bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–09–07
23 papers selected by
Fawaz Alzaïd, Sorbonne Université



  1. Nature. 2025 Sep;645(8079): 7
      
    Keywords:  Nutrition; Obesity; Public health
    DOI:  https://doi.org/10.1038/d41586-025-02750-0
  2. Science. 2025 Sep 04. 389(6764): 1062
      
    DOI:  https://doi.org/10.1126/science.aeb8662
  3. Cell. 2025 Aug 25. pii: S0092-8674(25)00921-3. [Epub ahead of print]
      The liver undergoes metabolic adaptations during gestation and lactation to meet evolving physiological demands, yet the precise processes, regulatory mechanisms, and functions remain unclear. Using high-resolution single-cell RNA sequencing, we systematically characterized hepatocyte adaptations in mice across pregnancy and postpartum stages. We discovered a cyclical hepatocyte trajectory ("pregnancy clock") that governs metabolic changes during gestation and postpartum recovery, reverting to pregestational states in non-lactating mice. Lactation induced a distinct branching trajectory characterized by elevated lipid synthesis and export. Deletion of glycoprotein 130 (gp130) disrupted hepatic adaptations during pregnancy, impairing fetal growth, whereas acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) deficiency postpartum impaired hepatic lipid biosynthesis and export, reducing milk lipid content and compromising offspring development. Comparative analysis with sheep highlighted conserved hepatic metabolic adaptation pathways despite genetic divergence between species. These insights clarify hepatocyte plasticity during pregnancy and lactation, identifying potential therapeutic targets to optimize maternal-fetal health and lactation performance, with implications for reproductive biology and livestock management.
    Keywords:  ACSS2; JAK/STAT signaling; gestation; gp130; hepatocyte adaptations; lactation; maternal liver function; pregnancy clock; sheep hepatocytes; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2025.08.007
  4. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  5. Nature. 2025 Sep;645(8079): 22-25
      
    Keywords:  Metabolism; Nutrition; Obesity; Policy; Public health
    DOI:  https://doi.org/10.1038/d41586-025-02754-w
  6. Nat Methods. 2025 Sep 03.
      T cells recognize antigens and induce specialized gene expression programs (GEPs), enabling functions like proliferation, cytotoxicity and cytokine production. Traditionally, different T cell classes are thought to exhibit mutually exclusive responses, including TH1, TH2 and TH17 programs. However, single-cell RNA sequencing has revealed a continuum of T cell states without clearly distinct subsets, necessitating new analytical frameworks. Here, we introduce T-CellAnnoTator (TCAT), a pipeline that improves T cell characterization by simultaneously quantifying predefined GEPs capturing activation states and cellular subsets. Analyzing 1,700,000 T cells from 700 individuals spanning 38 tissues and five disease contexts, we identify 46 reproducible GEPs reflecting core T cell functions including proliferation, cytotoxicity, exhaustion and effector states. We experimentally demonstrate new activation programs and apply TCAT to characterize activation GEPs that predict immune checkpoint inhibitor response across multiple tumor types. Our software package starCAT generalizes this framework, enabling reproducible annotation in other cell types and tissues.
    DOI:  https://doi.org/10.1038/s41592-025-02793-1
  7. Nat Aging. 2025 Sep 02.
      Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38+ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.
    DOI:  https://doi.org/10.1038/s43587-025-00952-9
  8. Sci Immunol. 2025 Sep 05. 10(111): eaeb8328
      A new orally bioavailable HO-1 inhibitor enhances tumor clearance after chemotherapy in mice by enhancing the recruitment of CD8 T cells.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb8328
  9. Sci Adv. 2025 Aug 29. 11(35): eads7381
      Uncovering the role of upstream open reading frames (uORFs) challenges conventional views of one protein per messenger RNA and reveals the capacity of some uORFs to encode microproteins that contribute to cellular biology and physiology. This study explores the functional role of a recently identified mitochondrial microprotein, SLC35A4-MP, in the brown adipose tissue of mice. Our findings reveal dynamic regulation of SLC35A4-MP expression during primary brown adipocyte differentiation in vitro and during cold exposure or high-fat diet (HFD)-induced obesity in mice. Using a knockout mouse model, we show that loss of SLC35A4-MP disrupts mitochondrial lipid composition, decreasing cardiolipins and phosphatidylethanolamine in brown adipose tissue from HFD-fed mice. SLC35A4-MP deficiency also impairs mitochondrial activity, alters mitochondrial number and morphology, and promotes inflammation. Knockout mice accumulate acylcarnitines during cold exposure, indicating defective fatty acid oxidation. These findings reveal SLC35A4-MP as a previously unrecognized microprotein in regulating mitochondrial function and tissue lipid metabolism, adding to the growing list of functional endogenous microproteins.
    DOI:  https://doi.org/10.1126/sciadv.ads7381
  10. Nature. 2025 Sep 03.
      Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process1. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life2. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.
    DOI:  https://doi.org/10.1038/s41586-025-09435-8
  11. Lancet Diabetes Endocrinol. 2025 Aug 22. pii: S2213-8587(25)00200-1. [Epub ahead of print]
      
    DOI:  https://doi.org/10.1016/S2213-8587(25)00200-1
  12. EMBO Rep. 2025 Aug 29.
      Mitochondrial damage represents a dramatic change in cellular homeostasis, necessitating metabolic adaptation and clearance of the damaged organelle. One rapid response to mitochondrial damage is peri-mitochondrial actin polymerization within 2 min, which we term ADA (Acute Damage-induced Actin). ADA is vital for a metabolic shift from oxidative phosphorylation to glycolysis upon mitochondrial dysfunction. In the current study, we investigated the effect of ADA on Pink1/Parkin mediated mitochondrial quality control. We show that inhibition of proteins involved in the ADA pathway significantly accelerates Parkin recruitment onto depolarized mitochondria. Addressing the mechanism by which ADA resists Parkin recruitment onto depolarized mitochondria, we found that ADA disrupts ER-mitochondria contacts in an Arp2/3 complex-dependent manner. Interestingly, overexpression of ER-mitochondria tethers overrides the effect of ADA, allowing rapid recruitment of not only Parkin but also LC3 after mitochondrial depolarization. During chronic mitochondrial dysfunction, Parkin and LC3 recruitment are completely blocked, which is reversed rapidly by inhibiting ADA. Taken together we show that ADA acts as a protective mechanism, delaying mitophagy following acute damage, and blocking mitophagy during chronic mitochondrial damage.
    Keywords:  Actin; Arp2/3 Complex; ER; LC3; Parkin
    DOI:  https://doi.org/10.1038/s44319-025-00561-y
  13. Nature. 2025 Sep 01.
      
    Keywords:  Ageing; Diseases; Epigenetics; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-02735-z