bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–03–16
nineteen papers selected by
Jessica Rosarda, Uniformed Services University
  1. Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response.
  2. Endoplasmic Reticulum Stress: Implications in Diseases.
  3. Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.
  4. Fatty Acid Trafficking Between Lipid Droplets and Mitochondria: An Emerging Perspective.
  5. Mitochondrial genetics, signalling and stress responses.
  6. Pre-Clinical Model of Dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis.
  7. Organizing principles underlying COPII-mediated transport.
  8. Lipid Dynamics at Membrane Contact Sites.
  9. Attenuating the neuronal response to chronic stress through transcription factor aggregation.
  10. Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.
  11. Targeted Lipidomics and Transcriptomics Unveil Aberrant Lipid Metabolic Remodeling in Visceral and Subcutaneous Adipose Tissue under ER Stress.
  12. Cell-Type-Specific Protein Metabolic Labeling and Identification Using the Methionine Subrogate ANL in Cells Expressing a Mutant Methionyl-tRNA Synthetase.
  13. Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.
  14. Lysosomal acidification impairment in astrocyte-mediated neuroinflammation.
  15. Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.
  16. Acetic acid-induced stress granules function as scaffolding complexes for Hog1 activation by Pbs2.
  17. C/EBP Homologous Protein Expression in Retinal Ganglion Cells Induces Neurodegeneration in Mice.
  18. Mechanisms and functions of lysosomal lipid homeostasis.
  19. Quality control of mitochondrial nucleoids.
  1. Isr J Chem. 2024 Dec;pii: e202300162. [Epub ahead of print]64(12):
    Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response.
    Kenny Chen, Matthew D Shoulders.
      The unfolded protein response (UPR) is a sensing and signaling pathway that surveys the endoplasmic reticulum (ER) for protein folding challenges and responds whenever issues are detected. UPR activation leads to upregulation of secretory pathway chaperones and quality control factors, as well as reduces the nascent protein load on the ER, thereby restoring and maintaining proteostasis. This paradigm-defining view of the role of the UPR is accurate, but it elides additional key functions of the UPR in cell biology. In particular, recent work has revealed that the UPR can shape the structure and function of N- and O-glycans installed on ER client proteins. This crosstalk between the UPR's response to protein misfolding and the regulation of glycosylation remains insufficiently understood. Still, emerging evidence makes it clear that the UPR, and particularly the IRE1-XBP1s arm of the UPR, may be a central regulator of protein glycosylation with important biological consequences. In this review, we discuss the crosstalk between proteostasis, the UPR, and glycosylation, present progress towards understanding biological functions of this crosstalk, and examine potential roles in diseases such as cancer.
    Keywords:  Endoplasmic reticulum stress; N-Glycosylation; O-Glycosylation; Protein folding; Proteostasis
    DOI:  https://doi.org/10.1002/ijch.202300162
  2. Protein J. 2025 Mar 13.
    Endoplasmic Reticulum Stress: Implications in Diseases.
    Neha Sylvia Walter, Varun Gorki, Rishi Bhardwaj, Pradeep Punnakkal.
      Endoplasmic reticulum (ER) is a specialized organelle that plays a significant role in cellular function. The major functions of ER include protein synthesis and transport, folding of proteins, biosynthesis of lipids, calcium (Ca2+) storage, and redox balance. The loss of ER integrity results in the induction of ER stress within the cell due to the accumulation of unfolded, improperly folded proteins or changes in Ca2+ metabolism and redox balance of organelle. This ER stress commences the Unfolded Protein Response (UPR) that serves to counteract the ER stress via three sensors inositol requiring protein-1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor-6 (ATF6) that serve to establish ER homeostasis and alleviates ER stress. Severe ER dysfunction ultimately results in the induction of apoptosis. Increasing shreds of evidence suggest the implication of ER stress in the development and progression of several diseases viz. tuberculosis, malaria, Alzheimer's disease, Parkinson's disease, diabetes, and cancer. Activation of ER stress can be beneficial for treating some diseases while inhibiting the process can be useful in others. A deeper understanding of these pathways can provide key insights in designing novel therapeutics to treat these diseases.
    Keywords:  Cancer; Diseases; ER Stress; Endoplasmic reticulum; Unfolded Protein Response
    DOI:  https://doi.org/10.1007/s10930-025-10264-x
  3. Cancer Lett. 2025 Mar 05. pii: S0304-3835(25)00177-6. [Epub ahead of print]617 217613
    Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms.
    Si Lu, Qimin Zhou, Rongjie Zhao, Lei Xie, Wen-Ming Cao, Yu-Xiong Feng.
      Endoplasmic reticulum (ER) is the critical organelle that regulates essential cellular processes, including protein synthesis, folding, and post-translational modification, as well as lipid metabolism and calcium homeostasis. Disruption in ER homeostasis leads to a condition known as ER stress, characterized by the accumulation of misfolded or unfolded proteins. This triggers the unfolded protein response (UPR), an adaptive pathway mediated by three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Increasing evidence highlights sustained UPR activation in malignant and immune cells within the tumor microenvironment (TME), which promotes tumor progression and metastasis while simultaneously impairing antitumor immunity. This review explores how UPR-driven intercellular signaling influences immunotherapy resistance, focusing on the alterations occurring in tumor cells as well as in the surrounding immune environment. By providing insights into these mechanisms, we aim to highlight the therapeutic potential of targeting the UPR pathways in modulating cancer immunity.
    Keywords:  Immunotherapy resistance; Tumor microenvironment; UPR
    DOI:  https://doi.org/10.1016/j.canlet.2025.217613
  4. Int J Biol Sci. 2025 ;21(5): 1863-1873
    Fatty Acid Trafficking Between Lipid Droplets and Mitochondria: An Emerging Perspective.
    Katarína Smolková, Klára Gotvaldová.
      The current understanding of lipid droplets (LDs) in cell biology has evolved from being viewed merely as storage compartments. LDs are now recognized as metabolic hubs that act as cytosolic buffers against the detrimental effects of free fatty acids (FAs). Upon activation, FAs traverse various cellular pathways, including oxidation in mitochondria, integration into complex lipids, or storage in triacylglycerols (TGs). Maintaining a balance among these processes is crucial in cellular FA trafficking, and under metabolically challenging circumstances the routes of FA metabolism adapt to meet the current cellular needs. This typically involves an increased demand for anabolic intermediates or energy and the prevention of redox stress. Surprisingly, LDs accumulate under certain conditions such as amino acid starvation. This review explores the biochemical aspects of FA utilization in both physiological contexts and within cancer cells, focusing on the metabolism of TGs, cholesteryl esters (CEs), and mitochondrial FA oxidation. Emphasis is placed on the potential toxicity associated with non-esterified FAs in cytosolic and mitochondrial compartments. Additionally, we discuss mechanisms that lead to increased LD biogenesis due to an inhibited mitochondrial import of FAs.
    Keywords:  CPT1; ferroptosis; lipid droplets; lipotoxicity; mitochondria; triglycerides
    DOI:  https://doi.org/10.7150/ijbs.105361
  5. Nat Cell Biol. 2025 Mar;27(3): 393-407
    Mitochondrial genetics, signalling and stress responses.
    Yasmine J Liu, Jonathan Sulc, Johan Auwerx.
      Mitochondria are multifaceted organelles with crucial roles in energy generation, cellular signalling and a range of synthesis pathways. The study of mitochondrial biology is complicated by its own small genome, which is matrilineally inherited and not subject to recombination, and present in multiple, possibly different, copies. Recent methodological developments have enabled the analysis of mitochondrial DNA (mtDNA) in large-scale cohorts and highlight the far-reaching impact of mitochondrial genetic variation. Genome-editing techniques have been adapted to target mtDNA, further propelling the functional analysis of mitochondrial genes. Mitochondria are finely tuned signalling hubs, a concept that has been expanded by advances in methodologies for studying the function of mitochondrial proteins and protein complexes. Mitochondrial respiratory complexes are of dual genetic origin, requiring close coordination between mitochondrial and nuclear gene-expression systems (transcription and translation) for proper assembly and function, and recent findings highlight the importance of the mitochondria in this bidirectional signalling.
    DOI:  https://doi.org/10.1038/s41556-025-01625-w
  6. Mol Metab. 2025 Mar 10. pii: S2212-8778(25)00027-4. [Epub ahead of print] 102120
    Pre-Clinical Model of Dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis.
    Amanda K Casey, Nathan M Stewart, Naqi Zaidi, Hillery F Gray, Hazel A Fields, Masahiro Sakurai, Carlos A Pinzon-Arteaga, Bret M Evers, Jun Wu, Kim Orth.
      The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the mFicDR371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of mFicDR371S mice appeared normal at birth, adult mFicDR371S mice displayed disturbed pancreatic islet organization that progressed with age. mFicDR371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.
    Keywords:  AMPylation; BiP; FicD; Islet biology; Neonatal Diabetes; Unfolded Protein Response; insulin
    DOI:  https://doi.org/10.1016/j.molmet.2025.102120
  7. Curr Opin Cell Biol. 2025 Mar 10. pii: S0955-0674(25)00030-4. [Epub ahead of print]94 102492
    Organizing principles underlying COPII-mediated transport.
    Julia R Flood, Caitlin A Mendina, Anjon Audhya.
      The early secretory pathway governs the transport of thousands of secreted and transmembrane proteins and lipids from the endoplasmic reticulum (ER) to juxtaposed ER-Golgi Intermediate Compartments (ERGIC). This process is largely directed by Coat Protein complex II (COPII), which accumulates on distinct, ribosome-free ER subdomains (transitional ER) to generate highly curved transport intermediates of various sizes and shapes. The rate of secretory flux from the ER can vary significantly, depending on cell type, environmental cues, and other factors, but the mechanisms that regulate COPII-mediated trafficking have been slow to emerge. Here, we focus on recent progress that has contributed to our understanding of how the early secretory pathway is structured to facilitate the export of cargoes from the ER into a chasm approximately 300-500-nm in size, prior to fusion with ERGIC membranes without the aid of cytoskeletal elements to guide their journey.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102492
  8. Annu Rev Biochem. 2025 Mar 11.
    Lipid Dynamics at Membrane Contact Sites.
    Karin M Reinisch, Pietro De Camilli, Thomas J Melia.
      In eukaryotes, lipid building blocks for cellular membranes are made largely in the endoplasmic reticulum and then redistributed to other organelles. Lipids are transported between organelles by vesicular trafficking or else by proteins located primarily at sites where different organelles are closely apposed. Here we discuss transport at organelle contact sites mediated by shuttle-like proteins that carry single lipids between membranes to fine-tune their composition and by the more recently discovered bridge-like proteins that tether two organelles and provide a path for bulk lipid movement. Protein-mediated lipid transport is assisted by integral membrane proteins that have roles in (a) lowering the energy barrier for lipid transfer between the membrane and the lipid transfer protein, a key parameter determining the transfer rate, and (b) scrambling lipids to counteract the bilayer asymmetry that would result from such transfer. Advances in this field are shedding new light on a variety of physiological mechanisms.
    DOI:  https://doi.org/10.1146/annurev-biochem-083024-122821
  9. Trends Neurosci. 2025 Mar 10. pii: S0166-2236(25)00038-4. [Epub ahead of print]
    Attenuating the neuronal response to chronic stress through transcription factor aggregation.
    Mathilde Solyga, Florence Besse.
      How do neurons cope with chronic stress? In a recent study using blind Drosophila models, Shekhar and colleagues uncovered that chronic sensory deprivation induces brain-wide accumulation of aggregates sequestering transcription factors of the Integrated Stress Response (ISR). However, this protective mechanism prevents cells from triggering adapted transcriptional responses upon exogenous stress.
    Keywords:  ATF4; RNP granules; condensation; integrated stress response; neurodegeneration; sensory deprivation
    DOI:  https://doi.org/10.1016/j.tins.2025.02.007
  10. Nat Commun. 2025 Mar 08. 16(1): 2338
    Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.
    Simon T Bond, Emily J King, Shannen M Walker, Christine Yang, Yingying Liu, Kevin H Liu, Aowen Zhuang, Aaron W Jurrjens, Haoyun A Fang, Luke E Formosa, Artika P Nath, Sergio Ruiz Carmona, Michael Inouye, Thy Duong, Kevin Huynh, Peter J Meikle, Simon Crawford, Georg Ramm, Sheik Nadeem Elahee Doomun, David P de Souza, Danielle L Rudler, Anna C Calkin, Aleksandra Filipovska, David W Greening, Darren C Henstridge, Brian G Drew.
      During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is known to be activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for activation of the mtISR remain mostly unknown. A gene often associated with mtDNA mutations/deletions is Polg1, which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe an inducible, tissue specific model of PolG mutation, which in muscle specific animals leads to rapid development of mitochondrial dysfunction and muscular degeneration in male animals from ~5 months of age. Detailed molecular profiling demonstrated robust activation of the mtISR in muscles from these animals. This was accompanied by striking alterations to enzymes in the mitochondrial folate cycle that was likely driven by a specific depletion in the folate cycle metabolite 5,10 methenyl-THF, strongly implying imbalanced folate intermediates as a previously unrecognised pathology linking the mtISR and mitochondrial disease.
    DOI:  https://doi.org/10.1038/s41467-025-57299-3
  11. J Proteome Res. 2025 Mar 11.
    Targeted Lipidomics and Transcriptomics Unveil Aberrant Lipid Metabolic Remodeling in Visceral and Subcutaneous Adipose Tissue under ER Stress.
    Ping He, Li Zhang, Peng Ma, Tianshu Xu, Zijing Wang, Li Li, Guanhua Du, Guifen Qiang, Cuiqing Liu.
      Endoplasmic reticulum (ER) stress is known to impair the function of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), disrupting lipid metabolism. Despite the crucial role lipid plays in regulating adipose tissue function, the specific lipidomic alterations in VAT and SAT under ER stress remain unclear. In this study, ER stress was induced in VAT and SAT, and targeted lipidomic and transcriptomic approaches were used to analyze lipid metabolism and gene expression profiles. The results revealed that VAT exhibited a stronger ER stress response, characterized by a significant increase in binding immunoglobulin protein (BiP) expression and notable lipidomic disruptions, especially in glycerides and sterols. These disruptions were marked by a decrease in protective polyunsaturated fatty acyl species and the accumulation of lipotoxic molecules. In contrast, SAT displayed less severe lipidomic alterations. Transcriptomic analysis indicated that VAT was more susceptible to immune activation, inflammation, and metabolic dysfunction, while SAT primarily showed alterations in protein folding processes. These findings underscore the tissue-specific mechanisms of ER stress adaptation in VAT and SAT. In conclusion, VAT appears to be a critical target for addressing metabolic dysfunction in obesity and related disorders, with potential therapeutic implications for managing ER stress-induced metabolic diseases.
    Keywords:  ER stress; lipidomics; subcutaneous adipose tissue; transcriptomics; visceral adipose tissue
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00952
  12. Methods Mol Biol. 2025 ;2899 111-126
    Cell-Type-Specific Protein Metabolic Labeling and Identification Using the Methionine Subrogate ANL in Cells Expressing a Mutant Methionyl-tRNA Synthetase.
    Rodrigo Alvarez-Pardo, Ella Doron-Mandel, Hector Albert-Gascó, Cristina Olmedo Salinas, Marko Jovanovic, Beatriz Alvarez-Castelao.
      The study of protein homeostasis in vivo is crucial for our understanding of the functions of cells and organisms. However, complex organisms, such as mammals, are built from heterogeneous tissues and cell-types. These cell-types are often specialized and react in different ways to the same physiological or pathological stimulus. Therefore, a major challenge in proteomics is the identification of proteomes and their behavior in a cell-type-specific manner. In this protocol, we describe a technique to label, enrich, and identify proteins from specific cell types. This technique is based on the expression of a mutant methionyl-tRNA synthetase (MetRS*) for incorporation of a bioorthogonal analog of methionine (ANL) into proteins. ANL can be subsequently bound to an alkyne by click-chemistry, which is used as a bait for protein purification followed by mass spectrometry identification.
    Keywords:  Azidonorleucine (ANL); Mass spectrometry (MS); Methionine-tRNA transferase (MetRS*, MARS); Noncanonical amino acids (NCAA); Protein degradation; Protein homeostasis; Protein synthesis
    DOI:  https://doi.org/10.1007/978-1-0716-4386-0_8
  13. Chembiochem. 2025 Mar 08. e202500048
    Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.
    Hannah Fremlén, Björn M Burmann.
      Cells in all kingdoms of life employ dedicated protein quality control machineries for both their cytosolic and membrane proteome ensuring cellular functionality. These crucial systems consist besides a large variety of molecular chaperones, ensuring a proper fold and consequently function of the client's proteome, of several proteases to clean out damaged, unfunctional and potentially toxic proteins. One of the key features underlying the functional cycle of these quality control systems is the inherent flexibility of their bound clients which for a long time impaired detailed structural characterization, with advanced high-resolution NMR spectroscopy in the last decade playing a key role contributing to the present understanding of their functional properties. Although these studies laid the foundation of the present knowledge of the mechanistic details of the maintenance of cytosolic proteins, the understanding of related systems employed for membrane associated as well as integral membrane proteins remains rather sparse to date. Herein, we review the crucial contributions of structural and dynamical biology approaches, possessing the power to resolve both structure and dynamics of such systems as well as enabling the elucidation of the functional repertoire of multimeric proteases involved in maintaining a functional membrane proteome.
    Keywords:  AAA+ proteases; Integral membrane protein proteases; Protein quality control; rhomboid proteases; signal peptidases
    DOI:  https://doi.org/10.1002/cbic.202500048
  14. J Neuroinflammation. 2025 Mar 10. 22(1): 72
    Lysosomal acidification impairment in astrocyte-mediated neuroinflammation.
    Jialiu Zeng, Jonathan Indajang, David Pitt, Chih Hung Lo.
      Astrocytes are a major cell type in the central nervous system (CNS) that play a key role in regulating homeostatic functions, responding to injuries, and maintaining the blood-brain barrier. Astrocytes also regulate neuronal functions and survival by modulating myelination and degradation of pathological toxic protein aggregates. Astrocytes have recently been proposed to possess both autophagic activity and active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete degradation of cellular cargos. Defective lysosomal acidification in astrocytes impairs their autophagic and phagocytic functions, resulting in the accumulation of cellular debris, excessive myelin and lipids, and toxic protein aggregates, which ultimately contributes to the propagation of neuroinflammation and neurodegenerative pathology. Restoration of lysosomal acidification in impaired astrocytes represent new neuroprotective strategy and therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, myelin and lipid mediated toxicity, and toxic protein aggregates, that contribute to lysosomal acidification impairment and associated autophagic and phagocytic dysfunction in astrocytes. We discuss the role of lysosomal acidification dysfunction in astrocyte-mediated neuroinflammation primarily in the context of neurodegenerative diseases along with other brain injuries. We then highlight re-acidification of impaired lysosomes as a therapeutic strategy to restore autophagic and phagocytic functions as well as lysosomal degradative capacity in astrocytes. We conclude by providing future perspectives on the role of astrocytes as phagocytes and their crosstalk with other CNS cells to impart neurodegenerative or neuroprotective effects.
    Keywords:  Acidic nanoparticles; Autophagy; Glial crosstalk; Lysosomal acidification; Lysosomal alkalization; Metabolic dysfunction; Neurodegeneration; Neuroinflammation; Neuroprotective; Phagocytosis
    DOI:  https://doi.org/10.1186/s12974-025-03410-w
  15. Biochem Biophys Res Commun. 2025 Mar 03. pii: S0006-291X(25)00296-7. [Epub ahead of print]756 151582
    Novel subcellular regulatory mechanisms of protein homeostasis and its implications in amyotrophic lateral sclerosis.
    Aisheng Zhan, Keke Zhong, Kejing Zhang.
      Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disorder. Protein aggregates induce various forms of neuronal dysfunction and represent pathological hallmarks in ALS patients. Reducing protein aggregates could be a promising therapeutic strategy for ALS. While most studies have focused on cytoplasmic protein homeostasis, neurons adaptively reduce aggregates across subcellular compartments during stress through previously uncharacterized mechanisms. Here, we summarize novel compartment-specific proteostatic mechanisms: (1) the ERAD/RESET pathways, (2) HSPs-mediated nuclear sequestration, (3) mitochondrial aggregate import (MAGIC), (4) neurite-localized UPS/autophagosome and NMP, and (5) exopher-mediated extracellular disposal. These mechanisms collectively ensure cellular stress adaptation and provide novel therapeutic targets for ALS treatment.
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151582
  16. J Cell Biol. 2025 May 05. pii: e202409072. [Epub ahead of print]224(5):
    Acetic acid-induced stress granules function as scaffolding complexes for Hog1 activation by Pbs2.
    Jongmin Lee, Kazuo Tatebayashi, David E Levin.
      Stress-activated protein kinases (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPK are not known. We show that the yeast SAPK Hog1 is activated by acetic acid through an intracellular mechanism that does not involve stimulation of the high osmolarity glycerol (HOG) signaling pathway beyond its basal level. Rather, acetic acid treatment drives the formation of stress granules, which function as a scaffold to bring Hog1 together with Pbs2, its immediately upstream activating kinase, in a stable assembly that leverages the basal activity of Pbs2 to phosphorylate Hog1. Deletion analysis of stress granule components revealed that the assembly is critical for both the acetic acid-induced activation of Hog1 and its association with Pbs2. Activated Hog1 remains associated with stress granules, which may have implications for its targeting.
    DOI:  https://doi.org/10.1083/jcb.202409072
  17. Int J Mol Sci. 2025 Feb 21. pii: 1858. [Epub ahead of print]26(5):
    C/EBP Homologous Protein Expression in Retinal Ganglion Cells Induces Neurodegeneration in Mice.
    William C Mayhew, Balasankara Reddy Kaipa, Linya Li, Prabhavathi Maddineni, Yogapriya Sundaresan, Abbot F Clark, Gulab S Zode.
      The progressive loss of retinal ganglion cell (RGC) axons leading to irreversible loss of vision is the pathological hallmark of glaucoma. However, the pathological mechanisms of RGC degeneration are not completely understood. Here, we investigated the role of chronic endoplasmic reticulum (ER) stress in glaucomatous neurodegeneration. To evaluate whether chronic ER stress-induced transcriptional factors, activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) are induced in RGCs; we utilized human donor tissue and the microbead occlusion model of glaucoma. Additionally, we performed the intravitreal injection of adeno-associated virus (AAV) 2 to express CHOP selectively in RGCs in C57BL/6 mice and evaluated its effect on RGC function and structure by pattern electroretinogram (PERG) and whole-mount retina staining with the RBPMS antibody. Here, we report that the ATF4-CHOP pathway is activated in the retinas of human glaucoma donor eyes and a mouse model of ocular hypertension. Further, the expression of CHOP in RGCs led to a significant loss of function, as evidenced by reduced PERG. Notably, the expression of CHOP in the retina induced a significant structural loss of RGCs within 15 weeks of injection. Altogether, our studies indicate that the expression of CHOP in RGCs leads to neurodegeneration in mice.
    Keywords:  ATF4; CHOP; ER stress; glaucoma; neurodegeneration; retinal ganglion cells
    DOI:  https://doi.org/10.3390/ijms26051858
  18. Cell Chem Biol. 2025 Feb 28. pii: S2451-9456(25)00035-2. [Epub ahead of print]
    Mechanisms and functions of lysosomal lipid homeostasis.
    Michael Ebner, Florian Fröhlich, Volker Haucke.
      Lysosomes are the central degradative organelle of mammalian cells and have emerged as major intersections of cellular metabolite flux. Macromolecules derived from dietary and intracellular sources are delivered to the acidic lysosomal lumen where they are subjected to degradation by acid hydrolases. Lipids derived from lipoproteins, autophagy cargo, or autophagosomal membranes themselves constitute major lysosomal substrates. Dysregulation of lysosomal lipid processing, defective export of lipid catabolites, and lysosomal membrane permeabilization underly diseases ranging from neurodegeneration to metabolic syndromes and lysosomal storage disorders. Mammalian cells are equipped with sophisticated homeostatic control mechanisms that protect the lysosomal limiting membrane from excessive damage, prevent the spillage of luminal hydrolases into the cytoplasm, and preserve the lysosomal membrane composition in the face of constant fusion with heterotypic organelles such as endosomes and autophagosomes. In this review we discuss the molecular mechanisms that govern lysosomal lipid homeostasis and, thereby, lysosome function in health and disease.
    Keywords:  contact sites; lipids; lysosomes; membrane homeostasis; phosphoinositides; signalling
    DOI:  https://doi.org/10.1016/j.chembiol.2025.02.003
  19. Trends Cell Biol. 2025 Mar 07. pii: S0962-8924(25)00039-X. [Epub ahead of print]
    Quality control of mitochondrial nucleoids.
    Hao Liu, Haixia Zhuang, Du Feng.
      Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.
    Keywords:  mitochondria; mitophagy; mtDNA; nucleoid-phagy; nucleoids
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.005
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