Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pat...Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Here we show that SLC25A12 plays a previously unrecognized role in stress signalling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signalling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signalling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies.
Wei N, Zhan H, Deng Y
… +12 more, Liu M, Xiao Y, Gong Y, Wang X, Guan P, Lou X, Xie Y, Wang Y, Li Z, Dai L, Hu H, Zhang H
Nat Cell Biol
· 2026 Jun · PMID 42191895
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Haematopoietic stem cells (HSCs) produce all blood and immune cells throughout life, but ageing progressively impairs their function, generating excessive myeloid and megakaryocyte cells at the expense of lymphocytes. Th...Haematopoietic stem cells (HSCs) produce all blood and immune cells throughout life, but ageing progressively impairs their function, generating excessive myeloid and megakaryocyte cells at the expense of lymphocytes. This lineage imbalance contributes to immune decline, chronic inflammation and increased disease susceptibility in the elderly, yet the underlying mechanisms remain poorly understood. Here we show that a specific Meg3 HSC subset (CD150Sca1CD24CD201CD9CD63 long-term HSCs) expands dramatically during ageing and drives this lineage skewing. Using multi-omics profiling, we found that inflammatory signals increase H3K23ac levels in aged Meg3 HSCs, enhancing PU.1 activity through recruitment of the reader protein TRIM24. This epigenetic mechanism promotes excessive megakaryocyte and myeloid production. Of note, disrupting H3K23ac-TRIM24 interaction in aged HSCs restored balanced lineage output and reduced inflammatory signals. Our findings reveal a key mechanism linking inflammation to HSC ageing and identify potential therapeutic targets for reversing ageing-related immune decline.
Nat Cell Biol
· 2026 Jun · PMID 42191894
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Numerous metabolic enzymes translocate from the endoplasmic reticulum (ER) membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane pro...Numerous metabolic enzymes translocate from the endoplasmic reticulum (ER) membrane bilayer to the lipid droplet (LD) monolayer, where they perform essential functions. Mislocalization of certain LD-targeted membrane proteins, including HSD17B13 and PNPLA3, is implicated in metabolic dysfunction-associated steatotic liver disease. However, the mechanisms governing the trafficking and accumulation of ER proteins on LDs remain poorly understood. Here using minimal fluorescence photon fluxes nanoscopy and highly inclined and laminated optical single-molecule tracking combined with machine learning, we show that HSD17B13, GPAT4 and the model cargo 'LiveDrop' diffuse at comparable speeds in the ER and on LDs, but become nano-confined upon reaching the LD surface. Mechanistic dissection of LiveDrop targeting revealed that this confinement, along with protein accumulation on LDs, depends on specific residues within its targeting motif. These residues mediate preferential interactions with nanoscale membrane domains, suggesting that LD-targeted proteins selectively partition into distinct lipid-protein environments that transiently alter local motion and concentrate them at the LD surface. Single-molecule trajectories further revealed bidirectional trafficking of LiveDrop across seipin-containing ER-LD bridges, providing direct evidence for lateral protein transfer across membrane contact sites. These findings establish nanodomain-based confinement as a key mechanism driving selective protein accumulation on LDs and reveal how membrane bridges between organelles facilitate protein sorting.
Rodríguez-Correa E, Grünschläger F, Nizharadze T
… +29 more, Anstee N, Al-Sabah J, Kumpost V, Sedlmeier A, Li C, Ball M, Fotopoulou F, Jayarajan J, Ghezzi I, Knoch J, Druce M, Aurich K, Büchler-Schäff M, Lux S, Hernández-Malmierca P, Gräsel J, Vonficht D, López-Osias M, González-Saiz E, Fernández-Pérez D, Mathioudaki A, Zaugg J, Rodríguez-Fraticelli A, Mikut R, Trumpp A, Höfer T, Hübschmann D, Haas S, Milsom MD
Nat Cell Biol
· 2026 Jun · PMID 42185517
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Haematopoietic stem cells (HSCs) display extensive molecular and functional heterogeneity. However, a cohesive model that explains the relationship and biological relevance of these diverse HSC states remains elusive. He...Haematopoietic stem cells (HSCs) display extensive molecular and functional heterogeneity. However, a cohesive model that explains the relationship and biological relevance of these diverse HSC states remains elusive. Here, by performing single-cell transplantations of over 1,000 highly purified murine long-term HSCs combined with in-depth phenotyping of their clonal progeny, we define kinetics-based reconstitution parameters which aligned HSCs into a single hierarchical trajectory reflective of functional potency. This approach revealed that previously identified lineage biases are actually transitory states along this linear trajectory, not a discrete stable condition. Single-cell secondary transplantations validated hierarchical ordering based on reconstitution kinetics, whereas mathematical modelling combined with experimental modulation of lineage-biased blood production revealed that apparent lineage-biased outputs actually arise from cell-extrinsic feedback regulation and clonal competition between slow- and fast-engrafting clones to fill mature lineages to their compartment size limit. This study reconciles multiple layers of HSC heterogeneity into a unifying framework.
Ge Z, Wang Z, Zhao E
… +28 more, Guo Y, Zhang L, Tian F, Li M, Ma Y, Ding F, He L, Sun S, Tong M, Xu W, Wang X, Zhang J, Wu L, Zhang Y, Niu L, Wang Q, Yin R, Li X, You Y, Rich JN, Wang X, Yao B, Shi Z, Yang Z, Ge X, Liu F, Chu B, Qian X
Glioblastoma stem cells (GSCs) are refractory to first-line treatment in the clinic, which includes irradiation (IR) and temozolomide (TMZ). Here we find that disrupting stress granules (SGs) sensitizes GSCs to IR/TMZ th...Glioblastoma stem cells (GSCs) are refractory to first-line treatment in the clinic, which includes irradiation (IR) and temozolomide (TMZ). Here we find that disrupting stress granules (SGs) sensitizes GSCs to IR/TMZ through ferroptosis. The profiling of SG proteins reveals the recruitment of iron-related proteins including ferritin. Mechanistically, G3BP1, an SG core protein, directly interacts with ferritin light chain in an IR/TMZ-induced G3BP1 methionine-333 oxidation-dependent manner. This interaction facilitates recruiting and sequestering ferritin into SGs, thereby restricting ferroptosis by limiting Fe content in the labile iron pool and preventing ferritinophagy. Disrupting G3BP1 and ferritin light chain binding using a screened small molecule, ciwujianoside C3, mitigates the restriction of SGs on ferroptosis, and resensitizes GSCs to IR/TMZ in both in vitro and animal models. These findings unveil a negative regulation of SGs on ferroptosis, and reveal a promising strategy to disrupt the SG-ferroptosis axis for treating glioblastomas and probably other types of cancer.
Downes KW, Flood JR, Nans A
… +3 more, Van der Verren SE, Audhya A, Zanetti G
Nat Cell Biol
· 2026 Jun · PMID 42162283
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Trafficking of secretory proteins from the endoplasmic reticulum (ER) to the Golgi apparatus comprises the first, essential steps towards the appropriate localization of 30% of eukaryotic proteins. Coat protein complexes...Trafficking of secretory proteins from the endoplasmic reticulum (ER) to the Golgi apparatus comprises the first, essential steps towards the appropriate localization of 30% of eukaryotic proteins. Coat protein complexes COPII and COPI are involved in the forward and retrograde transport of cargo and cargo receptors between the ER and the Golgi, respectively. Although COPII forms coated vesicles in vitro, the biogenesis, morphology and organization of transport carriers in mammalian cells is subject to debate. Here we use in situ cryo-electron tomography and super-resolution fluorescence microscopy to reveal the molecular architecture of ER exit sites in human cells that were not perturbed with drugs, temperature blocks or overexpression systems. We visualize ribosome-exclusion zones enriched with COPII- and COPI-coated vesicles and thus resolve the debate regarding the existence of COPII-coated vesicles. COPII vesicles derive from ER membranes, whereas COPI vesicles originate from vesicular-tubular clusters that constitute the ER-Golgi intermediate compartment (ERGIC). We quantify coated vesicle morphology and positioning with respect to other ER exit site components, providing a molecular description of the organization of the mammalian early secretory pathway.
Owing to the ability of extracellular vesicles (EVs) to encapsulate and transfer biomolecules for intercellular communication, EVs are recognized as promising candidates as biomarkers and therapeutic delivery vehicles. S...Owing to the ability of extracellular vesicles (EVs) to encapsulate and transfer biomolecules for intercellular communication, EVs are recognized as promising candidates as biomarkers and therapeutic delivery vehicles. Small EVs (S-EVs), below 200 nm in diameter, have previously been the major focus in the EV field, but large EVs (L-EVs) are gaining considerable interest, with many distinct subsets of L-EVs having been described in the past few years. Here we review L-EV biogenesis from a context-specific perspective, focusing on the biological settings that drive L-EV formation. We also discuss the roles of L-EVs in facilitating the removal of unwanted cellular content and intercellular communication. Finally, we identify key challenges in the L-EV field and discuss future investigations towards harnessing L-EVs for diagnostic and therapeutic applications.
Autorino C, Khoromskaia D, Harari L
… +8 more, Floris E, Booth H, Pallares-Cartes C, Petrasiunaite V, Dorrity M, Corominas-Murtra B, Hadjivasiliou Z, Petridou NI
Nat Cell Biol
· 2026 Jun · PMID 42135506
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During development, local mechanochemical cues within the cell microenvironment are translated into signalling pathways that drive cell fate decisions. Yet, as cells differentiate collectively, how global tissue-level pr...During development, local mechanochemical cues within the cell microenvironment are translated into signalling pathways that drive cell fate decisions. Yet, as cells differentiate collectively, how global tissue-level properties shape these instructive cues remains unclear. Here we show that a tissue-scale rigidity transition guides patterning by tuning the length scales and timescales of morphogen signalling. By combining rigidity percolation theory, reaction-diffusion modelling, quantitative imaging and optogenetics in zebrafish, we uncover dynamical global tissue rigidity patterns that actively shape the Nodal morphogen gradient by locally changing its concentration and accelerating its signalling activity. In this self-generated mechanism, Nodal, besides instructing meso-endoderm fate specification, increases cell-cell adhesion strength via regulating planar cell polarity genes. Once the adhesion strength reaches a critical point, it triggers a rigidity transition which, in turn, induces the collapse of tissue porosity. The abrupt tissue reorganization negatively feeds back on Nodal signalling, impacting both its length scales, by restricting Nodal diffusivity, and its timescales, by speeding up the expression of its antagonist Lefty, thereby ensuring timely signal termination and robust patterning. Overall, we uncover a multiscale regulatory mechanism by which positional information and tissue material properties dynamically tune one another.
Zhao Z, Wang J, Xiong X
… +18 more, Zhang S, Yang M, Wu H, Liu X, Ma X, Chen Y, Qiao Y, Cao J, Mei Y, Yao J, Du P, Wu Y, Jiang G, Zhao X, Liu Q, Xu Z, Zhou H, Suo G
Substantial evidence indicates that cancer stem cells (CSCs) drive breast cancer (BRC) initiation, progression, therapy resistance, recurrence and metastasis. Evaluating drug efficacy against patient-derived CSCs can adv...Substantial evidence indicates that cancer stem cells (CSCs) drive breast cancer (BRC) initiation, progression, therapy resistance, recurrence and metastasis. Evaluating drug efficacy against patient-derived CSCs can advance precision oncology. However, high-throughput isolation of functional CSCs from small clinical samples remains challenging. Tumoursphere formation, arising from the clonal expansion of a single cancer cell, is a standard in vitro method for CSC assay and enrichment. Here we show a microwell cell-chip culture platform that enables rapid, high-throughput generation of uniform micro-tumourspheres (MTSs) from limited BRC specimens, such as puncture biopsies, facilitating functional CSC enrichment and personalized drug testing within 8 days. Single-cell transcriptomics and limiting dilution tumour initiation assay confirm that MTSs recapitulate CSC functionality, uniformity and heterogeneity. MTSs predicted clinical outcomes in 16 patients with BRC with ~93.8% accuracy, underscoring their translational potential for personalized drug testing. Overall, this platform provides a robust tool for CSC-targeted precision medicine.
Major advances over the past few decades have highlighted the complex regulation of RNA from transcription to nuclear export and from translation to decay. Despite the emerging cellular landscape of malleable and multifu...Major advances over the past few decades have highlighted the complex regulation of RNA from transcription to nuclear export and from translation to decay. Despite the emerging cellular landscape of malleable and multifunctional RNA molecules, the role of RNA dysregulation in ageing, one of the most fundamental processes of human biology, is underappreciated. Here we focus on ageing-linked dysregulation of the mRNA life cycle. We summarize how RNA metabolism steadily deviates throughout ageing and senescence: in transcription, aged cells bias shorter genes at the expense of complex transcripts; in splicing, ageing-linked alternative exon usage is common; in translation, ribosomal collisions on mRNAs decouple transcriptional output from protein production; and in decay, aberrant RNAs accumulate due to poor degradation activity. We close by discussing how ageing-linked dysregulation of RNA biology can drive cellular stress and thus serve as a therapeutic target to reverse disease.
Xiong Z, Xu K, Lin Z
… +20 more, Kong F, Wang Q, Quan Y, Sha QQ, Li F, Zou Z, Liu L, Ji S, Chen Y, Zhang H, Fang J, Yu G, Liu B, Wang L, Wang H, Deng H, Yang X, Fan HY, Li L, Xie W
Tan JP, Liu Y, Fu Y
… +22 more, Liang L, Wu Y, Guo T, Jia S, Jiang Y, Yuan T, Li J, Li Y, Huang Z, Li S, Li J, Yan X, Liao Z, Liu X, Hu B, Fu S, Hao S, Tian L, Liu Z, Yu L, Liu L, Liu X
The early organogenesis stage is a critical phase of embryogenesis that lays the foundation for organ development, and is characterized by dynamic and spatially organized transcriptional programs. However, limited spatia...The early organogenesis stage is a critical phase of embryogenesis that lays the foundation for organ development, and is characterized by dynamic and spatially organized transcriptional programs. However, limited spatial transcriptomic information has constrained our understanding of early primate organogenesis. Here we present a comprehensive three-dimensional (3D) spatial transcriptomic atlas of cynomolgus monkey embryos at Carnegie stages (CS) 9 and 10, capturing key morphogenetic events including cardiogenesis, gut tube regionalization, neurulation, axial mesendoderm patterning and early somitogenesis. Using high-resolution spatial transcriptomics and 3D reconstruction, we identify spatially defined lineage domains across germ layers and resolve regionally restricted gene expression, transcription factor activity, and signalling landscapes along major embryonic axes, exemplified by the emergence of dorsoventrally patterned spinal cord subpopulations during neurulation. Cross-species comparisons with human and mouse datasets reveal conserved and species-biased transcriptional programs. Together, this atlas provides a foundational reference for studying early primate development.