bims-pideca 2026-03-22 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–03–22
nineteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.
Genomic modifiers of malignant and neurodevelopmental phenotypes in individuals with PTEN hamartoma tumor syndrome.
IGF-1 and insulin receptors in LepRb neurons jointly regulate body growth, bone mass, reproduction, and metabolism.
Technologies to measure and modulate protein subcellular localization.
Specific Features of Epithelial-Mesenchymal Transition Induced by Driver Mutations in the PI3K/AKT Signaling Pathway in Breast Epithelial Cells.
LazySlide: accessible and interoperable whole-slide image analysis.
A Long-Term Human Adipocyte Organoid Model Reveals Aging-Associated Responses to Intermittent Hypoxia.
A Computational Workflow for Cell Line Profiling by Imaging Mass Cytometry.
Diversity-in-a-dish: A practical framework for hiPSC model development.
From brown to white: Brown adipose tissue endothelial cells whiten in culture conditions.
Fine-tuning ERK activity enables proliferation-differentiation balance during lineage specification of human embryonic stem cells.
CellVoyager: AI CompBio agent generates new insights by autonomously analyzing biological data.
An Open-Source Workflow for Semi-Automated Spatial Profiling of Multiplex Immunofluorescent Images.
Nuclear Translocation of Mitochondrial Ferredoxin Reductase Is Regulated by AKT-Mediated Phosphorylation.
Distinct gene expression profiles in blood-brain barrier capillary endothelial cells between mice and humans.
Fructose-1,6-bisphosphate couples glycolytic activity to cell adhesion.
Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.
What is quantum biology?
Decoding disease-relevant variants with base and prime editors at scale.

Nat Metab. 2026 Mar 18.

Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.

Melanie Picot, Nesrine Hifdi, Mathilde Vaucourt, Melanie Mansat, Peng Li, Isabel Singer, Gaëtan Chicanne, Alexandre Stella, Shen Kuang, Caterina Miceli, Nathaniel F Henneman, Bernard Payrastre, Marie Vandromme, Odile Schiltz, Ivan Nemazanyy, Mariana E G de Araujo, Ganna Panasyuk, Julien Viaud, Michael Lämmerhofer, Karim Hnia.

Lysosomes act as metabolic signalling hubs that integrate nutrient availability to coordinate anabolic and catabolic programmes. Mechanistic target of rapamycin complex 1 (mTORC1) is activated at the lysosomal surface by amino acids through RagGTPases recruited by the lysosomal adaptor and MAPK and mTOR activator complex, yet the contribution of lysosomal lipid composition to this pathway remains unclear. Here we identify lysosomal phosphoinositides, PI3P and PI(3,5)P2, as key regulators of lysosomal adaptor and MAPK and mTOR activator complex stability and dynamics at the lysosome. These lipid pools are controlled by the phosphoinositide 3-phosphatase MTM1, mutated in myotubular myopathy, via endoplasmic reticulum-lysosome membrane contact sites. Under endoplasmic reticulum stress, MTM1-dependent phosphoinositide remodelling suppresses RagGTPase-mTORC1 signalling, thereby regulating anabolic-catabolic balance during myogenic differentiation. Restoring mTORC1 activity or lysosomal phosphoinositide homeostasis rescues Rag-dependent signalling and muscle growth in cellular and mouse models of myopathy, uncovering a lysosome-centred metabolic checkpoint with direct disease relevance.

DOI: https://doi.org/10.1038/s42255-026-01484-1
NPJ Genom Med. 2026 Mar 17.

Genomic modifiers of malignant and neurodevelopmental phenotypes in individuals with PTEN hamartoma tumor syndrome.

Developmental Synaptopathies Consortium

PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN variants, exhibits marked phenotypic heterogeneity, most notably cancer, neurodevelopmental disorders (NDD), or both. The basis for this divergence, even among carriers of identical PTEN variants, remains poorly defined. We performed whole-genome sequencing of 599 individuals with PHTS and family members, complemented by analyses of PTEN variant carriers from the All of Us Research Program. Analyses included both targeted evaluation of genes previously implicated in cancer and NDD and agnostic genome-wide single-variant and rare-variant burden testing. The analytic cohort comprised 543 PHTS probands, including individuals with NDD (n = 171), cancer (n = 221), both phenotypes (n = 21), or neither (n = 130) at the time of enrollment. Pathogenic or likely pathogenic variants in cancer-associated genes were identified in 37 (6.8%), most frequently in MITF, DICER1, and BRCA2, while 43 (7.9%) harbored variants in NDD-related genes, including DHCR7, POLG, and ARSA. Such secondary variants were less common in PTEN variant carriers in All of Us. Genome-wide analyses identified candidate modifier loci functionally linked to PTEN, including in ZNF713, TPTE2P1, and PDPK1. These findings demonstrate that PHTS phenotypes are shaped by complex gene-gene interactions beyond PTEN alone, informing mechanisms underlying the cancer-NDD dichotomy and advancing precision risk stratification.

DOI: https://doi.org/10.1038/s41525-026-00556-1
Mol Metab. 2026 Mar 16. pii: S2212-8778(26)00039-6. [Epub ahead of print] 102355

IGF-1 and insulin receptors in LepRb neurons jointly regulate body growth, bone mass, reproduction, and metabolism.

Mengjie Wang, Piotr J Czernik, Beata Lecka-Czernik, Jennifer W Hill.

  Leptin receptor (LepRb)-expressing neurons integrate metabolic and reproductive signals, yet the role of insulin-like growth factor 1 receptor (IGF1R) signaling within these neurons remains unclear. Because IGF-1 and insulin can partially activate each other's receptors, we generated mice lacking IGF1R selectively in LepRb neurons (IGF1RLepRb) as well as mice lacking both IGF1R and insulin receptor (IR) in LepRb neurons (IGF1R/IRLepRb). These models were used to assess body growth, skeletal development, reproductive function, energy balance, and metabolic homeostasis. Deletion of IGF1R alone in LepRb neurons delayed pubertal onset, impaired adult fertility, and accelerated reproductive aging, accompanied by transient postnatal growth retardation. IGF1R deficiency also altered trabecular and cortical bone structural parameters in both sexes, supporting a role for IGF1R signaling in coordinating growth, skeletal physiology, and reproductive function. Despite reduced food intake and increased energy expenditure in females after adjusting for lean mass, IGF1R deletion caused only modest metabolic alterations, with transient decreases in body weight and largely unchanged body composition and locomotor activity. In contrast, combined deletion of IGF1R and IR in LepRb neurons resulted in marked metabolic disturbances, including increased adiposity, reduced lean mass, lower energy expenditure, decreased locomotor activity, and impaired insulin sensitivity in males. These findings indicate cooperative roles of IGF1R and IR signaling within LepRb neurons in regulating body composition, energy balance, and glucose homeostasis. Together, our results demonstrate that IGF1R signaling in LepRb neurons primarily regulates reproductive development, skeletal physiology, and growth, whereas combined IGF1R and IR signaling is required for maintaining metabolic homeostasis. These findings identify LepRb neurons as an important neuroendocrine hub integrating IGF and insulin signaling to coordinate growth, reproduction, and metabolism in a sex-dependent manner.

Keywords:  Bone metabolism; Energy balance; Hypothalamus; IGF1 receptor; Insulin receptor; LepRb neurons; Neuroendocrine regulation; Reproductive function

DOI:  https://doi.org/10.1016/j.molmet.2026.102355
Nat Rev Mol Cell Biol. 2026 Mar 19.

Technologies to measure and modulate protein subcellular localization.

William Leineweber, Reika Tei, Anna Mäkiniemi, Alice Ting, Emma Lundberg.

How proteins localize to specific compartments, function in coordination with other biomolecules and, ultimately, contribute to diverse cellular activities are crucial questions in cell biology. Complicating the answers to these questions are multilocalizing and multifunctional proteins, whose impact on the cell depends on both spatial and temporal contexts. Therefore, contextualizing protein functions based on their subcellular localization is necessary to fully understand cell behaviours. Recent advances in instrumentation and protein labelling techniques are rapidly increasing the availability of tools, technologies and applications that measure and control protein localization and compartment-specific function. In this Review, we first discuss microscopy, mass spectrometry-based correlation profiling and proximity labelling methods that assign localizations to proteins, ranging from cellular compartments to protein-protein interactions. We next examine the available tools for manipulating protein localization and measuring the effects of these manipulations, including localization tags and bifunctional molecules. For each technology, we assess the strengths and weaknesses that ultimately determine their usefulness. We conclude with an outlook on future technological advances in the field of spatial subcellular proteomics and their potential implications for cell biology and clinical applications.

DOI: https://doi.org/10.1038/s41580-026-00957-1
Biochemistry (Mosc). 2026 Feb;91(2): 332-344

Specific Features of Epithelial-Mesenchymal Transition Induced by Driver Mutations in the PI3K/AKT Signaling Pathway in Breast Epithelial Cells.

Ali Dayoub, Anna O Zholudeva, Artem I Fokin, Alla S Ilnitskaya, Maria E Lomakina, Alexis M Gautreau, Antonina Yu Alexandrova.

  The PI3K/AKT signaling pathway is one of the most critical intracellular pathways, regulating cell proliferation, survival, and migration. Mutations in PI3K/AKT pathway components are frequently associated with progression and metastasis of malignant tumors. The initial stage of metastasis is epithelial-mesenchymal transition (EMT), during which tumor cells acquire the migratory capacity. The data on the impact of PI3K/AKT driver mutations on tumor cell motility are contradictory. We investigated EMT and changes in the motility of breast epithelial cells carrying four driver mutations commonly identified in malignant tumors and affecting different components of the PI3K/AKT pathway. Analysis of cell motility, expression of EMT markers, and morphology of adherens junctions (AJs) revealed that all these mutations induced partial EMT, as E-cadherin expression was preserved in all studied cell lines and cells maintained AJs. Analysis of EMT types induced by different mutations revealed that the increased cell motility did not correlate with the degree of EMT progression toward the mesenchymal phenotype. The greatest increase in the cell migratory capacity was observed for cells carrying the PIK3CA H1047R mutation, which induced the most pronounced mesenchymal phenotype, as well as for PTEN-/- cells, which retained the most epithelial phenotype. Our analysis showed that mutations indirectly affecting the MAPK/ERK pathway and promoting ERK activation have the greatest impact on EMT and cell motility.

Keywords:  E-cadherin; cell motility; cell–cell adherens junctions; partial EMT; vimentin

DOI:  https://doi.org/10.1134/S0006297925603570
Nat Methods. 2026 Mar 20.

LazySlide: accessible and interoperable whole-slide image analysis.

Yimin Zheng, Ernesto Abila, Eva Chrenková, Iva Buljan, Juliane Winkler, André F Rendeiro.

Histopathological data are foundational in both biological research and clinical diagnostics but remain siloed from modern multimodal and single-cell frameworks. Here we introduce LazySlide, an open-source Python package built on the scverse ecosystem for efficient whole-slide image analysis and multimodal integration. By leveraging vision-language foundation models and adhering to scverse data standards, LazySlide bridges histopathology with omics workflows. It supports tissue and cell segmentation, feature extraction, cross-modal querying and zero-shot classification, with minimal setup.

DOI: https://doi.org/10.1038/s41592-026-03044-7
Am J Physiol Cell Physiol. 2026 Mar 18.

A Long-Term Human Adipocyte Organoid Model Reveals Aging-Associated Responses to Intermittent Hypoxia.

Yunzhou Dong, Jingjing Wang, Feifei Feng, Isra H Ali, Lida Chen, Shahid Karim, Joshua M Bock, Virend K Somers.

  Obstructive sleep apnea (OSA), characterized by recurrent intermittent hypoxia (IH), is increasingly recognized as a driver of adipose tissue dysfunction, insulin resistance, and accelerated aging. However, current in vitro models inadequately recapitulate the long-term effects of IH on human adipocytes. Here, we developed a robust long-term human adipocyte organoid culture system that models IH-induced adipocyte aging in vitro. Human stromal vascular fraction (SVF) cells isolated from subcutaneous abdominal adipose tissue were embedded in Matrigel and seeded into Biofloat U-bottom 96-well plates. Using a 1:1 Matrigel-cell mixture and optimized seeding volumes (5-20 µL), adipocyte organoids formed within 10-12 days and maintained stable morphology and viability for more than 90 days. Matrigel was essential for structural integrity, whereas gelatin and low-melting agarose failed to support organoid formation. Subcutaneous preadipocyte medium supplemented with 10% FBS supported more robust adipogenic differentiation and long-term maintenance than Advanced/F12K medium. To model OSA-associated hypoxic stress, organoids were exposed to programmable IH. IH suppressed adipogenesis, as evidenced by reduced lipid accumulation, downregulation of adipogenic markers (PPARγ, adiponectin, FABP4), and reduced lipid droplets. Transmission electron microscopy revealed IH-induced ultrastructural abnormalities, including endoplasmic reticulum fragmentation, mitochondrial disruption, nuclear enlargement, and heterochromatin accumulation-features consistent with cellular senescence. IH further upregulated HIF1α, H2AX, repressive histone methylation marks (H3K9me3, H3K79me3, H4K20me3), and extracellular matrix remodeling proteins (fibronectin, LOX), while impairing insulin signaling as demonstrated by reduced PI3K and AKT phosphorylation. Collectively, these findings establish a physiologically relevant human adipocyte organoid platform for investigating IH-induced adipocyte dysfunction and aging.

Keywords:  Fat organoid aging model; Human adipocyte organoids; OSA; cellular aging; intermittent hypoxia

DOI:  https://doi.org/10.1152/ajpcell.00020.2026
Cytometry A. 2026 Mar 19.

A Computational Workflow for Cell Line Profiling by Imaging Mass Cytometry.

Alexandre Bouzekri, Amanda Esch, Olga Ornatsky.

  In single-cell spatial phenotyping biology, imaging mass cytometry (IMC) stands out as a cutting-edge, highly multiplexed technology driving discoveries across various disease areas. In vitro profiling relies on tumor-derived cancer cell lines, known for their diverse morphologies and phenotypes. A comprehensive analysis of those cell lines presents a direct challenge in predicting cancer progression and drug treatment responses. We demonstrate in our study an adaptable computational workflow we have named IMC Cell Line Profiler as a suite of versatile open-source tools for visual rendering and quantitative segmentation-based analysis of tumor-derived cell lines profiled by IMC. By leveraging our workflow with IMC resolution and multiplexing capabilities, we scrutinized the morphology, phenotypic traits, and spatial arrangement of 10 cultured cell lines from diverse tissues using custom panels of 20-30 metal-labeled antibodies. This allowed us to generate intricate high-dimensional datasets elucidating diverse cellular states with multiple markers. This computational approach was applied to a cisplatin exposure treatment in a resistant cell line to track morpho-phenotypic changes. Our IMC computational study presents new perspectives and applications to profile cell lines as new types of samples and expand the potential of IMC to new fields of discovery.

Keywords:  adherent cell lines; cisplatin drug treatment; computational workflow pipeline; high‐dimensional tools; imaging mass cytometry; morphological phenotypes; nuclear state classification; protein expression profiling; single‐cell imaging segmentation; visual rendering analysis

DOI:  https://doi.org/10.1002/cytoa.70009
Stem Cell Reports. 2026 Mar 19. pii: S2213-6711(26)00069-X. [Epub ahead of print] 102858

Diversity-in-a-dish: A practical framework for hiPSC model development.

Jesse Weidema, Hanna Lammertse, Martine de Vries, Christine Mummery, Megan Munsie, Nienke de Graeff.

  Human induced pluripotent stem cell (hiPSC) models inherit donor-specific variation, affecting experimental outcomes and generalizability. While diversity is widely discussed in biomedical research and extensively theorized in genomics, comparable guidance remains limited in hiPSC research. In response, this paper extends genomics frameworks to provide stem cell-specific recommendations for describing and reporting diversity and introduces a decision framework based on four criteria (experimental purpose, biological plausibility, platform readiness, and statistical power) to determine when and how diversity should be incorporated in hiPSC-based research. The overall goal is to establish a shared basis for transparent and reproducible diversity-related design and reporting.

Keywords:  diversity; human induced pluripotent stem cells; model validation; organ-on-chip; organoid; preclinical research

DOI:  https://doi.org/10.1016/j.stemcr.2026.102858
Mol Metab. 2026 Mar 12. pii: S2212-8778(26)00033-5. [Epub ahead of print] 102349

From brown to white: Brown adipose tissue endothelial cells whiten in culture conditions.

Tabea Elschner, Stephan Grein, Jana Sander, Staffan Hildebrand, Lara Heubach, Nina Pannwitz, Maria Mircea, Elba Raimundez, Vasiliki Karagiannakou, Anastasia Georgiadi, Joerg Heeren, Jan Hasenauer, Alexander Pfeifer, Kerstin Wilhelm-Jüngling.

  Endothelial cells (ECs) are central regulators of vascular and metabolic homeostasis, yet their organ- and depot-specific diversity remains underexplored. Two major types of adipose tissue (AT) can be distinguished that differ substantially in their physiological function and vascularization: white AT (WAT), which is the major energy storage and brown AT (BAT), which is highly vascularized and dissipates energy [1-5]. While ECs from these depots likely contribute to adipose function, their characterization has been hindered by technical limitations in isolation and culture. Here, we establish a protocol for isolating and expanding ECs from murine BAT and WAT, enabling transcriptomic and functional analyses across depots. We demonstrate that freshly isolated BAT-ECs express depot-enriched gene signatures, including Rgcc, Cdkn1c, Tcf15, Meox2, and Efnb1, several of which are dynamically regulated during cold-induced BAT activation. These findings reveal novel BAT-EC markers and highlight specialized endothelial programs that may support BAT function. However, we also uncover that culturing BAT-ECs profoundly remodels EC identity. Transcriptomic profiling shows that BAT-ECs rapidly downregulate BAT-enriched endothelial markers and acquire features resembling WAT-ECs. This dedifferentiation is accompanied by signatures of proliferation, adhesion remodeling, and endothelial-to-mesenchymal transition. While these changes present challenges for maintaining depot-specific identity in culture, they also provide a framework to better interpret experimental outcomes and to investigate EC plasticity. Taken together, our study delivers a novel isolation and culture protocol for adipose ECs, defines BAT-EC markers, and demonstrates how culture conditions reshape their identity. These insights build the foundation for future research of AT vasculature.

Keywords:  Endothelial cells; Heterogeneity; Plasticity; White adipose tissue; brown adipose tissue; cell isolation; culture

DOI:  https://doi.org/10.1016/j.molmet.2026.102349
PLoS Biol. 2026 Mar 17. 24(3): e3003711

Fine-tuning ERK activity enables proliferation-differentiation balance during lineage specification of human embryonic stem cells.

Chenyang Ma, Weikang Meng, Jinghan Huang, Wanling Zheng, Xiao Xu, Tao Cheng, Zhengyi Li, Yang Liu, Hao Shen, Feng He, Alessandro Esposito, Pengfei Xu, Ashok Venkitaraman, Jun Ma, Heng Xu, Hongqing Liang.

ERK is a key signaling mediator controlling both proliferation and lineage specification during embryo development. How ERK choreographs differentiation and proliferation to achieve balanced developmental outcomes in lineages with variable ERK activities remains unclear. To investigate this, we established multiplex quantitative live-cell imaging to track human pluripotent stem cell differentiation into mesendoderm (ME), a lineage specified by gastrulation morphogens and dependent on high ERK activity. We found that distinct morphogen combinations generate varying ERK activity levels, which correlate with heterogeneous ME fate choices despite relatively uniform cell cycle dynamics. To dissect how heterogenous ERK levels directly modulate and coordinate ME differentiation and proliferation, we engineered a synthetic spectrum of titrated ERK activities. Our results showed that ERK fine-tunes ME differentiation potential and cell division speed under nonoverlapping activity ranges, enabling quantitative control of ME fate specification without major effect on cell cycle progression. Mechanistically, this uncoupling stems from differential transcriptional and translational sensitivities of ME-specifying genes versus cell cycle genes to ERK input. Together, our findings reveal how a single signaling pathway quantitatively balances differentiation and proliferation during lineage commitment and embryogenesis.

DOI: https://doi.org/10.1371/journal.pbio.3003711
Nat Methods. 2026 Mar 17.

CellVoyager: AI CompBio agent generates new insights by autonomously analyzing biological data.

Samuel Alber, Bowen Chen, Eric Sun, Alina Isakova, Aaron J Wilk, James Zou.

Modern biology increasingly relies on complex, high-dimensional datasets such as single-cell RNA sequencing (scRNA-seq), which present a vast space of potential hypotheses. Systematically exploring this space is often impractical, as scRNA-seq analyses are time-consuming and require substantial computational and domain expertise. To address this challenge, we introduce CellVoyager, an AI agent built on large language models that autonomously generates and implements scRNA-seq analyses within a Jupyter notebook environment. We evaluate CellVoyager on CellBench, a benchmark of 76 published scRNA-seq studies, where it outperforms GPT-4o and o3-mini by up to 23% in predicting which analyses authors ultimately conducted, given only the papers' background sections. Across three in-depth case studies, CellVoyager generated novel findings in COVID-19, cell-cell communication and aging that experts consistently rated as creative and scientifically sound. These results demonstrate CellVoyager's potential to accelerate computational biology and uncover missing insights by autonomously analyzing biological data at scale.

DOI: https://doi.org/10.1038/s41592-026-03029-6
Curr Protoc. 2026 Mar;6(3): e70331

An Open-Source Workflow for Semi-Automated Spatial Profiling of Multiplex Immunofluorescent Images.

Alisha Dabb, Cynthia Morgan, Sophia Noble, Alfonso J Schmidt.

  Multiplex immunofluorescence microscopy facilitates the quantification and spatial analysis of cellular features within tissue sections, allowing greater understanding of disease progression or the effects of drug treatment or other exposures on cellular organization and tissue structure. Recent advances in image analysis and computational methods such as machine-learning-based cell segmentation and automated cell phenotyping have enhanced the depth of information gained from these historically qualitative images. However, many spatial analysis pipelines are technically challenging or require proprietary software or hardware, limiting accessibility and reproducibility. The free and open-source software QuPath provides a novel resource for quantifying and spatially profiling multiplex images. Here, we describe a detailed primary protocol for the semi-automated spatial analysis of 2D multiplex immunofluorescent images using QuPath, which uses object and pixel classification, cell distance, and cluster measurements for spatial profiling of tissue samples. This pipeline also includes the use of training images and basic scripting for batch processing to ensure that analysis is objective and standardized within and between projects. We also provide an alternate protocol that details a pipeline modification for whole-section images, and an extended protocol that describes the use of a free, browser-based tool to complete unsupervised, rapid processing and consolidation of the spatial data provided by QuPath, with automated reporting of cell spatial plots, cell-to-object measurements, and cell clustering data. These protocols provide an accessible, standardized, and scalable method for the spatial analysis of multiplex immunofluorescence microscopy images, facilitating reproducible quantification of cellular organization and tissue structure and thereby strengthening the integration of spatial data into translational research, biomarker discovery, and mechanistic studies. © 2026 Wiley Periodicals LLC. Basic Protocol 1: QuPath image processing Alternate Protocol: Whole-section image processing Basic Protocol 2: Use of the QuPath Spatial Analysis and Visualisation Tool.

Keywords:  QuPath; cell clustering; immunofluorescence microscopy; python; spatial

DOI:  https://doi.org/10.1002/cpz1.70331
Biochem J. 2026 Mar 20. pii: BCJ20250303. [Epub ahead of print]

Nuclear Translocation of Mitochondrial Ferredoxin Reductase Is Regulated by AKT-Mediated Phosphorylation.

Jin Zhang, Ken-Ichi Nakajima, Shakur Mohibi, Xinbin Chen.

  Ferredoxin reductase (FDXR) is the sole ferredoxin reductase in humans and plays an essential role for steroidogenesis and biosynthesis of heme and iron sulfur cluster (ISC) by transferring electrons from NADPH to ISC-containing ferredoxin 1 (FDX1) and FDX2. In this study, we found that while FDXR is classified as a mitochondria-localized flavoprotein, it can be translocated into the nucleus, especially in response to various stress signals. Next, we identified a bipartite NLS within amino acids 271-299 of FDXR, the disruption of which impairs its nuclear translocation. Further, we found that AKT can phosphorylate threonine 277 adjacent to the NLS in FDXR and subsequently enhances its nuclear translocation. Consistent with this, mutant FDXR(T277A), in which threonine 277 was substituted with alanine, impaired FDXR nuclear translocation. Together, our data provide evidence that the mitochondrial FDXR can be translocated to the nucleus, which is regulated by AKT-mediated phosphorylation, especially in response to cellular stress. Our data suggest that FDXR plays a role in the mitochondria-nucleus communication and stress responses.

Keywords:  AKT; FDXR; NLS; Nuclear locolization; Phosphorylation

DOI:  https://doi.org/10.1042/BCJ20250303
Microvasc Res. 2026 Mar 12. pii: S0026-2862(26)00033-6. [Epub ahead of print]166 104933

Distinct gene expression profiles in blood-brain barrier capillary endothelial cells between mice and humans.

Yuyang Miao, Jianhao Wang, Weihan Li, Maarja Andaloussi Mäe, Marie Jeansson, Lars Muhl, Liqun He.

   OBJECTIVE: Endothelial cells (ECs) are key structural and functional components of the blood-brain barrier (BBB). Mouse models are frequently used to study EC biology within the BBB, yet the extent to which human and mouse BBB ECs share conserved transcriptomic features remains unclear. Here, we systematically compare transcriptomic profiles of BBB capillary ECs from adult mice and humans.
METHODS: We analyzed single-cell and single-nucleus RNA-sequencing datasets from adult mouse and human BBB capillary ECs. Candidate species-specific genes were further validated using two whole brain vasculature datasets, along with data from Allen Brain Atlas and Human Protein Atlas.
RESULTS: Despite substantial overall conservation between species, 169 genes were consistently enriched in human BBB capillary ECs compared to mouse, whereas 386 genes were enriched in mouse BBB capillary ECs compared to human. Several genes, including A2M, RUNDC3B, BTNL9 and SPOCK3 exhibited predominant expression in human BBB capillary ECs, with minimal or undetected expression in mouse. Conversely, Tspan13, Pglyrp1, Ucp2 and Slco1c1 were specifically expressed in mouse BBB capillary ECs compared with human. Notably, a considerable proportion of differentially expressed genes belonged to the solute carrier (SLC) transporter family.
CONCLUSIONS: Our cross-species in-depth analysis reveals both broad conservation and distinct transcriptomic differences between human and mouse BBB capillary ECs. Together, our findings provide a valuable framework for interpreting mouse BBB data in a translational context and for guiding future studies of endothelial biology in the human brain.

Keywords:  Blood-brain barrier; Endothelial cells; Single-cell RNA-sequencing; Species difference

DOI:  https://doi.org/10.1016/j.mvr.2026.104933
Nat Cell Biol. 2026 Mar 16.

Fructose-1,6-bisphosphate couples glycolytic activity to cell adhesion.

Lennart Hoffmann, Marlen Duchmann, Katina Lazarow, Yun-Hsuan Huang, Fabian Lukas, Wen-Ting Lo, Regina Feil, Christopher Schmied, Martin Lehmann, John E Lunn, Ilaria Piazza, Jens P von Kries, Volker Haucke, Tanja Maritzen.

Cellular adhesion to the extracellular matrix is essential for morphogenesis, tissue integrity and survival signalling. The best understood adhesion structures are focal adhesions (FAs). In spite of their importance, our knowledge of upstream factors that integrate FA dynamics with other cellular processes, such as metabolism, remains fragmentary. Using a genome-wide screen, we identify aldolase A, a key glycolytic enzyme that converts fructose-1,6-bisphosphate (FBP), as a regulatory switch that links metabolic flux to FA assembly and cell morphogenesis. We show that cellular FBP serves as a signalling metabolite, which transmits information about the metabolic cell state to the actin-based machinery for cell adhesion and protrusion. This mechanism involves FBP binding to the Rac1 inhibitor RCC2 and a concomitant elevation of Rac1 activity resulting in actin reorganization, increased FA assembly and elevated protrusive activity. Here we predict this mechanism to be crucial for processes ranging from development to cancer.

DOI: https://doi.org/10.1038/s41556-026-01911-1
iScience. 2026 Mar 20. 29(3): 115171

Extracellular matrix signals promote actin-dependent mitochondrial elongation and activity.

Priya Gatti, Pritha Mukherjee, Priyanka Dey Talukdar, Wesley Freppel, Anahita Kasmaie, Joseph Kanou, Laurent Chatel-Chaix, Urmi Chatterji, Marc Germain.

  Mitochondria are crucial metabolic organelles regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signaling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from general ECM-regulated survival cues, we used mammospheres derived from breast cancer cells because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.

Keywords:  Biological sciences; Cell biology; Integrative aspects of cell biology; Organizational aspects of cell biology; Specialized functions of cells

DOI:  https://doi.org/10.1016/j.isci.2026.115171
Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2531134123

What is quantum biology?

Gregory D Scholes, Graham R Fleming.

  Quantum biology is the field at the intersection of quantum-related physics and the biology of living systems. The goal of the field is to determine if quantum phenomena underpin biological function at the macroscale. Such results, supported by compelling experimental evidence, will be important because they will show how quantum effects can have functional relevance, even in very complex and nominally classical systems. Here, we attempt to define the scope of quantum biology with a forward-facing view to help focus the research agenda. To that end, we propose open questions fundamental to consolidating the field of quantum biology. These open questions highlight the importance of developing suitable probes at the quantum scale, the possibility that classical biological machinery might simply mimic quantum systems, and of elucidating the ways quantum function can be amplified to the macroscale.

Keywords:  coherence; quantum biology; quantum mimics; quantum probes

DOI:  https://doi.org/10.1073/pnas.2531134123
Trends Biochem Sci. 2026 Mar 17. pii: S0968-0004(26)00029-0. [Epub ahead of print]

Decoding disease-relevant variants with base and prime editors at scale.

Ying Liu, Xuran Niu, Wensheng Wei.

  Interpreting variants of uncertain significance remains a central challenge in human genomics. Base and prime editors have launched a new era of precision functional genomics, enabling programmable, double-strand break-free introduction of point mutations and small indels directly within the genome. Here, we review the technological evolution of these editors and their transformative application in high-throughput functional screens. We highlight how base and prime editing platforms systematically annotate clinical variants, reveal mechanisms of drug resistance and immune evasion, and dissect fundamental biological processes at single-nucleotide resolution. Crucially, we address current challenges and future perspectives for precision editing screens. By enabling causal genotype-to-phenotype mapping, precision editing screens are redefining genomic variation interpretation and accelerating its translation into precision diagnostics and therapeutics.

Keywords:  base editing; functional genomics; prime editing; saturation mutagenesis; variants of uncertain significance

DOI:  https://doi.org/10.1016/j.tibs.2026.02.001