bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–09–07
twelve papers selected by
Jessica Rosarda, Uniformed Services University
  1. Potentiating the integrated stress response.
  2. The integrated stress response in the brain: cell type-specific functions in health and neurological disorders.
  3. The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.
  4. In vivo manipulation of the protein homeostasis network in rhabdomyosarcoma.
  5. PTMs as molecular encoders: reprogramming chaperones into epichaperomes for network control in disease.
  6. MitoTraP: mitochondrial protection for cellular proteostasis.
  7. CerS2 is a druggable target in triple-negative breast cancer.
  8. ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.
  9. Osmotic pressure-induced calcium response states.
  10. Quantitative Strategies for Decoding Organelle Ion Dynamics.
  11. Protein activities driven by amino acid composition.
  12. Genetically encoded tool for manipulation of ATP/ADP ratio in human cells.
  1. Nat Rev Drug Discov. 2025 Sep 03.
    Potentiating the integrated stress response.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-025-00147-2
  2. Trends Neurosci. 2025 Sep 02. pii: S0166-2236(25)00169-9. [Epub ahead of print]
    The integrated stress response in the brain: cell type-specific functions in health and neurological disorders.
    David Ho-Tieng, Vijendra Sharma, Nahum Sonenberg, Christos G Gkogkas, Arkady Khoutorsky.
      The integrated stress response (ISR) is an evolutionarily conserved signaling network that regulates protein synthesis in response to diverse cellular stressors to promote stress adaptation. The ISR also responds to physiological stimuli to modify the cellular proteome in an activity-dependent manner. Many common brain pathologies, including neurodegenerative and neurodevelopmental disorders, induce chronic cellular stress and subsequent ISR activation, which substantially contributes to disease progression. Importantly, various brain cell types exhibit disparate levels of sensitivity to cellular stress and differ in how the activation of the ISR influences their physiology. In this review, we highlight cell type-specific roles of the ISR in brain health and disease. We also discuss how therapeutically targeting the ISR in pathological states should account for the cell types being affected.
    Keywords:  astrocytes; brain; memory; microglia; neurons; protein synthesis; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.tins.2025.08.002
  3. Am J Pathol. 2025 Aug 26. pii: S0002-9440(25)00300-1. [Epub ahead of print]
    The Proteostasis Network in Proteinopathies: Mechanisms and Interconnections.
    Dariusz Pytel, Jody Fromm Longo.
      Proteinopathies are neurodegenerative disorders that are characterized by accumulation of misfolded toxic protein aggregates that lead to synaptic and neuronal dysfunction. Though genetically, clinically and pathologically distinct, a common feature of these diseases is disruption of protein homeostasis (proteostasis), which causes accumulation of misfolded proteins. The machinery mediating proteostasis exquisitely balances and interlaces protein synthesis, protein folding and trafficking, and protein degradation processes within the proteostasis network to maintain homeostasis. The proteostasis network governs a functional and dynamic proteome by modulating the timing, location, and stoichiometry of protein expression, surveillance and maintenance of protein folding and removal of misfolded or excess proteins. Although a functional proteome is essential for the health of all cell types, this is especially true for neurons which are prone to enhanced cellular stress. Aging is the most important risk factor for proteostasis decline and the development of proteinopathies. However, germline and somatic mutations can also functionally impair components of the proteostasis network. Post-mitotic cells, particularly neurons, are rendered further susceptible to proteostasis dysfunction due to their extended lifespan. This review discusses the interconnections between the functional components mediating proteostasis in neuronal cells and how aberrations in proteostasis contribute to neuronal dysfunction and disease.
    Keywords:  Alzheimer’s Disease; Amyotrophic Lateral Sclerosis; ER stress; ERAD; Frontotemporal Dementia; Huntington’s Disease; Parkinson’s Disease; UPR; aggregates; autophagy; protein homeostasis; proteinopathies
    DOI:  https://doi.org/10.1016/j.ajpath.2025.07.011
  4. Oncotarget. 2025 Aug 29. 16 681-696
    In vivo manipulation of the protein homeostasis network in rhabdomyosarcoma.
    Kristen Kwong, Yue Pan, Jacqueline Morales, Matthew Watson, David V Allegakoen, Alex G Lee, Trever G Bivona, Peter Wipf, Christopher J Guerriero, Jeffrey L Brodsky, Amit J Sabnis.
      The protein homeostasis (proteostasis) network includes quality control systems that coordinate protein synthesis, folding, localization, and degradation, and is deregulated in numerous diseases including cancer. Loss of proteostasis can activate lethal cellular stress responses, potentially opening a therapeutic window. Previous research demonstrated that MAL3-101, an inhibitor of heat shock protein 70-kD (HSP70) chaperones, selectively induces rhabdomyosarcoma (RMS) cell death via unfolded protein response (UPR) activation. RMS is the most common pediatric soft tissue sarcoma, and relapsed patients are rarely cured despite transient responses to DNA-damaging therapy. To examine whether MAL3-101 or more drug-like proteostasis inhibitors represent a new therapeutic strategy for RMS, we screened proteostasis components that might recapitulate the effects of MAL3-101 in vivo. We find that inhibition of VCP, which encodes the p97 ATPase that facilitates proteasome-dependent degradation, similarly activates the UPR and induces RMS apoptosis. In mouse models, a preclinical p97 inhibitor showed superior bioavailability and anti-tumor activity compared to MAL3-101. Patient-derived xenografts exhibited a spectrum of p97 inhibitor sensitivities, and RNA sequencing of resistant tumors revealed elevated autophagy, nominating a biomarker of proteostasis adaptability. Together, these findings confirm that proteostasis inhibition can slow RMS growth and suggest that targeting compensatory network components might yield synergistic outcomes.
    Keywords:  p97; preclinical therapeutics; protein homeostasis; rhabdomyosarcoma; unfolded protein response
    DOI:  https://doi.org/10.18632/oncotarget.28764
  5. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00169-0. [Epub ahead of print]
    PTMs as molecular encoders: reprogramming chaperones into epichaperomes for network control in disease.
    Feixia Chu, Sahil Sharma, Stephen D Ginsberg, Gabriela Chiosis.
      Recent discoveries reveal that post-translational modifications (PTMs) do more than regulate protein activity - they encode conformational states that transform chaperones into epichaperomes: multimeric scaffolds that rewire protein-protein interaction networks. This emerging paradigm expands the framework of chaperone biology in disease and provides a structural basis for systems-level dysfunction in disorders such as cancer and Alzheimer's disease. This review explores how PTMs within intrinsically disordered regions drive epichaperome formation, how these scaffolds selectively regulate disease-enabling functions, and why their disruption normalizes pathological networks. By highlighting PTMs as molecular encoders of supramolecular assemblies, we propose a shift from targeting proteins to targeting network architectures that sustain and perpetuate disease - a concept with broad implications for cell biology, disease propagation, and therapeutic design.
    Keywords:  chaperone reprogramming; intrinsically disordered regions; network-centric therapeutics; post-translational control; protein–protein interaction networks; supramolecular scaffolds
    DOI:  https://doi.org/10.1016/j.tibs.2025.07.006
  6. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]
    MitoTraP: mitochondrial protection for cellular proteostasis.
    Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.
      Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.
    Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
  7. bioRxiv. 2025 Aug 21. pii: 2025.08.15.670525. [Epub ahead of print]
    CerS2 is a druggable target in triple-negative breast cancer.
    Hissah Alatawi, Haritha H Nair, Lingbao Ai, Iqbal Mahmud, Abhishek Gour, Amandeep Singh, Doohyun Baek, Bowen Yan, Chandra K Maharjan, Weizhou Zhang, Brian K Law, Maria Zajac-Kaye, Christopher Vulpe, Olga A Guryanova, Arun K Sharma, Timothy J Garrett, Abhisheak Sharma, Coy D Heldermon, Sukwon Hong, Satya Narayan.
      Triple-negative breast cancer (TNBC) remains a significant clinical challenge due to its aggressive nature and lack of effective targeted therapies. The enzyme ceramide synthase 2 (CerS2), which synthesizes pro-apoptotic very long-chain ceramides (VLCCs), represents a promising therapeutic target. Here, we identify and characterize DH20931, a novel, first-in-class small-molecule agonist of CerS2. We demonstrate that DH20931 directly activates CerS2 with nanomolar potency, leading to significant VLCC accumulation in breast cancer cells. This lipotoxic event induces endoplasmic reticulum (ER) stress and triggers apoptosis via the canonical ATF4/CHOP/PUMA signaling pathway. Mechanistically, we uncover a novel interaction between CerS2 and the ER calcium channel, Inositol 1,4,5-trisphosphate receptor 1 (IP3R1). We demonstrate that DH20931 promotes this interaction, enhancing ER-mitochondria proximity and facilitating a CerS2-dependent flux of calcium (Ca²⁺) from the ER into mitochondria. This subsequent mitochondrial Ca²⁺ overload serves as a critical trigger for apoptosis. In preclinical evaluations, DH20931 potently inhibited the growth of TNBC cells in 2D and 3D cultures and significantly suppressed tumor progression in orthotopic and patient-derived xenograft (PDX) models, all while exhibiting a favorable safety profile. Our findings validate CerS2 as a druggable target in TNBC and establish a novel therapeutic strategy that leverages a coordinated attack on cancer cells through ER stress and calcium-mediated mitochondrial dysfunction.
    Highlights: DH20931 is a first-in-class, potent agonist of Ceramide Synthase 2 (CerS2).CerS2 activation induces ER stress and engages the ATF4/CHOP/PUMA apoptotic pathway.DH20931 promotes a novel CerS2-IP3R1 interaction, causing lethal mitochondrial calcium overload.Targeting CerS2 shows significant preclinical efficacy against triple-negative breast cancer.
    DOI:  https://doi.org/10.1101/2025.08.15.670525
  8. Nat Metab. 2025 Sep 01.
    ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation.
    Olivia I Coleman, Adam Sorbie, Alessandra Riva, Miriam von Stern, Stephanie Kuhls, Denise M Selegato, Luisa Siegert, Isabel Keidel, Nikolai Köhler, Jakob Wirbel, Tim Kacprowski, Andreas Dunkel, Josch K Pauling, Johannes Plagge, Diego Mediel-Cuadra, Sophia J Wagner, Ines Chadly, Sandra Bierwith, Tingying Peng, Thomas Metzler, Xin Li, Mathias Heikenwälder, Clemens Schafmayer, Sebastian Hinz, Christian Röder, Christoph Röcken, Michael Zimmermann, Philip Rosenstiel, Katja Steiger, Moritz Jesinghaus, Gerhard Liebisch, Josef Ecker, Christina Schmidt, Georg Zeller, Klaus-Peter Janssen, Dirk Haller.
      Endoplasmic reticulum unfolded protein responses contribute to cancer development, with activating transcription factor 6 (ATF6) involved in microbiota-dependent tumorigenesis. Here we show the clinical relevance of ATF6 in individuals with early-onset and late colorectal cancer, and link ATF6 signalling to changes in lipid metabolism and intestinal microbiota. Transcriptional analysis in intestinal epithelial cells of ATF6 transgenic mice (nATF6IEC) identifies bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype labelling confirm ATF6-related enrichment of long-chain fatty acids in colonic tissue of humans, mice and organoids. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including Desulfovibrio fairfieldensis, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01350-6
  9. FEBS Open Bio. 2025 Aug 29.
    Osmotic pressure-induced calcium response states.
    Zidan Gao, Keiji Naruse, Masatoshi Morimatsu.
      Osmotic pressure is essential for maintaining cellular homeostasis; however, the mechanisms by which cells sense and respond to acute osmotic stress remain incompletely understood. Here, we applied rapid osmotic pressure stimulation to cultured HEK293T cells and observed dynamic intracellular calcium responses. Acute hypotonic stimulation evoked calcium response patterns, whereas hypertonic and isotonic stress did not elicit similar effects. Mechanistically, these calcium signals originated from the endoplasmic reticulum via ryanodine receptor 2 and propagated to neighboring cells through Connexin 43-mediated gap junctions. These findings reveal a previously unrecognized role for calcium signaling in the acute cellular response to osmotic stress, providing new insights into the mechanisms of intercellular communication during osmotic adaptation.
    Keywords:  Connexin 43; calcium wave; hypotonic pressure; osmotic pressure; ryanodine receptor
    DOI:  https://doi.org/10.1002/2211-5463.70094
  10. Chembiochem. 2025 Aug 29. e202500557
    Quantitative Strategies for Decoding Organelle Ion Dynamics.
    Palapuravan Anees.
      Ion dynamics within cellular organelles are fundamental to numerous biochemical processes, maintaining homeostasis and enabling critical cellular functions. Despite continuous ion movement across organelle membranes, stable ionic gradients are preserved, creating optimal microenvironments for organelle-specific activities such as ATP production in mitochondria, lysosomal degradation, Golgi-mediated protein modifications, and DNA processing in the nucleus. These gradients are regulated by specialized membrane proteins, including ion channels and transporters, which facilitate selective and controlled ion flux. Dysfunction in these regulatory proteins is linked to various diseases, including neurodegenerative disorders, cardiovascular conditions, immune dysfunctions, and cancers. Understanding ion regulation mechanisms at the molecular level is not only essential for basic cell biology but also crucial for revealing pathological pathways and identifying therapeutic targets. Recent technological advances-such as fluorescent probes based on green fluorescent protein, small molecules, and DNA nanodevices-have significantly enhanced our ability to study ion dynamics with high spatial and temporal resolution. These tools enable both qualitative and quantitative analyses, offering insights into ion transport mechanisms and their physiological relevance. A comprehensive overview of the principles underlying functional imaging of ion dynamics is provided, current challenges in quantitative assessment are highlighted, and future directions in organelle-specific ion regulation are discussed.
    Keywords:  cell clamping; fluorescent probes; functional imaging of organelles; ion channels and transporters; organelle ion dynamics
    DOI:  https://doi.org/10.1002/cbic.202500557
  11. J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02492-5. [Epub ahead of print] 110640
    Protein activities driven by amino acid composition.
    Sean M Cascarina, Eric D Ross.
      A foundational concept in protein biochemistry is that the primary sequence of a protein determines its structure and function. However, some protein regions defy this constraint, with protein activity dictated more by amino acid composition than primary sequence. In this review, we examine the concept of "composition-driven protein activities". We discuss experimental criteria for classifying protein activities as driven by composition, how these criteria relate to primary sequence and composition, and how they have aided in characterizing existing examples of composition-driven activities. This emerging perspective provides a framework for thinking about the relationship between sequence and function in particular types of proteins.
    Keywords:  amino acid composition; biomolecular condensate; intrinsically disordered protein; liquid-liquid phase separation; low-complexity domain; prion; prion-like domain; stress granule; structure-function; transcription
    DOI:  https://doi.org/10.1016/j.jbc.2025.110640
  12. bioRxiv. 2025 Aug 23. pii: 2025.08.12.670003. [Epub ahead of print]
    Genetically encoded tool for manipulation of ATP/ADP ratio in human cells.
    Alex E Ekvik, Megan M Kober, Denis V Titov.
      The ability of cells to power energy-demanding processes depends on maintaining the ATP hydrolysis reaction a billion-fold away from equilibrium. Cells respond to changes in energy state by sensing changes in ATP, ADP, AMP, and inorganic phosphate. A key barrier to a better understanding of the maintenance of energy homeostasis is a lack of tools for direct manipulation of energy state in living cells. Here, we report the development of ATPGobble-a genetically encoded tool for controlling cellular ATP hydrolysis rate. We validated ATPGobble by showing that it doubles the energy demand, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK activity in human cells. We then used ATPGobble to systematically characterize the proteome and phosphoproteome changes caused by direct manipulation of the energy state. Our results establish ATPGobble as a powerful approach for dissecting the regulatory roles of energy state in human cells, opening new opportunities to study how cellular energy state governs physiology, stress responses, and disease processes.
    DOI:  https://doi.org/10.1101/2025.08.12.670003
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