bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–12–21
29 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
  2. How common is Alzheimer's? Blood-test study holds surprises.
  3. Immunological sin: how a person's earliest flu infections dictate life-long immunity.
  4. Mitochondrial RNA cytosolic leakage drives the SASP.
  5. Complex genetic effects linked to plasma protein abundance in the UK Biobank.
  6. The G3BP stress-granule proteins reinforce the integrated stress response translation programme.
  7. How the Romans built their empire of concrete.
  8. GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging.
  9. Multi-layered transcriptional control of glycogen metabolism coordinates thermogenic remodeling of white adipocytes in male mice.
  10. An integrated view of the structure and function of the human 4D nucleome.
  11. Carta offers a computational approach to inference of differentiation maps from cell lineages.
  12. Systematic maps reveal how human chromosomes are organized.
  13. Sodium disrupts mitochondrial energy metabolism to execute NECSO.
  14. Biobanks reveal genetic complexity in human evolution.
  15. The burden of silence.
  16. Linked data storage using DNA origami nanostructures.
  17. The hidden cost of video-call glitches.
  18. Structural basis for ACT1 oligomerization induced by IL-17 receptor hetero-tetramer.
  19. Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8+ T cells in mice.
  20. Siglec-F+ neutrophils promote the resolution of acute lung injury through ALOX15 induction.
  21. A cholesterol-responsive hepatic tRNA-derived small RNA regulates cholesterol homeostasis and atherosclerosis development.
  22. TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
  23. RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether.
  24. Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.
  25. VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
  26. Preventing cardiovascular risk in people with prediabetes.
  27. Single cell spatial transcriptomics integration deciphers the morphological heterogeneity of atherosclerotic carotid arteries.
  28. Flexible read-aware genotype imputation from sequence using biobank sized reference panels.
  29. Integrating polygenic signals and single-cell multiomics identifies cell-type-specific regulomes critical for immune- and aging-related diseases.
  1. Nat Cell Biol. 2025 Dec 19.
    Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
    Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.
      T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01835-2
  2. Nature. 2025 Dec 17.
    How common is Alzheimer's? Blood-test study holds surprises.
    Asher Mullard.
      
    Keywords:  Alzheimer's disease; Brain; Epidemiology
    DOI:  https://doi.org/10.1038/d41586-025-04133-x
  3. Nature. 2025 Dec 17.
    Immunological sin: how a person's earliest flu infections dictate life-long immunity.
    Amanda B Keener.
      
    Keywords:  Diseases; Immunology; Public health; Vaccines; Virology
    DOI:  https://doi.org/10.1038/d41586-025-03606-3
  4. Nat Commun. 2025 Dec 15. 16(1): 10992
    Mitochondrial RNA cytosolic leakage drives the SASP.
    Stella Victorelli, Madeline Eppard, Hélène Martini, Seung-Hwa Woo, Stacia P A Everts, Gung Lee, Nicholas Pirius, Nuan Han, Eugene Y Liang, Ana Catarina Franco, Yeaeun Han, Dominik Saul, Eva Nóvoa, Rubén Nogueiras, Patrick L Splinter, Steven P O'Hara, Olivia Morgenthaler, Lucía Valenzuela-Pérez, Hyun Se Kim Lee, Diana Jurk, Nicholas F LaRusso, Petra Hirsova, João F Passos.
      Senescent cells secrete proinflammatory factors known as the senescence-associated secretory phenotype (SASP), contributing to tissue dysfunction and aging. Mitochondrial dysfunction is a key feature of senescence, influencing SASP via mitochondrial DNA (mtDNA) release and cGAS/STING pathway activation. Here, we demonstrate that mitochondrial RNA (mtRNA) also accumulates in the cytosol of senescent cells, activating RNA sensors RIG-I and MDA5, leading to MAVS aggregation and SASP induction. Inhibition of these RNA sensors significantly reduces SASP factors. Furthermore, BAX and BAK play a key role in mtRNA leakage during senescence, and their deletion diminishes SASP expression in vitro and in a mouse model of Metabolic Dysfunction-Associated Steatohepatitis (MASH). These findings highlight mtRNA's role in SASP regulation and its potential as a therapeutic target for mitigating age-related inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-66159-z
  5. Nat Commun. 2025 Dec 14.
    Complex genetic effects linked to plasma protein abundance in the UK Biobank.
    FinnGen
      Understanding genetic associations of proteins is important for studying the molecular effect of genetic variation. A key component of this is to understand the role of complex genetic effects such as dominance and epistasis that are associated with plasma proteins. Therefore, we develop EIR-auto-GP, a deep learning-based approach, to identify complex effects that are associated with protein quantitative trait loci (pQTLs). Applying this method to the UK Biobank proteomics cohort of 48,594 individuals, we identify 123 proteins that are correlated with non-linear covariates and 15 with genetic dominance and epistasis. We uncover a novel interaction between the ABO and FUT3 loci and demonstrate dominance effects of the ABO locus on plasma levels of pathogen recognition receptors CD209 and CLEC4M. Furthermore, we replicate these findings and the methodology across Olink and mass spectrometry-based cohorts. Our approach presents a systematic, large-scale attempt to identify complex effects of plasma protein levels.
    DOI:  https://doi.org/10.1038/s41467-025-67235-0
  6. Nat Cell Biol. 2025 Dec 19.
    The G3BP stress-granule proteins reinforce the integrated stress response translation programme.
    Jarrett Smith, David P Bartel.
      When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs.
    DOI:  https://doi.org/10.1038/s41556-025-01834-3
  7. Nature. 2025 Dec 17.
    How the Romans built their empire of concrete.
      
    Keywords:  Archaeology; Materials science
    DOI:  https://doi.org/10.1038/d41586-025-04080-7
  8. Nat Aging. 2025 Dec 15.
    GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging.
    In Hwa Jang, Anna Carey, Victor Kruglov, Katie Nguyen, Jeffrey R Misialek, Stephanie H Cholensky, Declan M Smith, Suxia Bai, Timothy Nottoli, David A Bernlohr, Pamela L Lutsey, Christina D Camell.
      Aging is characterized by amplified inflammation, including proinflammatory macrophages and increased susceptibility to endotoxemia. Here we uncover a mechanism by which macrophages maintain their inflammatory phenotype through autocrine GDF3-SMAD2/3 signaling, which ultimately exacerbates endotoxemia. We show that inflammatory adipose tissue macrophages display an age-dependent increase in GDF3, a TGFβ-family cytokine. Lifelong systemic or myeloid-specific Gdf3 deletion leads to reduced endotoxic inflammation. Using pharmacological interventions to modulate the GDF3-SMAD2/3 axis, we demonstrate its role in regulating the inflammatory adipose tissue macrophage phenotype and endotoxemia lethality in old mice. Mechanistically, single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses suggest that GDF3 induces a shift toward an inflammatory state by limiting methylation-dependent chromatin compaction. Leveraging human adipose tissue samples and 11,084 participants from the atherosclerosis risk in communities study, we validate the relevance of GDF3 to aging in humans. These findings position the GDF3-SMAD2/3 axis as a critical driver of age-associated chromatin remodeling and a promising therapeutic target for mitigating macrophage-related inflammation in aging.
    DOI:  https://doi.org/10.1038/s43587-025-01034-6
  9. Nat Commun. 2025 Dec 16.
    Multi-layered transcriptional control of glycogen metabolism coordinates thermogenic remodeling of white adipocytes in male mice.
    Haipeng Fu, Seoyeon Lee, Nathan R Zemke, Weiwei Fan, Yunqing Wang, James Garza, David Tin, Bryce Villao, Bichen Zhang, Xianda Ma, Jinyang Zhang, Tangran Dong, Yuyao Ren, Michael Downes, Ronald M Evans, Bing Ren, Alan R Saltiel.
      Thermogenic activation of subcutaneous white adipocytes requires glycogen synthesis and turnover. Here we show that β-adrenergic stimulation induces a distinct glycogen metabolism gene program in inguinal white adipose tissue in a cell-autonomous and adipocyte-specific manner. Among these, Gys2 and Ppp1r3c are rapidly induced following acute β3-adrenergic receptor activation. We identify Gys2 as a direct transcriptional target of PKA-CREB signaling. In contrast, sustained expression of glycogen metabolism genes under chronic β3-adrenergic activation requires the coactivator PGC1α, whose loss blunts glycogen accumulation and thermogenic capacity. Mechanistically, PGC1α cooperates with estrogen-related receptors (ERRs) to regulate chromatin accessibility and gene transcription. Although deletion of ERRα is compensated by ERRγ, combined deletion of ERRα/β/γ abolishes expression of glycogen metabolism and thermogenic genes. Chromatin profiling confirm that ERRs directly control the glycogen metabolic program in beige adipocytes. Together, our results identify a multilayered transcriptional axis that sustains glycogen metabolism during β-adrenergic activation in male mice.
    DOI:  https://doi.org/10.1038/s41467-025-67515-9
  10. Nature. 2025 Dec 17.
    An integrated view of the structure and function of the human 4D nucleome.
    Job Dekker, Betul Akgol Oksuz, Yang Zhang, Ye Wang, Miriam K Minsk, Shuzhen Kuang, Liyan Yang, Johan H Gibcus, Nils Krietenstein, Oliver J Rando, Jie Xu, Derek H Janssens, Steven Henikoff, Alexander Kukalev, Willemin Andréa, Warren Winick-Ng, Rieke Kempfer, Ana Pombo, Miao Yu, Pradeep Kumar, Liguo Zhang, Andrew S Belmont, Takayo Sasaki, Tom van Schaik, Laura Brueckner, Daan Peric-Hupkes, Bas van Steensel, Ping Wang, Haoxi Chai, Minji Kim, Yijun Ruan, Ran Zhang, Sofia A Quinodoz, Prashant Bhat, Mitchell Guttman, Wenxin Zhao, Shu Chien, Yuan Liu, Sergey V Venev, Dariusz Plewczynski, Ibai Irastorza Azcarate, Dominik Szabó, Christoph J Thieme, Teresa Szczepińska, Mateusz Chiliński, Kaustav Sengupta, Mattia Conte, Andrea Esposito, Alex Abraham, Ruochi Zhang, Yuchuan Wang, Xingzhao Wen, Qiuyang Wu, Yang Yang, Jie Liu, Lorenzo Boninsegna, Asli Yildirim, Yuxiang Zhan, Andrea Maria Chiariello, Simona Bianco, Lindsay Lee, Ming Hu, Yun Li, R Jordan Barnett, Ashley L Cook, Daniel J Emerson, Claire Marchal, Peiyao Zhao, Peter J Park, Burak H Alver, Andrew J Schroeder, Rahi Navelkar, Clara Bakker, William Ronchetti, Shannon Ehmsen, Alexander D Veit, Nils Gehlenborg, Ting Wang, Daofeng Li, Xiaotao Wang, Mario Nicodemi, Bing Ren, Sheng Zhong, Jennifer E Phillips-Cremins, David M Gilbert, Katherine S Pollard, Frank Alber, Jian Ma, William S Noble, Feng Yue.
      The dynamic three-dimensional (3D) organization of the human genome (the 4D nucleome) is linked to genome function. Here we describe efforts by the 4D Nucleome Project1 to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.
    DOI:  https://doi.org/10.1038/s41586-025-09890-3
  11. Nat Methods. 2025 Dec 15.
    Carta offers a computational approach to inference of differentiation maps from cell lineages.
      
    DOI:  https://doi.org/10.1038/s41592-025-02904-y
  12. Nature. 2025 Dec 17.
    Systematic maps reveal how human chromosomes are organized.
    Elzo de Wit.
      
    Keywords:  Cell biology; Computational biology and bioinformatics; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-025-03808-9
  13. Nat Commun. 2025 Dec 13.
    Sodium disrupts mitochondrial energy metabolism to execute NECSO.
    Yuhui Qiao, Jianghuang Wang, Bohong Wang, Hong Zhou, Qianlin Ni, Wan Fu, Zeping Hu, Qing Zhong.
      Na+ influx is a critical pathological event in various conditions such as ischemia, hyperosmotic stress, and organ failure. Although persistent activation of the transient receptor potential cation channel subfamily M member 4 (TRPM4) by chemical agonist Necrocide 1 (NC1) triggers necrosis by sodium overload (NECSO), the underlying mechanism remains to be elucidated. Here, we demonstrate that Na+ influx promotes necrosis by suppressing mitochondrial energy production. TRPM4-mediated Na⁺ entry elevates mitochondrial Na⁺ and reduces mitochondrial Ca²⁺ via NCLX, inhibiting oxidative phosphorylation and the Trichloroacetic acid (TCA) cycle, leading to severe energy depletion. This results in Na/K-ATPase inactivation, loss of ion gradients, cellular swelling and lysis. Our study reveals how sodium overload in NECSO disrupts mitochondrial metabolism to cause energy failure, potentially underlying diseases with elevated Na⁺.
    DOI:  https://doi.org/10.1038/s41467-025-67181-x
  14. Nature. 2025 Dec 17.
    Biobanks reveal genetic complexity in human evolution.
      
    Keywords:  Genetics; Human behaviour
    DOI:  https://doi.org/10.1038/d41586-025-04079-0
  15. Science. 2025 Dec 18. 390(6779): 1314
    The burden of silence.
    Stephanie Bailey.
      
    DOI:  https://doi.org/10.1126/science.aee7297
  16. Nat Commun. 2025 Dec 17.
    Linked data storage using DNA origami nanostructures.
    Chenhao Zhang, Mo Xie, Lianhui Wang, Chunhai Fan, Jie Chao.
      DNA-based storage is an alternative solution for archiving vast cold data. Its future development aims to meet the demands of hot data storage, which requires rapid random access and efficient data modification. Here, we present a DNA origami nanostructure-enabled linked data storage (DONLDS) system that implements a linked list architecture. This system uses distinct DNA origami shapes as nodes to store diverse data (English letters, numerals, Chinese characters) in binary locations, achieving a storage density of 222.22 Gbit/cm2. Pointers, defined by DNA strands at the nanostructure edges, establish data positions. Furthermore, detachable DNA strands serve as instructions, enabling dynamic linking of pointers for accurate storage and their reversible detachment for dynamic data retrieval. The DONLDS system eliminates the need for full-structure traversal, enables parallel data storage, and supports data insertion and removal. This highlights its adaptability and accuracy in managing complex datasets.
    DOI:  https://doi.org/10.1038/s41467-025-66274-x
  17. Nature. 2025 Dec 17.
    The hidden cost of video-call glitches.
      
    Keywords:  Psychology; Society; Sociology
    DOI:  https://doi.org/10.1038/d41586-025-03820-z
  18. Nat Commun. 2025 Dec 16.
    Structural basis for ACT1 oligomerization induced by IL-17 receptor hetero-tetramer.
    Hui Zhang, Xiao-Chen Bai, Xuewu Zhang.
      The IL-17 receptors (IL-17Rs) play critical roles in immunity and inflammatory diseases. IL-17-induced heteromeric complexes between IL-17RA and another IL-17R trigger signaling by binding the downstream transducer ACT1 through interactions between their intracellular SEF/IL-17R (SEFIR) domains. The molecular mechanism of this process remains unclear. Here we present the cryo-EM structure of the complex of IL-17RA, IL-17RB and ACT1, showing that the IL-17RA and IL-17RB SEFIR domains form an asymmetric hetero-tetramer. The two IL-17RA SEFIR domains serve as the base to recruit ACT1, while IL-17RB stabilizes the IL-17RA dimer but makes no interaction with ACT1. IL-17RB, IL-17RA, and multiple ACT1 together form a double-stranded helical assembly. The C-terminal SEFIR extension (SEFEX) of IL-17RA acts as a molecular tendril to help anchor the ACT1 protomers. The structural model is supported by our mutational analyses. These findings reveal the basis for the formation for the signalosome of the IL-17 receptors and ACT1 critical for immune signaling.
    DOI:  https://doi.org/10.1038/s41467-025-67536-4
  19. Nat Commun. 2025 Dec 14.
    Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8+ T cells in mice.
    Srijana Pokhrel, Gayathri Dileepan, Melissa R Leonard, Robert T Warren, Mariam Salem, Allison J Yacapraro, Qiaoke Gong, Devin M Jones, Jasmine A Tuazon, Kaitlin A Read, Jacob S Yount, Gang Xin, Adriana Forero, Hazem E Ghoneim, Patrick L Collins, Emily A Hemann, Kenneth J Oestreich.
      CD8+ virtual memory T (TVM) cells rapidly respond to infection via antigen-independent bystander effector functions. While it is recognized that TVM cells arise independently of foreign antigen encounter, the mechanisms governing their development are not fully understood. Here, we identify the Ikaros transcription factor Aiolos as a negative regulator of TVM cell programming. We observe enhanced frequencies and numbers of TVM in the spleen, liver, and blood of unchallenged Aiolos-deficient (Ikzf3-/-) mice and in the lungs 1-day post-infection with influenza A virus (IAV). Furthermore, Ikzf3-/- TVM cells produce elevated IFN-γ and granzyme B in response to cytokine stimulation. Importantly, Aiolos-deficient mice control IAV more rapidly and exhibit reduced morbidity, indicating enhanced TVM cell functionality. Mechanistically, Aiolos represses the expression of the transcription factor Eomes and the IL-15R subunit CD122, known positive regulators of TVM gene program. Collectively, these findings establish Aiolos as a molecular repressor of TVM programming and responses.
    DOI:  https://doi.org/10.1038/s41467-025-67540-8
  20. Sci Immunol. 2025 Dec 19. 10(114): eaeb2657
    Siglec-F+ neutrophils promote the resolution of acute lung injury through ALOX15 induction.
    Luciana P Tavares, Thayse R Brüggemann, R Elaine Cagnina, Robert Nshimiyimana, Ana B Villaseñor-Altamirano, Rafael M Rezende, Toby B Lanser, Xiaoli Liu, Marjorie E Bateman, Nandini Krishnamoorthy, Stephanie Pons, Melody G Duvall, Raja-Elie E Abdulnour, Alexander Tavares, Kathleen J Haley, Rajesh K Krishnan, Charles N Serhan, Bruce D Levy.
      Neutrophils have vital proinflammatory protective functions, but gene expression changes in neutrophils found in inflamed tissues suggest additional proresolving effects. We identified a neutrophil subset with a distinct phenotype and function that emerges in mouse lungs during resolution of injury. These resolution-phase neutrophils increased expression of Siglec-F (sialic acid-binding Ig-like lectin F), Alox15 (12/15-lipoxygenase), and Csf1 (colony-stimulating factor 1). Siglec-F+ neutrophils promoted macrophage differentiation and produced specialized proresolving mediators that accelerated injury resolution. Neutrophil depletion hindered lung epithelial catabatic responses, whereas adoptive transfer of Siglec-F+ neutrophils accelerated restitution of lung epithelial cells. Transforming growth factor-β (TGF-β) and granulocyte-macrophage colony-stimulating factor (GM-CSF), acting via activator protein-1 (AP-1)/Jun, promoted expression of Siglec-F in mouse neutrophils and ALOX15 in mouse and human neutrophils. In patients with respiratory failure, ALOX15+ neutrophils were present in the bronchoalveolar lavage samples, and their frequency correlated with improved oxygenation. Thus, Siglec-F+ ALOX15+ proresolving neutrophils contribute to tissue injury responses.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb2657
  21. Nat Commun. 2025 Dec 15. 16(1): 11043
    A cholesterol-responsive hepatic tRNA-derived small RNA regulates cholesterol homeostasis and atherosclerosis development.
    Xiuchun Li, Rebecca Hernandez, Xudong Zhang, Sijie Tang, Xiaohong Yuan, Jing Wu, Kathy Pham, Hukam C Rawal, Erica C Heinrich, Shenglong Zhang, Qi Chen, Tong Zhou, Changcheng Zhou.
      Transfer RNA-derived small RNAs (tsRNAs) have emerged as crucial players in diverse biological processes. Yet, their involvement in lipid metabolism and cardiovascular disease remains elusive. Using an advanced PANDORA-seq method, we identify tsRNA-Glu-CTC as the most abundant tsRNA in mouse liver. Intriguingly, tsRNA-Glu-CTC is cholesterol responsive. Overexpression of tsRNA-Glu-CTC elicits hypercholesterolemia and hepatic steatosis, whereas its knockdown protects against diet-induced hypercholesterolemia and atherosclerosis in mice. Mechanistically, tsRNA-Glu-CTC regulates key hepatic lipogenic genes including Srebp2, a master regulator of lipid metabolism. tsRNA-Glu-CTC interacts with SREBP2 to regulate its own transcription through an E-box motif. We further identify site-specific RNA modifications of endogenous tsRNA-Glu-CTC by a mass spectrometry-based MLC-seq and demonstrate the modified tsRNA-Glu-CTC as a more potent regulator of cholesterol homeostasis compared to its unmodified synthetic counterpart. Collectively, our study reveals an important role of a liver-enriched tsRNA in lipid metabolism and cardiovascular health, opening new therapeutic avenues for cardiometabolic disease.
    DOI:  https://doi.org/10.1038/s41467-025-67387-z
  22. Nat Commun. 2025 Dec 17.
    TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
    Massimo Vetralla, Lena Wischhof, Asrat Kahsay, Vanessa Cadenelli, Enzo Scifo, Beijia Xie, Miriana Sbrissa, Maëlle Sandhira Habert, Dan Ehninger, Rosario Rizzuto, Daniele Bano, Diego De Stefani.
      The bidirectional transport of Ca2+ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca2+ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na+/Ca2+ exchanger. Its downregulation chronically elevates basal [Ca²⁺]mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways.
    DOI:  https://doi.org/10.1038/s41467-025-67647-y
  23. 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
  24. Nat Commun. 2025 Dec 15.
    Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.
    Alessia Angelin, Kierstin Keller, Peiran Lu, Joseph W Guarnieri, Gabrielle A Widjaja, Rasheed Sule, Kevin Janssen, Arnold Olali, Zimu Cen, Valeria Carosi, Maina Beauplan, Deborah G Murdock, Prasanth Potluri, Liming Pei, Douglas C Wallace.
      Primary mitochondrial disease (PMD) patients manifesting cardiomyopathy are twice as likely to die as other PMD patients. One PMD with cardiomyopathy is caused by null mutations in the heart-muscle isoform of the adenine nucleotide translocator (SLC25A4, ANT1) gene, with the severity of cardiomyopathy mediated by mitochondrial DNA. To optimize strategies for addressing mitochondrial cardiomyopathy, we generated an Ant1 null mouse and combined it with the ND6P25L mitochondrial DNA mutation to mimic the hypertrophic versus dilated cardiomyopathies observed in patients. Here, we transduce the neonatal Ant1-/- and Ant1-/-+ND6P25L mouse hearts with an AAV2/9-pDes-Gfp-mAnt1 cDNA vector. We show that restoration of just 10% of Ant1 gene expression was sufficient to ameliorate the cardiomyopathies in these mice. Proteomics and single-nucleus RNA sequencing reveal the reversal of dysregulated mitochondrial metabolic genes, including PGC1α, as well as cardiac contractile and extracellular matrix proteins. Hence, a modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41467-025-67134-4
  25. Nat Commun. 2025 Dec 16.
    VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
    Soo-Kyeong Lee, Hyun-Ji Ham, Semin Park, Hye Eun Lee, Ji Young Mun, Deok-Jin Jang, Jin-A Lee.
      Mutations in the gene VPS13B, which encodes a Golgi-associated protein, cause the neurodevelopmental disorder Cohen syndrome, but the protein's function is unclear. Here we show that this protein is essential for mitochondrial morphology and quality control. Cells lacking VPS13B, including neurons derived from Cohen syndrome patients, exhibit abnormally elongated and fused mitochondria with reduced membrane potential and impaired mitophagy. Mechanistically, the protein localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B or depletion of phosphatidylinositol-4-phosphate results in incomplete mitochondrial fission despite normal recruitment of Dynamin-related protein 1, indicating that lipid transfer by VPS13B is required for membrane fission. VPS13B links Golgi-derived lipid vesicles to the mitochondrial fission machinery, ensuring proper mitochondrial fission and quality control and potentially explaining the mitochondrial defects in Cohen syndrome.
    DOI:  https://doi.org/10.1038/s41467-025-67445-6
  26. Lancet Diabetes Endocrinol. 2025 Dec 12. pii: S2213-8587(25)00366-3. [Epub ahead of print]
    Preventing cardiovascular risk in people with prediabetes.
    Linda Mellbin, Lars Rydén.
      
    DOI:  https://doi.org/10.1016/S2213-8587(25)00366-3
  27. Nat Commun. 2025 Dec 18. 16(1): 11282
    Single cell spatial transcriptomics integration deciphers the morphological heterogeneity of atherosclerotic carotid arteries.
    Jessica Pauli, Daniel Garger, Fatemeh Peymani, Justus Wettich, Nadja Sachs, Johannes Wirth, Katja Steiger, Christina Hillig, Hanrui Zhang, Ira Tabas, Alan Tall, Mingyao Li, Muredach P Reilly, Daniela Branzan, Holger Prokisch, Michael P Menden, Lars Maegdefessel.
      The process of arterial atherosclerosis is characterised by accumulation of lipids and fibrous material with accompanying inflammation. As plaques progress, they restrict blood flow and cause rupture, which results in life threatening organ ischemia and dysfunction. Although extensively studied, a clear understanding of plaque heterogeneity and mechanisms that trigger their destabilization remains elusive. Our study reveals the molecular microarchitecture of human carotid artery plaques, using bulk and single-cell RNA sequencing combined with single-cell spatial transcriptomics, for which we present optimized cell segmentation algorithms. We identified distinct plaque morphologies linked to different cell type compositions, impacting early and advanced lesion formation, as well as destabilization. Spatial transcriptomics enabled us to further determine an inflammatory smooth muscle cell subtype, localize regions of neovascularization, and assign hotspots for macrophage activity within distinct cellular neighbourhoods across lesions. For different macrophage substates, we propose gradual and locally contained transdifferentiation of subluminal inflammatory HMOX1+ macrophages into a lipid-handling TREM2+ phenotype within border zones of the fibrous cap and necrotic core. Our findings provide insight into the complex heterogeneity of human atherosclerosis by unravelling location and proximity of different mural and immune cell substates involved in plaque progression and vulnerability.
    DOI:  https://doi.org/10.1038/s41467-025-67679-4
  28. Nat Commun. 2025 Dec 13.
    Flexible read-aware genotype imputation from sequence using biobank sized reference panels.
    Zilong Li, Anders Albrechtsen, Robert W Davies.
      Inexpensive and accurate genotyping methods are essential to modern genomics and health risk prediction. Here we introduce QUILT2, a scalable and read-aware imputation method that can efficiently use biobank scale haplotype reference panels. This allows for fast and accurate imputation using short reads, as well as long reads (e.g. Oxford Nanopore Technologies (ONT) 1X, r2 = 0.937 at common SNPs), linked-reads and ancient DNA. In addition, QUILT2 contains a methodological innovation that is designed to enable imputation of the maternal and fetal genome using cell free non-invasive prenatal testing (NIPT) data. Using a UK Biobank reference panel and simulated NIPT data, we see accurate imputation of the mother (0.25X, r2 = 0.966, common SNPs) and modest imputation of the fetus (0.25X, r2 = 0.465, fetal fraction of 10%) at low coverage, with fetal imputation accuracy rising with coverage (4.0X, fetal r2 = 0.894). We show using simulated data that this could enable both GWAS and PRS for the mother and fetus, which could create clinical opportunities, and if phenotypes can be collected alongside clinical NIPT, the potential for large GWAS.
    DOI:  https://doi.org/10.1038/s41467-025-67218-1
  29. Nat Aging. 2025 Dec 17.
    Integrating polygenic signals and single-cell multiomics identifies cell-type-specific regulomes critical for immune- and aging-related diseases.
    Yunlong Ma, Yinghao Yao, Yijun Zhou, Wei Dai, Jingjing Li, Yuanyuan Gui, Haojun Sun, Zhengbiao Zhu, Dingping Jiang, Cheng Chen, Chunyu Deng, Yizhou Huang, Haijun Han, Jianhong Zhou, Jianzhong Su.
      Single-cell multiomics provides critical insights into how disease-associated variants identified through genome-wide association studies (GWASs) influence transcription factor eRegulons within a specific cellular context; however, the regulatory roles of genetic variants in aging and disease remain unclear. Here, we present scMORE, a method that integrates single-cell transcriptomes and chromatin accessibility with GWAS summary statistics to identify cell-type-specific eRegulons associated with diseases. scMORE effectively captures trait-relevant cellular features and demonstrates robust performance across simulated and real single-cell datasets, and GWASs for 31 immune- and aging-related traits, including Parkinson's disease (PD). In the human midbrain, scMORE identifies 77 aging-relevant eRegulons implicated in PD across seven brain cell types and reveals sex-dependent dysregulation of these eRegulons in PD neurons compared to both young and aged groups. By linking genetic variation to cell type-resolved eRegulon activity, scMORE illuminates how variants shape trait-relevant regulatory networks and provides a practical framework for mechanistic interpretation of GWAS signals.
    DOI:  https://doi.org/10.1038/s43587-025-01027-5
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