bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–09–21
thirteen papers selected by
Jessica Rosarda, Uniformed Services University
  1. Primary Cilia-Mediated Hedgehog Signaling Regulates Cell Fate During ER Stress-Induced Life or Death Decisions.
  2. Cellular mechanism linking endoplasmic reticulum inheritance and cell cycle regulation of the nuclear genome.
  3. Leaflet-specific phospholipid imaging using genetically encoded proximity sensors.
  4. Neurons and astrocytes have distinct organelle signatures and responses to stress.
  5. A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice.
  6. Manipulating mitochondrial gene expression.
  7. Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice.
  8. The Role of Atp2a2-Mediated Calcium Imbalance and Endoplasmic Reticulum Stress in Hydrocortisone-Induced Neurotoxicity.
  9. Covariation MS uncovers a protein that controls cysteine catabolism.
  10. Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity.
  11. Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.
  12. Photocatalytic labelling-enabled subcellular-resolved RNA profiling and synchronous multi-omics investigation.
  13. Evolution of drug-binding residues in eukaryotic ribosomes.
  1. FASEB J. 2025 Sep 30. 39(18): e70982
    Primary Cilia-Mediated Hedgehog Signaling Regulates Cell Fate During ER Stress-Induced Life or Death Decisions.
    Jia Xu, Yongli Zhang, Junmin Pan.
      Primary cilia play critical roles in development and physiology. The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, is a fundamental cellular process. However, whether and how ER stress influences ciliary assembly and function remain poorly understood. Here, we demonstrate that ER stress promotes ciliogenesis and hedgehog (HH) signaling by upregulating cholesterol levels, thereby alleviating cellular damage. IRE1 and PERK, sensors of ER stress, positively regulate ciliogenesis by enhancing the trafficking of preciliary vesicles through upregulation of cellular cholesterol levels via activation of SREBP2. Furthermore, the cholesterol content in the ciliary membrane also increases during ER stress, leading to enhanced ciliary recruitment of Smoothened (SMO) and activation of HH signaling. The activation of HH signaling via primary cilium is crucial for protecting cells from stress-induced damage. Our findings unveil a pivotal role of cilia-mediated hedgehog signaling in cell fate determination under ER stress.
    Keywords:  ER stress; UPR; cholesterol; cilia or flagella; ciliogenesis; hedgehog signaling
    DOI:  https://doi.org/10.1096/fj.202500391RR
  2. bioRxiv. 2025 Sep 04. pii: 2025.09.04.674221. [Epub ahead of print]
    Cellular mechanism linking endoplasmic reticulum inheritance and cell cycle regulation of the nuclear genome.
    Ya-Shiuan Lai, Jesse Chao, Maho Niwa.
      Endoplasmic reticulum (ER) stress triggers activation of the ER surveillance (ERSU) pathway- a critical protective mechanism that transiently halts cortical ER inheritance to daughter cells and arrests cytokinesis by septin ring subunit Shs1 re-localization to the bud scar in response to ER stress. Once ER functional homeostasis is re-established, cells resume normal cell cycle progression; however, the molecular circuitry linking ER integrity to cell cycle regulation has remained largely unresolved. Here, we show that ER stress selectively disperse Bud2, a GAP for Bud1/Rsr1, severing its canonical role in cell polarity while integrating it into ER homeostasis signaling. Bud2 dispersion results in accelerated spindle pole body (SPB) duplication, spindle misorientation, defects in nuclear migration, and genome segregation errors under ER stress. Strikingly, a C-terminal truncation of Shs1 ( shs1-ΔCTD ) recapitulated the ER stress-induced dispersion of Bud2 phenotype even in the absence of ER stress, and delayed cell-cycle re-entry after ER homeostasis was regained-despite normal occurrence of typical ERSU hallmark events. Notably, Bud2 overexpression rescued the growth defects of shs1-ΔCTD mutants after ER homeostasis was re-established. Collectively, our findings reveal a new mechanistic axis whereby ER integrity coordinates organelle inheritance, cytoskeletal organization, and nuclear division via selective control of Bud2 and Shs1, establishing a direct regulatory bridge between ER status and mitotic fidelity.
    DOI:  https://doi.org/10.1101/2025.09.04.674221
  3. Nat Chem Biol. 2025 Sep 15.
    Leaflet-specific phospholipid imaging using genetically encoded proximity sensors.
    William M Moore, Roberto J Brea, Caroline H Knittel, Ellen Wrightsman, Brandon Hui, Jinchao Lou, Christelle F Ancajas, Michael D Best, Christopher J Obara, Neal K Devaraj, Itay Budin.
      The lipid composition of cells varies widely across organelles and between individual membrane leaflets. Transport proteins are thought to generate this heterogeneity, but measuring their functions in vivo has been hampered by limited tools for imaging lipids at relevant spatial resolutions. Here we present fluorogen-activating coincidence encounter sensing (FACES), a chemogenetic tool capable of quantitatively imaging subcellular lipid pools and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of conjugated molecules. We first apply this approach to identify roles for lipid transfer proteins that traffic phosphatidylcholine pools between the ER and mitochondria. We then show that transmembrane domain-containing FAPs can reveal the membrane asymmetry of multiple lipid classes in the trans-Golgi network and be used to investigate the mechanisms that generate it. Finally, we present that FACES can be applied to measure glycans and other molecule classes.
    DOI:  https://doi.org/10.1038/s41589-025-02021-z
  4. Cell Rep. 2025 Sep 15. pii: S2211-1247(25)01051-4. [Epub ahead of print]44(9): 116280
    Neurons and astrocytes have distinct organelle signatures and responses to stress.
    Shannon N Rhoads, Weizhen Dong, Chih-Hsuan Hsu, Ngudiankama R Mfulama, Ridhi Yarlagadda, Joey V Ragusa, Michael Ye, Andy Henrie, Maria Clara Zanellati, Graham H Diering, Todd J Cohen, Sarah Cohen.
      Neurons and astrocytes play critical yet divergent roles in brain physiology and neurological conditions. Intracellular organelles are integral to cellular function. However, an in-depth characterization of organelles in live neural cells has not been performed. Here, we use multispectral imaging to simultaneously visualize six organelles-endoplasmic reticulum (ER), lysosomes, mitochondria, peroxisomes, Golgi, and lipid droplets-in live primary rodent neurons and astrocytes. We generate a dataset of 173 z stack and 98 time-lapse images, accompanied by quantitative "organelle signature" analysis. Comparative analysis reveals a clear cell-type specificity in organelle morphology and interactions. Neurons are characterized by prominent mitochondrial composition and interactions, while astrocytes contain more lysosomes and lipid droplet interactions. Additionally, neurons display a more robust organelle response than astrocytes to acute oxidative or ER stress. Our data provide a systems-level characterization of neuron and astrocyte organelles that can be a reference for understanding cell-type-specific physiology and disease.
    Keywords:  CP: Cell biology; CP: Neuroscience; Golgi; astrocytes; endoplasmic reticulum; lipid droplets; lysosomes; microscopy; mitochondria; neurons; organelles; peroxisomes
    DOI:  https://doi.org/10.1016/j.celrep.2025.116280
  5. Sci Adv. 2025 Sep 19. 11(38): eadx2752
    A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice.
    Molly R Gallop, Renan F L Vieira, Peyton D Mower, Elijah T Matsuzaki, Willisa Liou, Faith E Smart, Seth Roberts, Kimberley J Evason, William L Holland, Amandine Chaix.
      Ketogenic diets (KDs)-very-low-carbohydrate and very-high-fat diets-have gained popularity as therapeutic against obesity and type 2 diabetes. However, their long-term effects on metabolic health remain understudied. Here, we show that, in male and female mice, a KD protects against weight gain and induces weight loss but over time leads to the development of hyperlipidemia, hepatic steatosis, and severe glucose intolerance. Unlike mice on conventional high-fat diet, KD-fed mice remain insulin sensitive and display low-insulin levels. Hyperglycemic clamp and ex vivo glucose-stimulated insulin secretion assays revealed systemic and cell-intrinsic impairments in insulin secretion. Transcriptomic profiling of islets from KD-fed mice indicated endoplasmic reticulum (ER)/Golgi stress and disrupted ER-Golgi protein trafficking, which were confirmed by electron microscopy showing a dilated Golgi network consistent with defective insulin granule trafficking and secretion. Together, these results suggest that long-term KD leads to multiple aberrations of metabolic parameters that caution their systematic use as a health-promoting dietary intervention.
    DOI:  https://doi.org/10.1126/sciadv.adx2752
  6. Biol Chem. 2025 Sep 15.
    Manipulating mitochondrial gene expression.
    Drishan Dahal, Luis D Cruz-Zargoza, Peter Rehling.
      Mitochondria are essential for cellular metabolism, serving as the primary source of adenosine triphosphate (ATP). This energy is generated by the oxidative phosphorylation (OXPHOS) system located in the inner mitochondrial membrane. Impairments in this machinery are linked to serious human diseases, especially in tissues with high energy demands. Assembly of the OXPHOS system requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. The mitochondrial DNA encodes for 13 protein components, which are synthesized by mitochondrial ribosomes and inserted into the inner membrane during translation. Despite progress, key aspects of how mitochondrial gene expression is regulated remain elusive, largely due to the organelle's limited genetic accessibility. However, emerging technologies now offer new tools to manipulate various stages of this process. In this review, we explore recent strategies that expand our ability to target mitochondria genetically.
    Keywords:  RNA; gene expression; genetic tools; mitochondria
    DOI:  https://doi.org/10.1515/hsz-2025-0170
  7. Cell Rep. 2025 Sep 16. pii: S2211-1247(25)01062-9. [Epub ahead of print]44(10): 116291
    Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice.
    Alejandro Martín-Ávila, Swananda R Modak, Hameetha B Rajamohamedsait, Andie Dodge, Dov B Shamir, Senthilkumar Krishnaswamy, Leslie A Sandusky-Beltran, Marilyn Walker, Yan Lin, Erin E Congdon, Einar M Sigurdsson.
      Tau protein truncated at Asp 421 is a characteristic feature of Alzheimer's disease and other tauopathies. Here, we show that a monoclonal antibody against Asp421, 5G2, cleared insoluble tau in the brains of JNPL3 mice, decreased tau levels in brain interstitial fluid in awake JNPL3 mice, improved in vivo neuronal function, and reduced microglial Iba-1 expression in PS19 mice, in which neuronal tau aggregation and dysfunction occurred earlier than microglial activation. For mechanistic insight using culture models, 5G2 prevented tau-mediated toxicity, cleared extra- and intracellular tau, and prevented microgliosis. TRIM21 knockdown reduced neuronal retention of tau antibodies and their acute but not longer-term efficacy. Inhibition of the endosomal/lysosomal pathway but not the proteasomal pathway blocked 5G2-mediated neuroprotection and tau clearance. These findings support targeting the Asp421 truncated tau protein to treat tauopathies, indicate that tau-associated neuronal dysfunction precedes microglial activation, and that intraneuronal antibody-mediated tau clearance is mostly via the lysosomes.
    Keywords:  Asp421 antibody; CP: Cell biology; CP: Neuroscience; TRIM21; calcium imaging; in vivo; microglia; neurons; tauopathy; truncated tau
    DOI:  https://doi.org/10.1016/j.celrep.2025.116291
  8. Cell Stress Chaperones. 2025 Sep 17. pii: S1355-8145(25)00057-4. [Epub ahead of print] 100112
    The Role of Atp2a2-Mediated Calcium Imbalance and Endoplasmic Reticulum Stress in Hydrocortisone-Induced Neurotoxicity.
    Weihua Kong, Pei Jiang, Xinglu Miao, Ben Sang, Shunxin Hu, Lei Feng.
      Glucocorticoids (GCs), as commonly used anti-inflammatory and immunosuppressive drugs, may induce neurotoxicity with long-term use, although the specific mechanisms remain unclear. This study utilized zebrafish as a model to investigate the mechanisms and potential intervention targets of hydrocortisone (HC)-induced neurotoxicity. Transcriptome analysis revealed that HC exposure significantly downregulated the expression of Atp2a2 (encoding the endoplasmic reticulum calcium pump SERCA2). Functional experiments confirmed that HC disrupts cellular calcium homeostasis: endoplasmic reticulum Ca²⁺ levels decreased, mitochondrial Ca²⁺ accumulation occurred, accompanied by mitochondrial membrane potential depolarization, increased reactive oxygen species (ROS) generation, and cell apoptosis. Additionally, fluorescent signals in brain and spinal cord neurons were weakened, and significant decreases in movement distance, time, and average speed were observed. Intervention experiments with the GR antagonist RU486 and the SERCA2 activator demonstrated that both could partially restore calcium homeostasis, reduce ROS and apoptosis, and improve motor behavior. The findings revealed that Hydrocortisone disrupted calcium homeostasis by downregulating Atp2a2, activates endoplasmic reticulum stress, and triggers mitochondrial dysfunction, ultimately leading to neuronal damage and behavioral abnormalities. SERCA2 may serve as a potential target for alleviating GC-associated neurotoxicity, and this study provides experimental evidence for elucidating its mechanisms.
    Keywords:  Zebrafish Glucocorticoids Neurotoxicity Endoplasmic reticulum stress Mitochondrial dysfunction Calcium homeostasis
    DOI:  https://doi.org/10.1016/j.cstres.2025.100112
  9. Nature. 2025 Sep 17.
    Covariation MS uncovers a protein that controls cysteine catabolism.
    Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.
      The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.
    DOI:  https://doi.org/10.1038/s41586-025-09535-5
  10. Brain. 2025 Sep 16. pii: awaf328. [Epub ahead of print]
    Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity.
    Laetitia Marcadet, Mari Carmen Pelaez, Antoine Desmeules, Jeanne Serrano, Zhan Cheng, Sahara Khademullah, Elahe Parham, Jaimee Kennedy, Claire Troakes, Caroline Vance, Jorge Soliz, Heather D Durham, Liang Li, Paul A Dutchak, Chantelle F Sephton.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, muscle atrophy, and systemic energy imbalance. Increasing evidence suggests a metabolic shift in ALS from glucose metabolism toward fatty acid utilization; however, the downstream consequences of this reprogramming on disease progression and neuropathology remain poorly defined. We investigated neurometabolic changes in ALS using in vitro and in vivo models of familial ALS expressing the human fused in sarcoma variant R521G (hFUSR521G), along with post-mortem spinal cord tissue from ALS-FUS cases. A combination of unbiased quantitative metabolomic profiling, immunolabeling, and biochemical and molecular approaches were employed. Mass spectrometry of cortical tissue from hFUSR521G mice and littermates revealed a significant increase in acylcarnitine moieties, key substrates used in mitochondrial β-oxidation and cellular energy production. Complementary cytohistological analyses in hFUSR521G mice demonstrated increased lipid droplets (LDs) and peroxidized lipids in both neurons and astrocytes, consistent with our post-mortem findings in spinal cords of individuals carrying FUS R495X or K510E mutations. Arimoclomol, previously shown to ameliorate behavioral phenotypes in this ALS mouse model, was found to enhance lipid metabolism and reduce lipotoxicity in hFUSR521G mice and in cultured neurons and astrocytes expressing FUS R521G. Mechanistically, arimoclomol enhanced LD-mitochondrial contacts and stimulated mitochondrial β-oxidation-dependent lipid catabolism under both basal and pro-inflammatory conditions. This effect was abrogated by etomoxir, an irreversible inhibitor of CPT1, the rate-limiting enzyme of the carnitine shuttle, highlighting a CPT1-dependent mechanism for lipid mobilization. Together, these findings reveal a previously unrecognized role for mitochondrial lipid metabolism in ALS pathogenesis and identify a therapeutic pathway for mitigating the cytotoxic consequences of lipid and acylcarnitine accumulation in FUS-associated ALS.
    Keywords:  fatty acid oxidation (FAO); glycolysis; ketolysis; nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB); withaferin A
    DOI:  https://doi.org/10.1093/brain/awaf328
  11. Trends Cancer. 2025 Sep 16. pii: S2405-8033(25)00204-3. [Epub ahead of print]
    Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.
    Huiyu Li, Wenyi Jin, Junhong Liu, Yundong Zhou, Xiaoli Shan, Yubiao Zhang, Yongliang Kou, Chunyan Deng, Cheng Jin, Junjie Kuang, Yui-Leung Lau, João Conde, Baozhen Huang, Queran Lin.
      The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.
    Keywords:  ROS; chimeric antigen receptor (CAR); metabolism; mitochondria; tumor immunotherapy
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.006
  12. Nat Chem. 2025 Sep 16.
    Photocatalytic labelling-enabled subcellular-resolved RNA profiling and synchronous multi-omics investigation.
    Yunpeng Bi, Lishan Yu, Qidong Deng, Linghao Kong, Fuhu Guo, Yuchen Zhang, Ruixiang Wang, Peng R Chen, Jun Liu, Xinyuan Fan.
      Understanding cellular functions in health and disease requires dissecting spatiotemporal variations in the subcellular transcriptome. Existing methods for mitochondrial RNA profiling suffer from limitations, including low resolution, contamination and dependence on genetic manipulation. Here we present a bioorthogonal photocatalytic labelling and sequencing strategy (CAT-seq) that enables high-resolution, in situ profiling of mitochondrial RNA in living cells without genetic manipulation. We identified a quinone methide probe for efficient RNA labelling. Rigorous validation and optimization enabled CAT-seq to successfully profile mitochondrial RNA and track RNA dynamics in HeLa cells. We further applied CAT-seq to the challenging RAW 264.7 macrophages, revealing an underlying mitochondrial translational remodelling pathway. By leveraging the chemistry of quinone methide warheads, we established an orthogonal labelling system enabling synchronous RNA and protein multi-omics profiling within the same sample. Together, assisted by bioorthogonal photocatalytic chemistry, CAT-seq offers a general, non-genetic and well-compatible approach for subcellular-resolved RNA and multi-omics investigations, particularly in studies of intact primary living samples that are otherwise challenging to access.
    DOI:  https://doi.org/10.1038/s41557-025-01946-1
  13. Cell Rep. 2025 Sep 11. pii: S2211-1247(25)01015-0. [Epub ahead of print]44(9): 116244
    Evolution of drug-binding residues in eukaryotic ribosomes.
    Lewis I Chan, Chinenye L Ekemezie, Charlotte R Brown, Karla Helena-Bueno, Tom A Williams, Sergey V Melnikov.
      Drugs that target eukaryotic ribosomes are becoming increasingly important as research tools and potential therapies against cancer and pathogenic eukaryotes. However, in the absence of comparative studies, we currently do not know how many eukaryotes possess ribosomal drug-binding sites identical to those in humans and how many significantly differ from those in humans. To address this, we traced the evolutionary history of individual ribosomal drug-binding residues from the emergence of eukaryotes to the present day. We found that ribosomal drug-binding sites are divergent across eukaryotic clades, with some of the clades exhibiting more substitutions in their ribosomal drug-binding sites compared to humans than humans do compared to bacteria. Overall, our work provides a resource for understanding the evolutionary divergence of drug-binding sites in eukaryotic ribosomes, which may inform the use of ribosome inhibitors as research tools and lineage-specific drugs against eukaryotic parasites.
    Keywords:  CP: Molecular biology; antimicrobial resistance; ribosome; ribosome-targeting antibiotics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116244
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