bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–03–30
fifteen papers selected by
Jessica Rosarda, Uniformed Services University
  1. Cellular Stress Responses and Associated Diseases: A Focus on Heat Shock Proteins.
  2. Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α.
  3. Serine mistranslation induces the integrated stress response through the P stalk.
  4. Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
  5. Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart.
  6. Plasticity of the mammalian integrated stress response.
  7. Metabolism Meets Translation: Dietary and Metabolic Influences on tRNA Modifications and Codon Biased Translation.
  8. Mechanisms of COPII coat assembly and cargo recognition in the secretory pathway.
  9. Emerging Roles of m7G-Cap Hypermethylation and Nuclear Cap-Binding Proteins in Bypassing Suppression of eIF4E-Dependent Translation.
  10. Targeting polyunsaturated fatty acids desaturase FADS1 inhibits renal cancer growth via ATF3-mediated ER stress response.
  11. Establishing the Role of Liver Fatty Acid-Binding Protein in Post-Golgi Very-Low-Density Lipoprotein Trafficking Using a Novel Fluorescence-Based Assay.
  12. Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.
  13. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  14. The role of heat shock proteins in fracture healing-a narrative review.
  15. mitoXplorer 3.0, A Web Tool for Exploring Mitochondrial Dynamics in Single-cell RNA-seq Data.
  1. Cell Biochem Biophys. 2025 Mar 24.
    Cellular Stress Responses and Associated Diseases: A Focus on Heat Shock Proteins.
    Bandana Kumari.
      Cellular stress response is the response of the cell at molecular level in order to combat various environmental stressors / viral infections. These stressors can be either intra or extracellular. In the beginning of the insult cell tries to recoup from these adverse events by various mechanism like heat shock protein response, unfolded protein response, mitochondrial stress signaling, DNA damage response etc. However, if these stressors exceed the cellular capacity to coup with it, it leads to programmed cell death and senescence. Also, chronic stress and cortisol released in response to cellular stress decreases telomerase activity which is needed to replenish telomeres which are protective casing at the end of a strand of DNA. Too low telomeres lead to cell death or cell become pro-inflammatory leading to aging process and other health associated risks like cardiovascular diseases neurodegenerative diseases, autoimmune diseases, cancers etc.
    Keywords:  Cellular stress; DNA damage response; Heat shock protein response; Mitochondrial stress signaling; Unfolded protein response
    DOI:  https://doi.org/10.1007/s12013-025-01724-3
  2. RSC Med Chem. 2025 Mar 18.
    Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α.
    Breanna L Zerfas, Yingpeng Liu, Jianwei Che, Katherine A Donovan, John M Hatcher, Fidel Huerta, Rebecca J Metivier, Radosław P Nowak, Leah Ragosta, Tiffany Tsang, Eric S Fischer, Lyn H Jones.
      IRE1α is an ER protein involved in the unfolded protein response (UPR) and dysregulation of the ER stress pathway has been implicated in several diseases. Inhibitors of the cytoplasmic endonuclease or kinase domains of the enzyme have limited utility and targeted degradation would address additional scaffolding functions of the protein. Here, we describe the design and development of IRE1α proteolysis targeting chimeras (PROTACs) based on a lysine-reactive salicylaldehyde RNase inhibitor, and present the structure-activity relationships (SARs) that delivered the first highly selective degraders of a native ER-membrane associated protein. Medicinal chemistry optimization exploited ternary complex computational modelling to inform design, HiBiT-SpyTag IRE1α degradation and NanoBRET cereblon occupancy cell-based assays to generate SARs, and mass spectrometry-based proteomics to assess broad selectivity in an unbiased manner. Merging IRE1α and CRBN ligand chemotypes provided the truncated chimera CPD-2828 with physicochemical properties more akin to an oral molecular glue degrader than a traditional PROTAC.
    DOI:  https://doi.org/10.1039/d5md00028a
  3. J Biol Chem. 2025 Mar 25. pii: S0021-9258(25)00296-0. [Epub ahead of print] 108447
    Serine mistranslation induces the integrated stress response through the P stalk.
    Hong Zhang, Jiqiang Ling.
      Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that support robust and accurate protein synthesis. A rapidly expanding number of studies show that mutations in aaRSs lead to multiple human diseases, including neurological disorders and cancer. How aaRS mutations impact human health is not fully understood. In particular, our knowledge of how aminoacylation errors affect stress responses and fitness in eukaryotic cells remains limited. The integrated stress response (ISR) is an adaptive mechanism in response to multiple stresses. However, chronic activation of the ISR contributes to the development of multiple diseases such as neuropathies. In this study, we show that Ser misincorporation into Ala and Thr codons, resulting from either aaRS editing defects or mutations in tRNAs, actives the ISR. We further demonstrate that activation of the ISR by Ser mistranslation does not depend on the accumulation of uncharged tRNAs, but rather requires the P stalk associated with the ribosome, implying that ribosome stalling and collision are involved. Our work highlights that certain types of aminoacylation errors can lead to chronic activation of the ISR, potentially affecting fitness and disease progression.
    Keywords:  AlaRS; ThrRS; Translational fidelity; stress response; tRNA misacylation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108447
  4. J Cell Biol. 2025 May 05. pii: e202405060. [Epub ahead of print]224(5):
    Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
    Yazhen Huo, Xinlu Liu, Chen Lu, Tao Li, Zaili Yang, Fenfen Xu, Si Chen, Kailin Yin, Likun Wang.
      Under endoplasmic reticulum (ER) stress (ERS), cells initiate the unfolded protein response (UPR) to maintain ER homeostasis. Recent studies revealed ERS transmission between cells and tissues, by activating the cell-nonautonomous UPR in cells that do not experience ERS directly. Here, we report that ERS triggers a rapid release of ceramide independent of the UPR, but requiring the acid sphingomyelinase activity. Carried by lipoproteins, ceramide is delivered to receiving cells to induce the UPR and regulate cell functions at multiple aspects, including lipid accumulation, cell death, and cytokine production. Mechanistically, extracellular ceramide stimulates ceramide synthesis at the transcription level in receiving cells, leading to ceramide accumulation in the ER so as to reduce membrane fluidity to disrupt ER calcium homeostasis, thus activating the UPR. Sphingomyelin counterbalanced the effect of ceramide. UPR induction is the frontline response to protect cells from ceramide insult. Our study suggests ceramide-mediated ERS transmission as a universal cell-cell communication model regulating a wide range of physiological events.
    DOI:  https://doi.org/10.1083/jcb.202405060
  5. J Cardiovasc Aging. 2025 Jan;pii: 4. [Epub ahead of print]5(1):
    Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart.
    Sakthijothi Muthu, Zinnia Tran, Jayapalraja Thilagavathi, Tanvi Bolarum, Edouard I Azzam, Carolyn K Suzuki, Venkatesh Sundararajan.
       Introduction: Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known.
    Aim: This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging.
    Methods and Results: We utilized 10- and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, Tfam; however, selective mtDNA genes, such as mt-Cytb and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including Lonp1, Yme1l1, Afg3l2, and Spg7, were significantly induced, with a substantial induction of Clpp and Clpx. However, age-associated differences were not observed in the induction of mt chaperones (Hspa9 and Hspd1), but significant induction of Dnaja2, a mitochondrial co-chaperone, was observed. The ER stress transcription factors Xbp1 and Atf6 were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone Hsp90b with no change in Hspa5 and Dnajb9 chaperones. However, induction of Dnm1l was significant, whereas Mfn1 and Fis1 were downregulated in contrast to Mfn2, suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels.
    Conclusion: These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.
    Keywords:  Aging; endoplasmic reticulum stress; heart; mitochondrial stress; oxidative stress
    DOI:  https://doi.org/10.20517/jca.2024.17
  6. Nature. 2025 Mar 26.
    Plasticity of the mammalian integrated stress response.
    Chien-Wen Chen, David Papadopoli, Krzysztof J Szkop, Bo-Jhih Guan, Mohammed Alzahrani, Jing Wu, Raul Jobava, Mais M Asraf, Dawid Krokowski, Anastasios Vourekas, William C Merrick, Anton A Komar, Antonis E Koromilas, Myriam Gorospe, Matthew J Payea, Fangfang Wang, Benjamin L L Clayton, Paul J Tesar, Ashleigh Schaffer, Alexander Miron, Ilya Bederman, Eckhard Jankowsky, Christine Vogel, Leoš Shivaya Valášek, Jonathan D Dinman, Youwei Zhang, Boaz Tirosh, Ola Larsson, Ivan Topisirovic, Maria Hatzoglou.
      An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the 'canonical' integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2α-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2α-p induction activates the eIF4E-ATF4-PCK2 axis to maintain energy homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-08794-6
  7. Wiley Interdiscip Rev RNA. 2025 Mar-Apr;16(2):16(2): e70011
    Metabolism Meets Translation: Dietary and Metabolic Influences on tRNA Modifications and Codon Biased Translation.
    Sherif Rashad, Aseel Marahleh.
      Transfer RNA (tRNA) is not merely a passive carrier of amino acids, but an active regulator of mRNA translation controlling codon bias and optimality. The synthesis of various tRNA modifications is regulated by many "writer" enzymes, which utilize substrates from metabolic pathways or dietary sources. Metabolic and bioenergetic pathways, such as one-carbon (1C) metabolism and the tricarboxylic acid (TCA) cycle produce essential substrates for tRNA modifications synthesis, such as S-Adenosyl methionine (SAM), sulfur species, and α-ketoglutarate (α-KG). The activity of these metabolic pathways can directly impact codon decoding and translation via regulating tRNA modifications levels. In this review, we discuss the complex interactions between diet, metabolism, tRNA modifications, and mRNA translation. We discuss how nutrient availability, bioenergetics, and intermediates of metabolic pathways, modulate the tRNA modification landscape to fine-tune protein synthesis. Moreover, we highlight how dysregulation of these metabolic-tRNA interactions contributes to disease pathogenesis, including cancer, metabolic disorders, and neurodegenerative diseases. We also discuss the new emerging field of GlycoRNA biology drawing parallels from glycobiology and metabolic diseases to guide future directions in this area. Throughout our discussion, we highlight the links between specific modifications, their metabolic/dietary precursors, and various diseases, emphasizing the importance of a metabolism-centric tRNA view in understanding many pathologies. Future research should focus on uncovering the interplay between metabolism and tRNA in specific cellular and disease contexts. Addressing these gaps will guide new research into novel disease interventions.
    Keywords:  codon; epitranscriptome; mRNA translation; metabolism; tRNA modifications
    DOI:  https://doi.org/10.1002/wrna.70011
  8. Nat Rev Mol Cell Biol. 2025 Mar 25.
    Mechanisms of COPII coat assembly and cargo recognition in the secretory pathway.
    Katie W Downes, Giulia Zanetti.
      One third of all proteins in eukaryotes transit between the endoplasmic reticulum (ER) and the Golgi to reach their functional destination inside or outside of the cell. During export, secretory proteins concentrate at transitional zones of the ER known as ER exit sites, where they are packaged into transport carriers formed by the highly conserved coat protein complex II (COPII). Despite long-standing knowledge of many of the fundamental pathways that govern traffic in the early secretory pathway, we still lack a complete mechanistic model to explain how the various steps of COPII-mediated ER exit are regulated to efficiently transport diverse cargoes. In this Review, we discuss the current understanding of the mechanisms underlying COPII-mediated vesicular transport, highlighting outstanding knowledge gaps. We focus on how coat assembly and disassembly dictate carrier morphogenesis, how COPII selectively recruits a vast number of cargo and cargo adaptors, and finally discuss how COPII mechanisms in mammals might have adapted to enable transport of large proteins.
    DOI:  https://doi.org/10.1038/s41580-025-00839-y
  9. Viruses. 2025 Mar 05. pii: 372. [Epub ahead of print]17(3):
    Emerging Roles of m7G-Cap Hypermethylation and Nuclear Cap-Binding Proteins in Bypassing Suppression of eIF4E-Dependent Translation.
    Kathleen Boris-Lawrie, Jessica Liebau, Abdullgadir Hayir, Xiao Heng.
      Translation regulation is essential to the survival of hosts. Most translation initiation falls under the control of the mTOR pathway, which regulates protein production from mono-methyl-guanosine (m7G) cap mRNAs. However, mTOR does not regulate all translation; hosts and viruses alike employ alternative pathways, protein factors, and internal ribosome entry sites to bypass mTOR. Trimethylguanosine (TMG)-caps arise from hypermethylation of pre-existing m7G-caps by the enzyme TGS1 and are modifications known for snoRNA, snRNA, and telomerase RNA. New findings originating from HIV-1 research reveal that TMG-caps are present on mRNA and license translation via an mTOR-independent pathway. Research has identified TMG-capping of selenoprotein mRNAs, junD, TGS1, DHX9, and retroviral transcripts. TMG-mediated translation may be a missing piece for understanding protein synthesis in cells with little mTOR activity, including HIV-infected resting T cells and nonproliferating cancer cells. Viruses display a nuanced interface with mTOR and have developed strategies that take advantage of the delicate interplay between these translation pathways. This review covers the current knowledge of the TMG-translation pathway. We discuss the intimate relationship between metabolism and translation and explore how this is exploited by HIV-1 in the context of CD4+ T cells. We postulate that co-opting both translation pathways provides a winning strategy for HIV-1 to dictate the sequential synthesis of its proteins and balance viral production with host cell survival.
    Keywords:  CBP80/NCBP3; DHX9/RNA helicase A-responsive structure; cap exchange; epigenetic modification; m2,2,7-guanosine cap; trimethylguanosine cap (TMG-cap)
    DOI:  https://doi.org/10.3390/v17030372
  10. Biomed Pharmacother. 2025 Mar 22. pii: S0753-3322(25)00200-8. [Epub ahead of print]186 118006
    Targeting polyunsaturated fatty acids desaturase FADS1 inhibits renal cancer growth via ATF3-mediated ER stress response.
    Gioia Heravi, Zhenjie Liu, Mackenzie Herroon, Alexis Wilson, Yang-Yi Fan, Yang Jiang, Nivisa Vakeesan, Li Tao, Zheyun Peng, Kezhong Zhang, Jing Li, Robert S Chapkin, Izabela Podgorski, Wanqing Liu.
       OBJECTIVE: Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study.
    METHOD AND RESULTS: We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo. Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response, as well as impaired biosynthesis of nucleotides, possibly accounting for the cell cycle arrest.
    CONCLUSION: Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target.
    Keywords:  ATF3; ER stress; FADS1; Kidney cancer; PUFA
    DOI:  https://doi.org/10.1016/j.biopha.2025.118006
  11. Int J Mol Sci. 2025 Mar 07. pii: 2399. [Epub ahead of print]26(6):
    Establishing the Role of Liver Fatty Acid-Binding Protein in Post-Golgi Very-Low-Density Lipoprotein Trafficking Using a Novel Fluorescence-Based Assay.
    Kayli Winterfeldt, Fahim Rejanur Tasin, Shadab A Siddiqi.
      The liver plays a crucial role in maintaining lipid homeostasis by converting toxic free fatty acids into VLDL, which the body uses for energy. Even minor changes in VLDL formation and secretion can result in serious health conditions such as atherosclerosis and non-alcoholic fatty liver disease. Despite the importance of VLDL, the proteins and signaling pathways involved in its regulation remain largely unknown. This study aims to develop a novel methodology to study intracellular VLDL transport events and explore the role of liver fatty acid-binding protein (LFABP) in VLDL transport and secretion. Current methods to study VLDL are often tedious, time-consuming, and expensive, underscoring the need for an alternative approach. We designed a new immunofluorescence-based assay to track the formation and secretion of VLDL in cells over time using fluorescently tagged TopFluor oleic acid. Confocal microscopy confirmed that TopFluor oleic acid enters hepatocytes and colocalizes with the ER, Golgi, and plasma membrane. Additionally, the collection of cell culture media revealed that TopFluor was incorporated into VLDL particles, as confirmed by fluorescence readings and ApoB100 immunoblots. This novel assay provides a valuable tool for further research into the mechanisms of VLDL regulation and the development of potential therapeutic targets for related diseases. Utilizing this assay, we identified LFABP as a key regulatory protein in post-Golgi VLDL trafficking. Our data suggest that LFABP plays a crucial role in this process, and its functional impairment leads to reduced VLDL secretion.
    Keywords:  Golgi; apolipoprotein B100; liver fatty acid-binding protein (LFABP); post-Golgi VLDL transport vesicle (PG-VTV); very-low-density lipoprotein (VLDL)
    DOI:  https://doi.org/10.3390/ijms26062399
  12. Mol Metab. 2025 Mar 20. pii: S2212-8778(25)00035-3. [Epub ahead of print] 102128
    Microglial ER stress response via IRE1α regulates diet-induced metabolic imbalance and obesity in mice.
    L Stilgenbauer, Q Chen, D Pungi, N James, H Jayarathne, L Koshko, S Scofield, K Zhang, M Sadagurski.
       BACKGROUND: Chronic high-fat diet (HFD) feeding triggers hypothalamic inflammation and systemic metabolic dysfunction associated with endoplasmic reticulum (ER) stress. Glial cells, specifically microglia and astrocytes, are central mediators of hypothalamic inflammation. However, the role of Inositol-Requiring Enzyme 1α (IRE1α), a primary ER stress sensor, in glial cells and its contributions to metabolic dysfunction remains elusive.
    OBJECTIVES: To investigate the role of IRE1α in microglia in mediating HFD-induced metabolic dysfunction.
    METHODS: Using novel conditional knockout mouse models (CX3CR1GFPΔIRE1 and TMEM119ERΔIRE1), we deleted IRE1α in immune cells or exclusively in microglia and studied its impact on metabolic health and hypothalamic transcriptional changes in mice fed with HFD for 16 weeks.
    RESULTS: Deleting IRE1α in microglia significantly reduced LPS-induced pro-inflammatory cytokine gene expression in vitro. IRE1α deletion in microglia protected male mice from HFD-induced obesity, glucose intolerance, and hypothalamic inflammation, with no metabolic benefits observed in female mice. RNA-sequencing revealed significant transcriptional reprogramming of the hypothalamus, including upregulation of genes related to mitochondrial fatty acid oxidation, metabolic adaptability, and anti-inflammatory responses.
    CONCLUSIONS: Our findings reveal that IRE1α-mediated ER stress response in microglia significantly contributes to hypothalamic inflammation and systemic metabolic dysfunction in response to HFD, particularly in males, demonstrating an important role of microglial ER stress response in diet-induced obesity and metabolic diseases.
    Keywords:  ER stress; Hypothalamic inflammation; Hypothalamus; Microglia; Neuroinflammation; UPR
    DOI:  https://doi.org/10.1016/j.molmet.2025.102128
  13. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  14. Eur J Trauma Emerg Surg. 2025 Mar 26. 51(1): 154
    The role of heat shock proteins in fracture healing-a narrative review.
    Klemens Trieb, T Huber, S Senck, Franz Landauer.
      Fracture healing is a physiological process that is always accompanied by an immunologically mediated inflammatory reaction, resulting in primary bone healing. Heat shock proteins (HSPs) are omnipresent stress proteins produced by cells in response to exposure to stressful conditions, which function as intracellular proteins that accomplish protein folding and transport intracellularly. This narrative review aims to shed light on the underlying molecular mechanisms of HSPs with respect to the currently available Medline literature. The initial search for "heat shock protein AND fracture" identified 70 studies; after reviewing the texts and checking for content, 9 studies remained. The second search for "heat shock protein AND trauma AND bone" identified 67 studies. After manually searching through the titles and abstracts, six articles remained, three of which were already found in the first search. One study was excluded because it did not include HSPs or fractures, resulting in two additional papers being included. The third search for "heat shock protein AND osteogenesis imperfecta AND fracture" resulted in nine studies. After reviewing the texts, three articles that were already included from the first search remained. This review highlights the significant potential of HSPs and the established HSP investigations related to fracture healing. Our review indicates that, despite the few studies available, those that were selected are very important for identifying research approaches and areas that require further study.
    Keywords:  Bioengineering; Expression; Fracture; Heat shock protein
    DOI:  https://doi.org/10.1007/s00068-025-02838-2
  15. J Mol Biol. 2025 Feb 12. pii: S0022-2836(25)00070-1. [Epub ahead of print] 169004
    mitoXplorer 3.0, A Web Tool for Exploring Mitochondrial Dynamics in Single-cell RNA-seq Data.
    Margaux Haering, Andrea Del Bondio, Helene Puccio, Bianca H Habermann.
      Mitochondria are essential eukaryotic organelles, primarily recognized for their roles in ATP production, cellular metabolism and signalling. It is widely accepted that their structure, composition and function differ across cell types. However, little is known about mitochondrial variability within the same cell type. A comprehensive understanding of mitochondrial function and dynamics requires investigation at both, the individual cell type and single-cell resolution. Based on our mitoXplorer 2.0 web tool, we introduce mitoXplorer 3.0 with new features adapted for analysing single-cell sequencing data, focusing only on mitochondria. We developed a formatting script, scXplorer, which generates mitoXplorer 3.0 compatible files for data upload. The script generates pseudo-bulk transcriptomes of cell types from scRNA-seq data, enabling differential expression analysis and subsequent mitochondria-centric analysis with mitoXplorer classical interfaces. It also creates a single-cell expression matrix only containing mitochondria-associated genes (mito-genes), which can be analysed for cell-to-cell variability with novel, interactive interfaces created for mitoXplorer 3.0: these new interfaces help to identify sub-clusters of cell types based only on mito-genes and offer in-depth mitochondria-centric analysis of subpopulations. We demonstrate the usability and predictive power of mitoXplorer 3.0 through analysis of single-cell transcriptome data from a Spinocerebellar Ataxia Type 1 study. Our analysis identified several mitochondrial processes and genes significantly affected in SCA1 Purkinje cells, potentially contributing to mitochondrial dysfunction and subsequent Purkinje cell degeneration in this disease. MitoXplorer 3.0 is freely available at https://mitoxplorer3.ibdm.univ-amu.fr.
    Keywords:  data integration; mitoXplorer; mitochondria; single-nuclei sequencing; visual data mining
    DOI:  https://doi.org/10.1016/j.jmb.2025.169004
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