bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–05–10
twelve papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
  2. 'FILMing' the metabolic landscape of individual cell organelles.
  3. Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
  4. Monocyte-derived macrophages drive neurological tissue damage through mitochondrial reactive oxygen species.
  5. Population-based genome-wide association study of plasma complex lipid species.
  6. Mitochondrially tethered Mmm1 can function as a sole lipid transporter at ER-mitochondria contacts.
  7. Structural basis for double-stranded DNA cytosine deamination by BaDTF3 and its application in mitochondrial genome editing.
  8. FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
  9. Astrocytic cholesterol jams brain clearance in AD.
  10. HuR coordinates systemic aging through platelet infiltration.
  11. 5'tRNA-derived fragments modulate β-cell homeostasis and islet macrophage activation in type 2 diabetes.
  12. High-fat diet feeding induces organ-specific vascular remodeling with distinct temporal dynamics in male mice.
  1. Nat Metab. 2026 May 08.
    Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
      
    DOI:  https://doi.org/10.1038/s42255-026-01532-w
  2. Nat Methods. 2026 May 07.
    'FILMing' the metabolic landscape of individual cell organelles.
      
    DOI:  https://doi.org/10.1038/s41592-026-03091-0
  3. Nat Commun. 2026 05 07. pii: 4195. [Epub ahead of print]17(1):
    Mitochondria serve as a holdout compartment for aggregation-prone proteins hindering efficient degradation.
    Maria E Gierisch, Enrica Barchi, Mirco Marogna, Moritz H Wallnöfer, Maria Ankarcrona, Luana Naia, Florian A Salomons, Nico P Dantuma.
      The accumulation of protein aggregates has been causatively linked to the pathogenesis of neurodegenerative diseases. Here, we conduct a genome-wide CRISPR-Cas9 screen to identify cellular factors that regulate the degradation of an aggregation-prone reporter. Genes encoding proteins involved in mitochondrial homeostasis, including the translation factor eIF5A, are enriched among suppressors of the degradation of the reporter. Genetic or chemical inhibition of eIF5A leads to dissociation of the aggregation-prone substrate from mitochondria, which is accompanied by enhanced ubiquitin-dependent proteasomal degradation. The presence of an aggregation-prone, amphipathic helix that localizes the reporter to mitochondria is crucial for the stimulatory effect of eIF5A inhibition on proteasomal degradation. Additionally, inhibition of eIF5A also enhances degradation of mutant huntingtin and α-synuclein, two disease-associated proteins that contain amphipathic helices and mislocalize to mitochondria. We propose that mitochondria serve as a holdout compartment for aggregation-prone proteins. Therefore, preventing mitochondrial localization of aggregation-prone proteins may offer a viable therapeutic strategy for reducing disease-associated proteins in neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-026-72783-0
  4. Sci Immunol. 2026 May 08. 11(119): eadw5197
    Monocyte-derived macrophages drive neurological tissue damage through mitochondrial reactive oxygen species.
    Juan Villar-Vesga, Donatella De Feo, Pauline Clément, Viola Bugada, Elèni Meuffels, Hannah Van Hove, Mitchell Bijnen, James King, Sophie Grundschober, Can Ulutekin, Maria Pena-Francesch, Sara Costa-Pereira, Laura Oberbichler, Violetta Gogoleva, Jeanne Kim, Katarina Wendy Schmidt, Musadiq A Bhat, Deborah Greis, Frauke Seehusen, Francesco Prisco, Urvashi Dalvi, Dietmar Benke, Bettina Schreiner, Tommaso Patriachi, Florian Ingelfinger, Isabelle C Arnold, Christian Münz, Melanie Greter, Aiman S Saab, Burkhard Becher, Sarah Mundt.
      Reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs) are widely believed to drive tissue damage in multiple sclerosis (MS), yet the distinct roles of central nervous system (CNS)-resident versus CNS-invading MPs remain unclear. Here, we combined single-cell profiling and conditional gene targeting to map and modulate ROS production across CNS MPs in a preclinical mouse model of MS. We show that monocyte-derived macrophages (MdMs) exhibit a higher oxidative stress gene signature and produce more ROS than microglia (Mglia). Challenging previous assumptions, our findings reveal that phagocytic NADPH oxidase 2 is dispensable for neuroinflammation. In contrast, quenching mitochondrial ROS (mtROS) through mitochondria-targeted catalase (mCAT) expression in MdMs, but not in Mglia, ameliorated disease severity in acute neuroinflammation. Although core phagocyte functions were unaltered in mCAT-expressing MdMs, our results demonstrate a direct neurotoxic role of mtROS. In sum, we identify MdMs as the primary driver of ROS-mediated oxidative neurological tissue damage.
    DOI:  https://doi.org/10.1126/sciimmunol.adw5197
  5. Nat Commun. 2026 05 02. pii: 3984. [Epub ahead of print]17(1):
    Population-based genome-wide association study of plasma complex lipid species.
    Elvire N Landstra, Mohammed A Imtiaz, Valentina Talevi, Fabian Eichelmann, Matthias B Schulze, N Ahmad Aziz, Monique M B Breteler.
      The human lipidome comprises numerous complex lipids, dysregulation of which can contribute to the pathogenesis of a wide range of diseases. Despite the high heritability of parts of the lipidome, the genetic architecture of many circulating lipid species and their structure remains mostly unknown. Thus, we perform genome-wide association studies on 970 lipid species and 267 fatty acid composite measures using samples from the population-based Rhineland Study (n = 6096). We validate our findings using corresponding data from two other independent cohorts, including FinnGen (n = 7266) and EPIC-Potsdam (n = 1188). Out of 217 lead genomic loci, we find 136 to be novel, such as FDFT1. Using mendelian randomization and individual-level gene expression data, we identify 43 possible causal associations between candidate genes and corresponding lipid species, including FDFT1 - diacylglycerol (16:0/18:0). Our findings provide new insights into the intricate genetic underpinnings of lipid metabolism, which may facilitate risk stratification and discovery of new therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-72542-1
  6. J Cell Biol. 2026 Jul 06. pii: e202411196. [Epub ahead of print]225(7):
    Mitochondrially tethered Mmm1 can function as a sole lipid transporter at ER-mitochondria contacts.
    Christian Covill-Cooke, Takashi Hirashima, Shin Kawano, Joe Ganellin, Andrew Moody, Sabine N S van Schie, Arun T John Peter, Chika Horie Saito, Toshiya Endo, Benoît Kornmann.
      Yeast mitochondria receive the majority of their lipids from the ER via the heterotetrameric ERMES lipid transport complex. This complex is thought to establish a lipid-transporting bridge of fixed composition spanning the space between both organelles. Intriguingly, however, some of the lipid-transporting components of the complex can be replaced by an artificial ER-mitochondria tether without lipid transport activity, questioning ERMES' relevance in lipid transport. Here, we show that Mmm1, one of the four ERMES subunits, alone is sufficient to support ERMES function when it is artificially tethered to mitochondria, provided its lipid-binding domain is intact. Combined with our previous finding that the absence of Mdm12 and Mdm34 can be rescued by the presence of Mmm1 and the artificial tethering protein ChiMERA, our results suggest that Mmm1 can act as the sole lipid transporter at the ER-mitochondrial contact sites, provided that Mdm10 is present, even in the absence of the other two subunits. Thus, our work reconciles ERMES' importance in lipid transport with the fact that the lipid transport activity of some of its components is not strictly necessary for function.
    DOI:  https://doi.org/10.1083/jcb.202411196
  7. Nat Commun. 2026 May 05.
    Structural basis for double-stranded DNA cytosine deamination by BaDTF3 and its application in mitochondrial genome editing.
    Lulu Yin, Chae Jin Lim, Ke Shi, Jae Hee Yoon, Bong-Kook Ko, Seungmin Ryou, Jin-Soo Kim, Hideki Aihara.
      Bacterial deaminase toxin family (BaDTF) proteins are weapons used in bacterial warfare, and they are useful tools in base editing, epigenetics analyses, and genomic footprinting applications. Our previous studies revealed the mechanisms of 5'-TC-specific cytosine deamination in double-stranded (ds)DNA by DddA from BaDTF1 and sequence context-independent single-stranded (ss)DNA cytosine deamination by SsdA from BaDTF2. Here, we show that a representative member of BaDTF3, DddB, deaminates cytosines specifically in dsDNA, but with a broad sequence context preference. Our crystal structure of DddB bound to dsDNA reveals a distinct mechanism of substrate engagement, in which a helix-hairpin-helix motif inserted into the minor groove of dsDNA promotes flipping of the target cytosine into the enzyme active site. Based on the structural information, we generate both monomeric and split DddB-derived cytosine base editors (BdCBE) and demonstrate that they can perform CRISPR-free mitochondrial base editing in human cells, with an expanded targeting scope compared to the DddA-derived DdCBEs. Our studies highlight the mechanistic diversity among BaDTF proteins and expand the repertoire of dsDNA deaminase enzymes for genome editing and other applications.
    DOI:  https://doi.org/10.1038/s41467-026-72730-z
  8. Nat Methods. 2026 May 07.
    FILM: mapping organellar metabolism by mid-infrared photothermal-modulated fluorescence.
    Jianpeng Ao, Jiaze Yin, Haonan Lin, Guangrui Ding, Youchen Guan, Marzia Savini, Bethany Weinberg, Dashan Dong, Qing Xia, Zhongyue Guo, Bowen Liu, Biwen Gao, Ji-Xin Cheng, Meng C Wang.
      Metabolism unfolds within specific organelles in eukaryotic cells. Lysosomes are highly metabolically active organelles, and their metabolic states dynamically influence signal transduction, cellular homeostasis and organismal physiopathology. Despite the importance of lysosomal metabolism, a method for its in vivo measurement is currently lacking. Here we report a fluorescence-detected mid-infrared photothermal microscope (FILM) implemented with optical boxcar demodulation, artificial intelligence-assisted data denoising and spectral deconvolution, to map metabolic activity and composition of individual lysosomes in living cells and organisms. Using this method, we uncovered lipolysis and proteolysis heterogeneity across lysosomes within the same cell, as well as early-onset lysosomal dysfunction during organismal aging. In addition, we discovered organelle-level metabolic changes associated with diverse lysosomal storage diseases. This method holds the broad potential to profile metabolic fingerprints of individual organelles within their native context and quantitatively assess their dynamic changes under different physiological and pathological conditions, providing a high-resolution chemical cellular atlas.
    DOI:  https://doi.org/10.1038/s41592-026-03090-1
  9. Nat Neurosci. 2026 May 05.
    Astrocytic cholesterol jams brain clearance in AD.
    Daan Verhaege, Jonathan Kipnis.
      
    DOI:  https://doi.org/10.1038/s41593-026-02310-3
  10. Nat Commun. 2026 May 07.
    HuR coordinates systemic aging through platelet infiltration.
    Cihang Liu, Ying Wang, Tianjiao Xia, Jing Lin, Qianzan Liao, Yanyan Li, Yiqiang Zhang, Congxiu Miao, Xia Yi, Luyang Sun, Zhengliang Ma, Xiaolei Cheng, Bin Jiang, Feng Tian, Zhenyu Ju, Baohua Liu, Wei Kong, Yi Fu, Zhongzhou Yang, Junling Liu, Hao Tang, Xiaoping Gu, Wengong Wang.
      Aging involves morphological and functional changes across different organs, but how these changes are linked among the different organs remains to be elucidated. Here, we uncover a central role of platelets in systemic aging. In aged mice, the levels of platelet-secreted pro-inflammatory factors (PSPF) increased greatly in the serum and platelets, leading to a diffuse increase of platelet infiltration in the brain, liver, lung, kidney, and aortic root. The RNA-binding protein HuR/ELAVL1, a major regulator of RNA metabolism, promoted the production of PSPF in platelets. Platelet-specific deletion of HuR reduced the expression of PSPF in platelets, alleviated platelet infiltration in the brain, liver, lung, kidney, and aortic root, and delayed systemic aging. By using single-nucleus sequencing, platelet-specific HuR ablation was found to alleviate p53 and pro-inflammatory signaling pathways in liver, lung, and brain tissues in aged mice. Our findings highlight a role of platelets in coordinating aging traits across organs.
    DOI:  https://doi.org/10.1038/s41467-026-72481-x
  11. Nat Commun. 2026 May 04.
    5'tRNA-derived fragments modulate β-cell homeostasis and islet macrophage activation in type 2 diabetes.
    Cristina Cosentino, Rémy Klein, Véronique Menoud, Claudiane Guay, Elena Aiello, Stefano Auddino, Gianfranco Di Giuseppe, Gea Ciccarelli, Alessandra Galli, Francesco Alabiso, Eleonora Mangano, Flora Brozzi, Karim Bouzakri, Stefania D'Adamo, Silvia Cetrullo, Giuseppe Quero, Andrea Mari, Sergio Alfieri, Andrea Giaccari, Teresa Mezza, Francesco Dotta, Guido Sebastiani, Romano Regazzi.
      Obesity and diabetes impose chronic stress on pancreatic β-cells, while reprogramming of islet-resident macrophages (iMACs) accelerates dysfunction. Here, we identify transfer RNA-derived fragments (tRFs) as previously unrecognized mediators of islet remodeling under metabolic stress. 5'tRFGlu(CTC) and 5'tRFGly(GCC) are elevated in β-cells and iMACs from db/db mice and in islets from individuals with type 2 diabetes; 5'tRFGlu(CTC) also rises in prediabetes and inversely correlates with insulin secretion. Lipotoxicity triggers 5'tRF biogenesis, and targeted inhibition of 5'tRFGlu(CTC) preserves β-cell viability and function under palmitate exposure. In a β-cell/macrophage co-culture model, β-cell contact shapes a distinct iMAC-like phenotype that shifts after palmitate treatment. Inhibiting 5'tRFGlu(CTC) in iMAC-like cells prevents their activation switch and protects β-cells from lipotoxicity. Mechanistically, 5'tRFGlu(CTC) interacts with RNA-binding proteins to control immune activation, extracellular matrix remodeling, and oxidative stress pathways. These findings position tRFs as central effectors of cellular stress responses in both endocrine and immune cells.
    DOI:  https://doi.org/10.1038/s41467-026-72641-z
  12. Commun Biol. 2026 May 09.
    High-fat diet feeding induces organ-specific vascular remodeling with distinct temporal dynamics in male mice.
    Emmi Pakarinen, Satu Paavonsalo, Madeleine H Lackman, Yelin Subashi, Hanna M Ruddock, Sinem Karaman.
      Obesity-induced changes in adipose vasculature are well documented, but systematic analyses in other tissues have not been as extensive. Here, we analyze the vessel-covered area and endothelial cell (EC) numbers in seven non-adipose organs (liver, heart, intestine, kidney, lung, ear skin, retina) in male mice after short-term high-fat diet (HFD) feeding (5 days or 5 weeks), long-term HFD feeding (10 weeks), and weight loss (5 weeks of HFD followed by 5 weeks of chow feeding). We show HFD-induced morphological changes in the liver, heart, kidney, and intestinal vasculatures, and a negative correlation between body weight and vessel density in most of the analyzed tissues. Interestingly, changes in vessel area do not always reflect alterations in EC numbers. Additionally, both the intestine and ear skin show preserved vessel perfusion in response to obesity. This study provides a comprehensive analysis of how different HFD feeding durations affect organotypic vasculature and reports that HFD feeding induces organ-specific vascular remodeling with distinct temporal dynamics in mice.
    DOI:  https://doi.org/10.1038/s42003-026-10092-4
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