enzymes that fine-tune lipid species according to cellular demands. In this study, we identify a mechanism through which the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) modulates the activity of the acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that channels polyunsaturated fatty acids (PUFAs) into phosphatidylcholine (PC) via the Lands cycle. Through integrated biochemical, proteomic, and lipidomic analyses in both cellular and animal models, we demonstrate that MAM formation enhances ACSL4 activity, promoting arachidonic acid (AA) activation and its preferential incorporation into PC in concert with the MAM-localized lysophospholipid acyltransferase 4 (LPCAT4). Our findings further uncover an unexpected link between this pathway and the pathogenesis of Alzheimer's disease (AD). We show that elevated levels of C99-the β-secretase cleavage product of amyloid precursor protein (APP)-induce MAM remodeling through cholesterol clustering, which in turn activates ACSL4 and alters PC composition. This effect is mirrored in AD models as well as in fibroblasts, neurons, and immune cells derived from both familial and sporadic AD patients, all of which exhibit chronically increased C99 levels, heightened ACSL4 activity, and enrichment of PUFA-containing PC species, leading to lipid imbalance and membrane dysfunction. Together, these results establish MAMs as dynamic lipid-regulatory hubs that coordinate ACSL4-dependent membrane remodeling and highlight the contribution of MAM dysregulation to lipid abnormalities observed in AD.
    DOI:  https://doi.org/10.1101/2025.11.25.690197
  4. Cancer Res. 2025 Dec 15.
    Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.
    Lili Bao, Keying Li, Yue Fan, Zhen Ge, Yang Zeng, Tian Xia, Qicheng Zhang, Si Pan, Wenhui Chen, Haimeng Yin, Bo You.
      Anoikis resistance is a phenomenon wherein cells survive under anchorage-independent conditions, which is critical for cancer cell dissemination and metastasis. To identify strategies to overcome anoikis resistance, we employed a 3D suspension culture model combined with proteomic screening, identifying a relationship between the dynamin-like protein Drp1 and anoikis resistance in nasopharyngeal carcinoma (NPC). Drp1 facilitated the generation of new mitochondria and the removal of damaged ones by regulating fission and mitophagy, thereby enabling tumor cells to overcome anoikis. Furthermore, the interaction of Drp1 and BIP was enhanced during anoikis resistance, which increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) to maintain mitochondrial dynamic equilibrium. Mechanistically, CaMKKβ activated the AMPK-MFF-Drp1 and AMPK-mTOR-Drp1 pathways through O-GlcNAcylation modification, thus recruiting Drp1 to MAMs. Notably, the Drp1-BIP complex served as a prognostic indicator for NPC clinical outcome and metastatic risk. Collectively, these results elucidate a mechanism by which Drp1 regulates anoikis resistance through mitochondrial dynamics and provide a feasible treatment strategy for managing NPC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0622
  5. Eur J Med Res. 2025 Dec 17.
    Identification and validation of biomarkers related to mitochondria-associated endoplasmic reticulum membranes in type 2 diabetes mellitus using peripheral blood transcriptomics.
    Sufen Li, Yanqiong Yan, Qianjun Luo, Ruifei Tian, Jiahe Yan.
       BACKGROUND: The pathological hallmarks of Type 2 diabetes mellitus (T2DM) are impaired insulin sensitivity and insufficient insulin secretion. As the primary insulin source, pancreatic β-cell decline or dysfunction is key to T2DM progression. Disrupted mitochondria-associated endoplasmic reticulum membranes (MAMs) may compromise β-cell viability and function. This study aimed to identify MAMs-related biomarkers in T2DM pathogenesis.
    METHODS: Data were obtained from public databases, and the biomarkers related to MAMs in T2DM were identified by differential expression analysis, WGCNA, supervised machine learning, and expression validation. Subsequently, a nomogram for predicting the prevalence of T2DM was developed, and the performance was evaluated. Additionally, we conducted immune infiltration analysis, GSEA, and molecular docking were performed to analyze the underlying mechanisms of the identified biomarkers. Finally, RT-qPCR was used to further validate the expression trends of these biomarkers.
    RESULTS: Three key biomarkers-DUSP26, SLC15A1, and TBX1-were discovered, and the nomogram developed using these markers exhibited strong predictive accuracy for T2DM risk. Interestingly, these biomarkers were predominantly associated with the olfactory transduction pathway and neuroactive ligand-receptor interactions. Additionally, five distinct immune cell types were identified (p < 0.05). Among these, Th2 cells showed the highest positive correlation with activated CD4 T cells (r = 0.45), whereas activated dendritic cells displayed the strongest negative correlation with activated CD4 T cells (r = -0.42). Furthermore, all 3 biomarkers displayed favorable binding abilities with all 3 therapeutic agents for T2DM (< -5.0 kcal/mol), suggesting the potential of biomarkers in the treatment of T2DM. Ultimately, the trend of 3 biomarker expression in the clinical samples was consistent with the GSE184050 and GSE15932, with up-regulated expression, revealing the reliability of biomarker identification.
    CONCLUSION: The biomarkers DUSP26, SLC15A1, and TBX1 related to MAMs in T2DM were identified, which supplied a theoretical basis for T2DM-related mechanistic studies and clinical treatment.
    Keywords:  Biomarkers; Immune infiltration analysis; Machine learning; Mitochondria-associated endoplasmic reticulum membranes; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1186/s40001-025-03681-2
  6. Biol Chem. 2025 Dec 17.
    Jack of all trades - the lipid droplet organization (LDO) proteins are multifunctional organelle surface receptors.
    Beatriz Leite, Maria Bohnert.
      The literature on the lipid droplet organization (LDO) proteins Ldo16 and Ldo45 reads like a guided tour through the lipid droplet life cycle. Both yeast Ldo16/45 and their metazoan counterparts, the LDAF1/promethin proteins, were originally identified based on their connection to the lipodystrophy protein seipin, a key player in lipid droplet biogenesis. Mechanistic follow-up studies support a role of LDAF1/LDO as conserved integral component of the seipin lipid droplet biogenesis complex. However, at the same time, additional LDO functions beyond lipid droplet formation were identified in yeast. Together with Vac8, Ldo16/45 act as tethers for formation of vacuole lipid droplet (vCLIP) contact sites, structures that are crucial for lipid droplet breakdown via microautophagy during glucose starvation. Ldo45 additionally recruits the lipid transfer protein Pdr16 to vCLIP. Furthermore, Ldo16 was identified as a central player in the process of actomyosin-based lipid droplet motility, by acting as a receptor for the myosin adaptor protein Ldm1. Based on these findings, we suggest an overarching molecular role of the LDO proteins as multifunctional lipid droplet surface receptors that are optimized to coordinate the different aspects of the lipid droplet life cycle through an interplay with different effector proteins.
    Keywords:  Sei1, seipin; lipid droplet motility protein 1 (Ldm1); lipid droplet organization (LDO) protein of 16/45 kDa (Ldo16, Ldo45); type V myosin motor protein Myo2; vacuole lipid droplet (vCLIP) contact site; vacuole related protein 8 (Vac8)
    DOI:  https://doi.org/10.1515/hsz-2025-0216
  7. Biol Chem. 2025 Dec 18.
    There and back again: a cell biologist's journey from organelles to molecules.
    Emma J Fenech, Yury S Bykov.
      Eukaryotic life is defined by the presence of organelles. Organelles, in turn, were classically defined as specialized membrane-bound compartments composed of a unique set of macromolecules which support specific functions. Over the last few decades, a concerted effort into uncovering which components are present in each organelle has shaped our view of cell biology. However, despite some organelles already being visualized over 100 years ago, we are still discovering new organelle residents. Furthermore, our concept of both 'organelles' and 'compartmentalization' has evolved together with our deepening understanding in a number of fields. These include: organelle substructure and organization; the network of contact sites which interconnects all organelles; and membraneless organelles and phase-separated condensates. This review explores how image- and mass spectrometry-based methods can be used to understand the spectrum of where components are localized: from complexes, to subdomains, and whole organelles. The components we mainly focus on are proteins of the mitochondria and secretory pathway organelles.
    Keywords:  contact sites; mass spectrometry; microscopy; organelle subdomains; organelles; protein complexes
    DOI:  https://doi.org/10.1515/hsz-2025-0185
  8. J Cell Sci. 2024 Dec 15. pii: jcs264075. [Epub ahead of print]138(24):
    Ribosome-binding protein 1 maintains peroxisome biogenesis.
    Kaneez Fatima, Helena Vihinen, Ani Akpinar, Tamara Somborac, Anja Paatero, Eija Jokitalo, Ville Paavilainen, Pekka Katajisto, Svetlana Konovalova.
      Peroxisomes are single-membrane-bound organelles essential for human health, yet the mechanisms of peroxisome biogenesis are not fully understood. Here using a systematic double screening approach, we identified ribosome-binding protein 1 (RRBP1) as a novel peroxisome biogenesis factor in human cells. Deletion of RRBP1 in HEK293T cells led to a reduction in both peroxisome number and peroxisomal protein levels as well as in defects in processing of peroxisomal matrix proteins, such as ACOX1 and thiolase. However, cell proliferation and protein translation were not altered in cells lacking RRBP1. RRBP1 depletion did not affect peroxisome-endoplasmic reticulum (ER) contact sites, and pexophagy did not contribute to the reduction of peroxisomes in RRBP1 knockout cells. Instead, in the absence of RRBP1, peroxisomal proteins were processed by proteasomal degradation, suggesting that RRBP1 plays a role in the insertion of these proteins into ER membranes and their stabilization. Altogether, our results show that RRBP1 promotes peroxisome biogenesis in human cells, highlighting the power of systematic approaches in discovering novel factors of organellar biogenesis.
    Keywords:  CRISPR/Cas9; Peroxisome; Peroxisome biogenesis; RRBP1
    DOI:  https://doi.org/10.1242/jcs.264075
  9. Diabetologia. 2025 Dec 15.
    α7 Nicotinic acetylcholine receptor activation rescues mitochondrial dysfunction in gestational diabetes mellitus by competing with p66Shc for VDAC1 binding.
    Lulu Ji, Yaru Nai, Zhiguo Chen, Yu Zhong, Hengxuan Zhu, Yanyi Huang, Xiaoli Zhang, Yuexiao Wang, Xiting Yang, Qiongtao Wang, Hanyang Hu, Lin Wang.
       AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is associated with placental hormone-induced insulin resistance; however, the mechanisms connecting hyperglycaemia to mitochondrial dysfunction remain incompletely understood. This study aimed to investigate the role of the α7 nicotinic acetylcholine receptor (α7nAChR) in regulating mitochondrial Ca2⁺ homeostasis in trophoblasts under hyperglycaemic stress, and to explore whether its dysregulation contributes to placental mitochondrial pathology in GDM.
    METHODS: Clinical placental samples from GDM pregnancies were analysed to assess α7nAChR expression, mitochondrial morphology and Ca2⁺ signalling pathways. Complementary in vitro and murine models of hyperglycaemia were employed to examine molecular interactions involving α7nAChR, voltage-dependent anion channel 1 (VDAC1) and p66Shc. Mitochondrial-associated endoplasmic reticulum membranes were studied to evaluate pathological Ca2⁺ transfer mechanisms. Pharmacological activation of α7nAChR was performed using PNU-282987 (PNU) or GTS-21, and RNA-seq was conducted to analyse downstream transcriptional changes related to mitochondrial dysfunction and cellular senescence.
    RESULTS: Clinical analysis revealed reduced α7nAChR expression, mitochondrial vacuolisation and dysregulated Ca2⁺ signalling pathways in GDM placentas. Under hyperglycaemic conditions, disrupted α7nAChR-VDAC1 interactions facilitated competitive binding of the pro-oxidant p66Shc to VDAC1, promoting pathological Ca2⁺ transfer from the endoplasmic reticulum to mitochondria via mitochondrial-associated endoplasmic reticulum membranes. This led to mitochondrial permeability transition pore overactivation, loss of mitochondrial membrane potential and induction of cellular senescence. Pharmacological activation of α7nAChR with PNU or GTS-21 restored α7nAChR-VDAC1 coupling, attenuated p66Shc-mediated oxidative stress and reversed mitochondrial Ca2⁺ overload. RNA-seq confirmed that PNU treatment normalised gene expression profiles associated with endoplasmic reticulum stress and cellular senescence.
    CONCLUSIONS/INTERPRETATION: This study identifies a non-canonical role for α7nAChR in maintaining mitochondrial Ca2⁺ homeostasis by competitively regulating VDAC1-p66Shc interactions under hyperglycaemic conditions. The findings reveal a mechanistic link between α7nAChR dysfunction, mitochondrial Ca2⁺ overload and cellular senescence in GDM placentas. Targeting α7nAChR with pharmacological agents such as GTS-21 may offer a novel therapeutic approach to ameliorate mitochondrial dysfunction and placental pathology in GDM by restoring Ca2⁺ dynamics.
    Keywords:  Gestational diabetes mellitus; Mitochondrial calcium homeostasis; Placental dysfunction; VDAC1; p66Shc; α7nAChR
    DOI:  https://doi.org/10.1007/s00125-025-06640-y
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