bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–12–07
twenty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.
  2. The 'silent' brain cells that shape our behaviour, memory and health.
  3. Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
  4. Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
  5. Protein restriction reshapes aging across organs.
  6. A foundation for tomorrow's discoveries in cell biology.
  7. Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
  8. Lack of intestinal Mucin-1 impairs intestinal epithelial barrier and promotes metabolic dysfunction-associated steatotic liver disease in male mice.
  9. Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress.
  10. China's scientific clout is growing as US influence wanes: the data show how.
  11. Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
  12. A guide to transcriptomic deconvolution in cancer.
  13. Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.
  14. Architecture of the neutrophil compartment.
  15. Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
  16. Continuous Glucose Monitoring in Older Adults With Diabetes and Alzheimer Disease and Related Dementias-Promise and Perspective.
  17. Diabetes research enters the biobank era: searching for the truth in a deep well.
  18. Lipid dependence of connexin-32 gap junction channel conformations.
  19. VAPB is a negative regulator of STING-mediated innate immune signaling.
  20. A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice.
  21. Fat sensory cues in early life program central response to food and obesity.
  1. Nat Commun. 2025 Dec 04. 16(1): 10909
    Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.
    Cindy Dong, Alison Finigan, Nichola Figg, Benjamin Jenkins, Albert Koulman, Suvagata R Chowdhury, Anne-Marie Tricolici, Jordi Lambert, Sebnem Oc, Helle F Jørgensen, Julien Prudent, Michael P Murphy, Martin Bennett, Emma Yu.
      Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barth's Syndrome, which is characterised by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs). MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low-density lipoprotein in a NFκB-dependent manner. Silencing tafazzin or overexpression of mutant tafazzin decreases VSMC cardiolipin content and mitochondrial respiration, and promotes apoptosis and atherosclerosis. In contrast tafazzin overexpression increases respiration, protects against apoptosis and increases features of plaque stability. Tafazzin therefore has important effects on VSMC mitochondrial function and atherosclerosis, and is a potential therapeutic target in atherosclerotic disease.
    DOI:  https://doi.org/10.1038/s41467-025-65873-y
  2. Nature. 2025 Dec;648(8092): 23-25
    The 'silent' brain cells that shape our behaviour, memory and health.
    Alison Abbott.
      
    Keywords:  Alzheimer's disease; Brain; Cell biology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-03912-w
  3. Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]
    Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
    Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.
      The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.
    Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor
    DOI:  https://doi.org/10.1016/j.cell.2025.11.002
  4. Nat Commun. 2025 Dec 01.
    Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
    J Botella, E Perri, N J Caruana, S López-Calcerrada, M Brischigliaro, N A Jamnick, V Oorschot, N J Saner, J Díaz-Lara, D F Taylor, A Garnham, E Fernández-Vizarra, C Ugalde, G Ramm, D A Stroud, M Lazarou, D J Bishop.
      Exercise is a key lifestyle intervention for mitochondrial health, yet the molecular mechanisms by which different exercise prescriptions regulate mitochondrial remodeling remain unclear. We conducted an open-label counterbalanced randomized controlled trial (ACTRN12617001105336) and observed that sprint-interval exercise (SIE; n = 14), compared to moderate-intensity continuous exercise (MICE; n = 14), induces a mitochondrial stress signature and unfolded protein response (UPRmt). SIE triggers morphological and structural mitochondrial alterations along with activation of the integrated stress response (ISR) and mitochondrial quality control (MQC) pathways. Following eight weeks of training, moderate-intensity continuous training (MICT) increases mitochondrial content, complex I activity, and displays an enrichment of tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) proteins, while sprint-interval training (SIT) improves respiratory function and upregulates pathways involved in 1-carbon metabolism and protein quality control. We identify COX7A2L accumulating in III2 + IV1 supercomplexes only after SIT. These findings elucidate how exercise intensity shapes mitochondrial remodeling, informing tailored exercise prescriptions.
    DOI:  https://doi.org/10.1038/s41467-025-66625-8
  5. Nat Aging. 2025 Dec 03.
    Protein restriction reshapes aging across organs.
    Qingzhong Ren.
      
    DOI:  https://doi.org/10.1038/s43587-025-01043-5
  6. Nat Cell Biol. 2025 Dec 05.
    A foundation for tomorrow's discoveries in cell biology.
    Ruth R Cheng, Rebecca L Bradford.
      
    DOI:  https://doi.org/10.1038/s41556-025-01824-5
  7. Nat Commun. 2025 Dec 01. 16(1): 10817
    Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
    Mrityunjoy Mondal, Enzo Scifo, Rossella Erminia Ciliberti, Lena Wischhof, Tannaz Norizadeh Abbariki, Joshua Jackson, Ioanna-Maria Menegatou, Viktoria Zeisler-Diehl, Jan Riemer, Benjamin Jussila, Christopher E Hopkins, Sylwia Kierszniowska, Lukas Schreiber, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.
      Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRK-1 inhibition downregulates DRP-1 expression, reduces mitochondrial network fragmentation, and attenuates excessive autophagy, thereby rescuing the survival defects of wah-1 mutants maintained on low-lipid diets. Together, these findings suggest that nutrition, and particularly lipid intake, may ameliorate certain disease phenotypes associated with an inherited mutation that disrupts mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1038/s41467-025-66900-8
  8. Nat Commun. 2025 Dec 05.
    Lack of intestinal Mucin-1 impairs intestinal epithelial barrier and promotes metabolic dysfunction-associated steatotic liver disease in male mice.
    Zecheng Li, Runchuan Gu, Donghai Liu, Yijia Zhang, Yijin Qin, Xinyu Li, Yuan Qiao, Ziyao Li, Jing Guo, Jun Wang, Hua Meng, Liang Peng.
      Accumulating evidence suggests that a compromised intestinal epithelial barrier (IEB) contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the exact mechanisms remain unclear. Here we reveal that intestinal mucin 1 (MUC1) levels and glycosylation are decreased in both humans and male mice with MASLD. Enterocyte-specific Muc1 knockout aggravates high-fat diet (HFD)-induced IEB impairment and MASLD progression in male mice. Mechanistically, HFD feeding reduces the glycosylation of intestinal epithelial MUC1, triggering its clathrin-mediated endocytosis and NEDD4-mediated lysosomal degradation, which subsequently induces β-Catenin degradation and ultimately impaires the IEB. Notably, enterocyte-specific overexpression of cytoplasmic-tail-deleted MUC1 protects against IEB impairment and mitigates MASLD progression. These findings indicate that reduced intestinal epithelial MUC1 levels facilitate the progression of MASLD. Preserving the glycosylation and levels of intestinal MUC1 to maintain IEB integrity is a potential therapeutic strategy to explore for MASLD.
    DOI:  https://doi.org/10.1038/s41467-025-67034-7
  9. Nat Commun. 2025 Dec 02. 16(1): 10842
    Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress.
    Anna Platzek, Klára Odehnalová, Julia P Schessner, Georg H H Borner, Sebastian Schuck.
      Sophisticated techniques are available for systematic studies of yeast cell biology. However, it remains challenging to investigate protein subcellular localization changes on a proteome-wide scale. Here, we apply Dynamic Organellar Mapping by label-free mass spectrometry to detect localization changes of native, untagged proteins during endoplasmic reticulum (ER) stress. We find that hundreds of proteins shift between cellular compartments. For example, we show that numerous secretory pathway proteins accumulate in the ER, thus defining the extent and selectivity of ER retention of misfolded proteins. Furthermore, we identify candidate cargo proteins of the ER reflux pathway, determine constituents of reticulon clusters that segregate from the remainder of the ER and provide evidence for altered nuclear pore complex composition and nuclear import. These findings uncover protein relocalization as a major aspect of cellular reorganization during ER stress and establish Dynamic Organellar Maps as a powerful discovery tool in yeast.
    DOI:  https://doi.org/10.1038/s41467-025-66946-8
  10. Nature. 2025 Dec 04.
    China's scientific clout is growing as US influence wanes: the data show how.
    Jeff Tollefson.
      
    DOI:  https://doi.org/10.1038/d41586-025-03956-y
  11. Nat Commun. 2025 Dec 03.
    Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
    Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.
      Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.
    DOI:  https://doi.org/10.1038/s41467-025-66656-1
  12. Nat Rev Cancer. 2025 Dec 02.
    A guide to transcriptomic deconvolution in cancer.
    Yaoyi Dai, Shuai Guo, Yidan Pan, Carla Castignani, Matthew D Montierth, Peter Van Loo, Wenyi Wang.
      Cancer tissues are heterogeneous mixtures of tumour, stromal and immune cells, where each component comprises multiple distinct cell types and/or states. Mapping this heterogeneity and understanding the unique contributions of each cell type to the tumour transcriptome is crucial for advancing cancer biology, yet high-throughput expression profiles from tumour tissues only represent combined signals from all cellular sources. Computational deconvolution of these mixed signals has emerged as a powerful approach to dissect both cellular composition and cell-type-specific expression patterns. Here, we provide a comprehensive guide to transcriptomic deconvolution, specifically tailored for cancer researchers, presenting a systematic framework for selecting and applying deconvolution methods, considering the unique complexities of tumour tissues, data availability and method assumptions. We detail 43 deconvolution methods and outline how different approaches serve distinctive applications in cancer research: from understanding tumour-immune surveillance to identifying cancer subtypes, discovering prognostic biomarkers and characterizing spatial tumour architecture. By examining the capabilities and limitations of these methods, we highlight emerging trends and future directions, particularly in addressing tumour cell plasticity and dynamic cell states.
    DOI:  https://doi.org/10.1038/s41568-025-00886-9
  13. Sci Transl Med. 2025 Dec 03. 17(827): eadw7428
    Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.
    Tanya N Weerakkody, Hanna Sabelström, Shan V Andrews, Jean Paul Chadarevian, Marcus Y Chin, David Tatarakis, Nicholas E Propson, Do Jin Kim, Richard Theolis, Gian Carlo G Parico, Hiwot Misker, Jennifer E Kung, Abira Bandyopadhyay, Yaneth Robles Colmenares, Taggra-Nicole Jackson, Ahlam N Qerqez, Srijana Balasundar, Sonnet S Davis, Connie Ha, Rajarshi Ghosh, Ritesh Ravi, Anil Rana, Kyla Germain, Arnold Tao, Ken Xiong, Dylan Braun, Karthik Raju, Kang-Chieh Huang, Lihong Zhan, Jing L Guo, Hoda Safari Yazd, Lily Sarrafha, Joia Kai Capocchi, Jonathan Hasselmann, Alina L Chadarevian, Christina Tu, Kimiya Mansour, Ghazaleh Eskandari-Sedighi, Niccolò Tesi, Sven van der Lee, Marc Hulsman, Georgii Oshegov, Yolande Pijnenburg, Meredith Calvert, Henne Holstege, Jung H Suh, Gilbert Di Paolo, Hayk Davtyan, Joseph W Lewcock, Mathew Blurton-Jones, Kathryn M Monroe.
      The Alzheimer's disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell-derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator-activated receptor and signal transducer and activator of transcription 1/3 mediated PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.
    DOI:  https://doi.org/10.1126/scitranslmed.adw7428
  14. Nature. 2025 Dec 03.
    Architecture of the neutrophil compartment.
    Daniela Cerezo-Wallis, Andrea Rubio-Ponce, Mathis Richter, Emanuele Pitino, Immanuel Kwok, Giovanni Marteletto, Ana Cristina Guanolema-Coba, Changming Shih, Run-Kai Huang, Ana Moraga, Natalia Borbaran Bravo, Samuel Doré, Sergio Callejas, David G Aragonés, Daniel Jiménez-Carretero, Daniel Martin, Samuel Ovadia, Tommaso Vicanolo, Georgiana Crainiciuc, Jon Sicilia, Tong Deng, Anjelica Martin, Jing Zhang, Maria Isabel Cuartero, Diego Moncada Giraldo, Alicia Garcia-Culebras, Alejandra Aroca-Crevillen, Sandra Martín-Salamanca, Carlos Torroja, Max Ruiz, Irene Ruano, Melissa S F Ng, Jian Hou, You Wang, Ming Zhang, Jun Pu, Ana Herruzo, David Chang van Oordt, Seokyoon Chang, Alexander E Downie, Fei Chen, Andrea L Graham, William C Gause, Pierre O Fiset, Jonathan D Spicer, Holger Heyn, Maria A Zuriaga, Juan A Bernal, Irina A Udalova, Maria A Moro, Katrien de Bock, Ana Dopazo, Jose J Fuster, Fátima Sánchez-Cabo, Juan C Nieto, Gabriel F Calvo, Julia Skokowa, Oliver Soehnlein, Daniela F Quail, Logan A Walsh, Lai Guan Ng, Andrés Hidalgo, Iván Ballesteros.
      Neutrophils exhibit remarkable phenotypic and functional diversity across tissues and diseases1,2, yet the lack of understanding of how this immune compartment is globally organized challenges translation to the clinic. Here we performed single-cell transcriptional profiling of neutrophils spanning 47 anatomical, physiological and pathological scenarios to generate an integrated map of the global neutrophil compartment in mice, which we refer to as NeuMap. NeuMap integrates and expands existing models3,4 to generate fundamental new insights; it reveals that neutrophils organize in a finite number of functional hubs that distribute sequentially during maturation to then branch out into interferon-responsive and immunosuppressive states, as well as a functionally silent state that dominates in the healthy circulation. Computational modelling and timestamp analyses identify prototypical trajectories that connect these hubs, and reveal that the dynamics and preferred paths vary during health, inflammation and cancer. We show that TGFβ, IFNβ and GM-CSF push neutrophils along the different trajectories, and projection of chromatin accessibility sites onto NeuMap reveals that the transcription factor JUNB controls angiogenic and immunosuppressive states and promotes tissue revascularization. The architecture of NeuMap appears to be conserved across sex, environmental and genetic backgrounds, as well as in humans. Finally, we show that NeuMap enables inference of the pathophysiological state of the host by profiling blood neutrophils. Our study delineates the global architecture of the neutrophil compartment and establishes a framework for exploration and exploitation of neutrophil biology.
    DOI:  https://doi.org/10.1038/s41586-025-09807-0
  15. Nat Commun. 2025 Dec 05.
    Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
    Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.
      The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-66901-7
  16. JAMA Netw Open. 2025 Dec 01. 8(12): e2541947
    Continuous Glucose Monitoring in Older Adults With Diabetes and Alzheimer Disease and Related Dementias-Promise and Perspective.
    Thaer Idrees, Elena Toschi.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.41947
  17. J Clin Invest. 2025 Dec 01. pii: e199728. [Epub ahead of print]135(23):
    Diabetes research enters the biobank era: searching for the truth in a deep well.
    Decio L Eizirik, Priscila L Zimath.
      Loss of circulating insulin resulting from autoimmune destruction of β cells is the defining characteristic of type 1 diabetes (T1D), but islet dysfunction in T1D affects both β cells and α cells. Advances in multiomic analyses and the systematic collection of diseased human pancreata are enabling new approaches for diabetes research; hypotheses can be generated from observations in the affected human tissue and then tested in human islets, stem cell-derived islets, or humanized mice. The study by dos Santos and colleagues that appears in this issue of the JCI is an excellent example of the advantages and challenges posed by this approach. Through integrated analyses that combined electrophysiological and transcriptomic profiling, the authors provided detailed insights into the mechanisms leading to α cell dysfunction in islets from individuals with T1D.
    DOI:  https://doi.org/10.1172/JCI199728
  18. Nat Commun. 2025 Dec 05.
    Lipid dependence of connexin-32 gap junction channel conformations.
    Pia Lavriha, Carina Fluri, Jorge Enrique Hernández González, Volodymyr M Korkhov.
      Connexin-32 (Cx32) gap junction channels (GJCs) mediate intercellular coupling in various tissues, including myelinating Schwann cells. Mutations in Cx32, such as W3S, are associated with X-linked Charcot-Marie-Tooth (CMT1X) disease. Lipids regulate Cx32 GJC permeation, although the regulatory mechanism is unclear. Here, we determine the cryo-EM structures of Cx32 GJCs reconstituted in nanodiscs, revealing that phospholipids block the Cx32 GJC pore by binding to the site formed by N-terminal gating helices. The phospholipid-bound state is contingent on the presence of a sterol molecule in a hydrophobic pocket formed by the N-terminus: the N-terminal helix of Cx32 fails to sustain a phospholipid binding site in the absence of cholesterol hemisuccinate. The CMT1X-linked W3S mutant which has an impaired sterol binding site adopts a conformation of the N-terminus incompatible with phospholipid binding. Our results indicate that different lipid species control connexin channel gating directly by influencing the conformation of the N-terminal gating helix.
    DOI:  https://doi.org/10.1038/s41467-025-67004-z
  19. Sci Adv. 2025 Dec 05. 11(49): eaea3996
    VAPB is a negative regulator of STING-mediated innate immune signaling.
    Wangsheng Ji, Yin Zhang, Lianfei Zhang, Qingqing Liu, Shengbo Niu, Yuqun Feng, Feilong Chen, Xinqi Liu, Xia Li.
      Stimulator of IFN genes (STING) is an endoplasmic reticulum (ER) signaling receptor involved in the type I interferon response to pathogen- or self-derived cytosolic double-stranded DNA. Excessive activation of STING is associated with many diseases, but the regulatory mechanism of STING activation remains to be further elucidated. Here, we identify VAPB as a negative regulator of STING-mediated innate immune response. VAPB deficiency increases the expression of type I interferons under resting conditions or upon stimulation. Mechanistically, VAPB associates and translocates with STING, thereby regulating STING translocation, oligomerization, and recruitment of TBK1. In vivo, deficiency of VAPB enhances the expression of type I interferons and prevents lethality following HSV-1 infection. Furthermore, VAPB P56S, a pathogenic mutation causing amyotrophic lateral sclerosis (ALS), can promote STING-mediated innate immune response under resting conditions, which might contribute to further understanding of the relationship between cGAS-STING pathway and ALS. Our study identifies VAPB as a critical regulating factor in cGAS-STING-mediated innate immune responses.
    DOI:  https://doi.org/10.1126/sciadv.aea3996
  20. Nat Commun. 2025 Dec 02.
    A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice.
    Yingying Zhang, Brianna Watson, Ajitanuj Rattan, Tyrone Lee, Smriti Chawla, Ludwig Geistlinger, Yilin Guan, Finley B Lord, Minghe Ma, Takashi Miwa, Madhu Golla, Barbara J Caldarone, Wen-Chao Song, Jeffrey R Moffitt, Michael C Carroll.
      Recent studies have found non-immunological roles of the classical complement pathway (CP) in brain development and its involvement in neuropsychiatric and neurodegenerative diseases. However, multiple complement activation pathways exist beyond the CP, but their expression and function remain poorly understood in the brain. Using MERFISH, we constructed a comprehensive spatial transcriptomic atlas of the complement system in mouse brains from late embryonic stage to adulthood. Here we show that most complement genes are expressed locally with a remarkable degree of cellular, spatial, and temporal heterogeneity and that complement regulatory mechanisms are distinct from the periphery. Beyond confirming the known expression of the CP, our measurements reveal endogenous expression of the alternative pathway (AP), notably the AP activator Masp3 in immature brains. Masp3 deficiency alters molecular structure of the brain and causes working spatial memory defects, indicating a role of Masp3 in brain maturation, potentially via modulation of AP activity.
    DOI:  https://doi.org/10.1038/s41467-025-66048-5
  21. Nat Metab. 2025 Dec 01.
    Fat sensory cues in early life program central response to food and obesity.
    Laura Casanueva Reimon, Ayden Gouveia, André Carvalho, Joscha N Schmehr, Mouna El Mehdi, Rolando D Moreira-Soto, Carlos G Ardanaz, Janice Bulk, Lionel Rigoux, Paul Klemm, Anna Lena Cremer, Frederik Dethloff, Yvonne Hinze, Heiko Backes, Patrick Giavalisco, Sophie M Steculorum.
      Maternal obesity predisposes offspring to metabolic diseases. Here, we show that non-nutritive sensory components of a high-fat diet (HFD), beyond its hypercaloric, obesogenic effects, are sufficient to alter metabolic health in the offspring. To dissociate the caloric and sensory components of HFD, we fed dams a bacon-flavoured diet, isonutritional to a normal chow diet but enriched with fat-related odours. Offspring exposed to these fat-related odours during development display metabolic inflexibility and increased adiposity when fed HFD in adulthood independently of maternal metabolic health. Developmental exposure to fat-related odours shifts mesolimbic dopaminergic circuits and Agouti-related peptide (AgRP) hunger neurons' responses to phenocopy those of obese mice, including a desensitization of AgRP neurons to dietary fat. While neither neonatal optogenetic activation of sensory circuits nor passive exposure to fat-related odours is sufficient to alter metabolic responses to HFD, coupling optogenetic stimulation of sensory circuits with caloric intake exacerbates obesity. Collectively, we report that fat-related sensory cues during development act as signals that can prime central responses to food cues and whole-body metabolism regulation.
    DOI:  https://doi.org/10.1038/s42255-025-01405-8
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