bims-raghud 2025-05-11 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–05–11
twelve papers selected by
Irene Sambri, TIGEM

Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model.
Lymphatic endothelial mTORC1 instructs metabolic and developmental signaling during lymphangiogenesis.
mTORC1 cooperates with tRNA wobble modification to sustain the protein synthesis machinery.
mTOR inhibitors in targeting autophagy and autophagy-associated signaling for cancer cell death and therapy.
Clinically Sporadic Folliculin-mutated Renal Epithelial Neoplasms Represent a Mixture of True Somatic Folliculin-mutated and Occult Birt-Hogg-Dubé Syndrome-associated Cases: Morphologic and Molecular Overlap With TSC/MTOR-mutated Eosinophilic Renal Neoplasms and MiT Family Translocation Renal Cell Carcinoma.
Endothelial cell metabolism in cardiovascular physiology and disease.
The role of mitochondrial mRNA translation in cellular communication.
TFE3/TFEB Altered Renal Cell Carcinomas in End-Stage Renal Disease Setting: A Single Institution Clinicopathological Study of 4 Cases.
Key Mechanisms in Lysosome Stability, Degradation and Repair.
Exosomes, autophagy, and cancer: A complex triad.
Activation of lysosomal iron triggers ferroptosis in cancer.
Podocytes in health and glomerular disease.

Sci Adv. 2025 May 09. 11(19): eadr5703

Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model.

Abhilash P Appu, Maria B Bagh, Nisha Plavelil, Avisek Mondal, Tamal Sadhukhan, Satya P Singh, Neil J Perkins, Aiyi Liu, Anil B Mukherjee.

Neurodegeneration is a devastating manifestation in most lysosomal storage disorders (LSDs). Loss-of-function mutations in CLN1, encoding palmitoyl-protein thioesterase-1 (PPT1), cause CLN1 disease, a devastating neurodegenerative LSD that has no curative treatment. Numerous proteins in the brain require dynamic S-palmitoylation (palmitoylation-depalmitoylation) for trafficking to their destination. Although PPT1 depalmitoylates S-palmitoylated proteins and its deficiency causes CLN1 disease, the underlying pathogenic mechanism has remained elusive. We report that Niemann-Pick C1 (NPC1), a polytopic membrane protein mediating lysosomal cholesterol egress, requires dynamic S-palmitoylation for trafficking to the lysosome. In Cln1-/- mice, Ppt1 deficiency misroutes NPC1-dysregulating lysosomal cholesterol homeostasis. Along with this defect, increased oxysterol-binding protein (OSBP) promotes cholesterol-mediated activation of mechanistic target of rapamycin C1 (mTORC1), which inhibits autophagy contributing to neurodegeneration. Pharmacological inhibition of OSBP suppresses mTORC1 activation, rescues autophagy, and ameliorates neuropathology in Cln1-/- mice. Our findings reveal a previously unrecognized role of CLN1/PPT1 in lysosomal cholesterol homeostasis and suggest that suppression of mTORC1 activation may be beneficial for CLN1 disease.

DOI: https://doi.org/10.1126/sciadv.adr5703
Dev Cell. 2025 May 02. pii: S1534-5807(25)00250-3. [Epub ahead of print]

Lymphatic endothelial mTORC1 instructs metabolic and developmental signaling during lymphangiogenesis.

Fei Han, Summer Simeroth, Jie Zhu, Irma Gryniuk, Atul Pranay, Weiqing Chen, Yuan Wang, Yuanyuan Cai, Zhiyuan Shen, Guangyu Wang, Courtney T Griffin, Lijun Xia, Pengchun Yu.

  The lymphatic vasculature comprises lymphatic capillaries and collecting vessels. To support lymphatic development, lymphatic endothelial cells (LECs) utilize nutrients to fuel lymphangiogenic processes. Meanwhile, LECs maintain constant prospero homeobox 1 (PROX1) expression critical for lymphatic specification. However, molecular mechanisms orchestrating nutrient metabolism while sustaining PROX1 levels in LECs remain unclear. Here, we show that loss of RAPTOR, an indispensable mechanistic target of rapamycin complex 1 (mTORC1) component, downregulates PROX1 and impairs lymphatic capillary growth and differentiation of collecting lymphatics in mice. Mechanistically, mTORC1 inhibition in mouse and human LECs causes Myc reduction, which decreases hexokinase 2 (HK2) and glutaminase (GLS), inhibiting glycolysis and glutaminolysis. Myc or HK2/GLS ablation impedes lymphatic capillary and collecting vessel formation. Interestingly, mTORC1 regulation of PROX1 is independent of Myc-HK2/GLS signaling. Moreover, genetic interaction analysis indicates that Myc and PROX1 play crucial roles in mTORC1-regulated lymphatic development. Collectively, our findings identify mTORC1 as a key regulator of metabolic programs and PROX1 expression during lymphangiogenesis.

Keywords:  Myc; PROX1; glutaminase; glutaminolysis; glycolysis; hexokinase 2; lymphangiogenesis; lymphatic endothelial cell; lymphatic vessel; mTORC1

DOI:  https://doi.org/10.1016/j.devcel.2025.04.012
Nat Commun. 2025 May 06. 16(1): 4201

mTORC1 cooperates with tRNA wobble modification to sustain the protein synthesis machinery.

Julia Hermann, Toman Borteçen, Robert Kalis, Alexander Kowar, Catarina Pechincha, Vivien Vogt, Martin Schneider, Dominic Helm, Jeroen Krijgsveld, Fabricio Loayza-Puch, Johannes Zuber, Wilhelm Palm.

Synthesizing the cellular proteome is a demanding process that is regulated by numerous signaling pathways and RNA modifications. How precisely these mechanisms control the protein synthesis machinery to generate specific proteome subsets remains unclear. Here, through genome-wide CRISPR screens we identify genes that enable mammalian cells to adapt to inactivation of the kinase mechanistic target of rapamycin complex 1 (mTORC1), the central driver of protein synthesis. When mTORC1 is inactive, enzymes that modify tRNAs at wobble uridines (U34-enzymes), Elongator and Ctu1/2, become critically essential for cell growth in vitro and in tumors. By integrating quantitative nascent proteomics, steady-state proteomics and ribosome profiling, we demonstrate that the loss of U34-enzymes particularly impairs the synthesis of ribosomal proteins. However, when mTORC1 is active, this biosynthetic defect only mildly affects steady-state protein abundance. By contrast, simultaneous suppression of mTORC1 and U34-enzymes depletes cells of ribosomal proteins, globally inhibiting translation. Thus, mTORC1 cooperates with tRNA U34-enzymes to sustain the protein synthesis machinery and support the high translational requirements of cell growth.

DOI: https://doi.org/10.1038/s41467-025-59185-4
Biochim Biophys Acta Rev Cancer. 2025 May 06. pii: S0304-419X(25)00084-8. [Epub ahead of print] 189342

mTOR inhibitors in targeting autophagy and autophagy-associated signaling for cancer cell death and therapy.

Prakash Kumar Senapati, Kewal Kumar Mahapatra, Amruta Singh, Sujit Kumar Bhutia.

  The mechanistic target of rapamycin (mTOR) is a protein kinase that plays a central regulatory switch to control multifaceted cellular processes, including autophagy. As a nutrient sensor, mTOR inhibits autophagy by phosphorylating and inactivating key regulators, including ULK1, Beclin-1, UVRAG, and TFEB, preventing autophagy initiation and lysosomal biogenesis. It also suppresses autophagy-related protein expression, prioritizing growth over cellular recycling. Under nutrient deprivation, mTORC1 activity decreases, allowing autophagy to restore cellular homeostasis. Hyperautophagic activities lead to autophagic cell death; sometime after the point of no return, the cell goes for non-apoptotic, non-necrotic cell death i.e., Autosis. In cancer, the crosstalk between autophagy and mTOR is context-dependent, driving either cell survival or autophagy-dependent cell death. Using mTOR inhibitors, autophagic cell death can be induced to regulate cell growth, and proliferation is a potential therapeutic option for cancer treatment. mTOR inhibitors are broadly categorized into two types, i.e., natural and synthetic mTOR inhibitors. Although several studies in preclinical and clinical trials of various synthetic mTOR inhibitors are now in focus for cancer therapies, limited work has been done to explore autophagic cell death-inducing mTOR inhibitors. In addition, many natural mTOR inhibitors display better efficacy over synthetic mTOR inhibitors due to their lower toxicity, biocompatibility, and potential to overcome drug resistance, highlighting the current status of mTOR inhibitors in inducing autophagic cell death for cancer treatment.

Keywords:  Autophagic cell death; Autophagy; Cancer therapy; mTOR inhibitors; mTOR signaling

DOI:  https://doi.org/10.1016/j.bbcan.2025.189342
Am J Surg Pathol. 2025 May 05.

Clinically Sporadic Folliculin-mutated Renal Epithelial Neoplasms Represent a Mixture of True Somatic Folliculin-mutated and Occult Birt-Hogg-Dubé Syndrome-associated Cases: Morphologic and Molecular Overlap With TSC/MTOR-mutated Eosinophilic Renal Neoplasms and MiT Family Translocation Renal Cell Carcinoma.

Pedram Argani, Ezra Baraban, Oksana Yaskiv, Huili Li, Swati Bhardwaj, Katya Dombrowski, Tamara L Lotan, Ying S Zou, Sunil H Patel, Betina Katz, Qi Cai, Rohit Mehra, Norman Barker, Jonathan Dudley, Doreen N Palsgrove.

  Germline mutations in the folliculin (FLCN) gene define Birt-Hogg-Dubé syndrome, which is associated with a variety of renal neoplasms; however, the role of FLCN mutations in sporadic renal neoplasms has not been well-defined. We identified 8 oncocytic/cystic renal neoplasms that presented as sporadic tumors and harbored FLCN mutations and no other genetic alterations characteristic of another established subtype. On further workup, 5 seem to harbor true somatic FLCN mutations, whereas the other 3 represent neoplasms associated with occult Birt-Hogg-Dubé syndrome. Patients were all females ranging in age from 25 to 77 years, and all neoplasms were confined to the kidney. The neoplasms overlapped morphologically with TSC/MTOR-mutated eosinophilic renal neoplasms and TFE3/TFEB-rearranged renal cell carcinoma. All neoplasms extensively expressed GPNMB, a downstream marker of TFE3/TFEB pathway activation, which is logical given the known molecular interplay of folliculin with TSC/MTOR/TFE3/TFEB. All 3 occult syndromic cases demonstrated multiple chromosome losses and gains not seen in the 5 sporadic neoplasms. In conclusion, diffuse GPNMB expression in the absence of TSC/MTOR/TFE3/TFEB alterations, particularly when the morphology suggests the presence of the latter, is a clue to FLCN-mutated renal epithelial neoplasms, which in a subset of cases may be a clue to occult Birt-Hogg-Dubé syndrome.

Keywords:  Birt-Hogg-Dube; Folliculin; mutation; renal cell carcinoma

DOI:  https://doi.org/10.1097/PAS.0000000000002413
Nat Rev Cardiol. 2025 May 09.

Endothelial cell metabolism in cardiovascular physiology and disease.

Alessandra Pasut, Eleonora Lama, Amaryllis H Van Craenenbroeck, Jeffrey Kroon, Peter Carmeliet.

Endothelial cells are multifunctional cells that form the inner layer of blood vessels and have a crucial role in vasoreactivity, angiogenesis, immunomodulation, nutrient uptake and coagulation. Endothelial cells have unique metabolism and are metabolically heterogeneous. The microenvironment and metabolism of endothelial cells contribute to endothelial cell heterogeneity and metabolic specialization. Endothelial cell dysfunction is an early event in the development of several cardiovascular diseases and has been shown, at least to some extent, to be driven by metabolic changes preceding the manifestation of clinical symptoms. Diabetes mellitus, hypertension, obesity and chronic kidney disease are all risk factors for cardiovascular disease. Changes in endothelial cell metabolism induced by these cardiometabolic stressors accelerate the accumulation of dysfunctional endothelial cells in tissues and the development of cardiovascular disease. In this Review, we discuss the diversity of metabolic programmes that control endothelial cell function in the cardiovascular system and how these metabolic programmes are perturbed in different cardiovascular diseases in a disease-specific manner. Finally, we discuss the potential and challenges of targeting endothelial cell metabolism for the treatment of cardiovascular diseases.

DOI: https://doi.org/10.1038/s41569-025-01162-x
J Cell Sci. 2025 May 01. pii: jcs263753. [Epub ahead of print]138(9):

The role of mitochondrial mRNA translation in cellular communication.

Eleonora Zilio, Tim Schlegel, Marta Zaninello, Elena I Rugarli.

  Mitochondria are dynamic and heterogeneous organelles that rewire their network and metabolic functions in response to changing cellular needs. To this end, mitochondria integrate a plethora of incoming signals to influence cell fate and survival. A crucial and highly regulated node of cell-mitochondria communication is the translation of nuclear-encoded mitochondrial mRNAs. By controlling and monitoring the spatio-temporal translation of these mRNAs, cells can rapidly adjust mitochondrial function to meet metabolic demands, optimise ATP production and regulate organelle biogenesis and turnover. In this Review, we focus on how RNA-binding proteins that recognise nuclear-encoded mitochondrial mRNAs acutely modulate the rate of translation in response to nutrient availability. We further discuss the relevance of localised translation of these mRNAs for subsets of mitochondria in polarised cells. Finally, we highlight quality control mechanisms that monitor the translation process at the mitochondrial surface and their connections to mitophagy and stress responses. We propose that these processes collectively contribute to mitochondrial specialisation and signalling function.

Keywords:  Cell signalling; Mitochondria; RNA-binding proteins; Ribosome quality control; Translation; mRNA

DOI:  https://doi.org/10.1242/jcs.263753
Hum Pathol. 2025 May 06. pii: S0046-8177(25)00070-X. [Epub ahead of print] 105783

TFE3/TFEB Altered Renal Cell Carcinomas in End-Stage Renal Disease Setting: A Single Institution Clinicopathological Study of 4 Cases.

Andrea Mladenovic, Lara R Harik, Kristin K Deeb, Elizabeth M Genega, Faisal Saeed, Jatin S Gandhi.

   INTRODUCTION: Translocation renal cell carcinoma (tRCC) are morphologically distinct tumors having an underlying disease defining molecular alterations (commonly TFE3/TFEB gene alterations). Their occurrence in the setting of end stage renal disease (ESRD) has been rarely reported. This study was undertaken to assess the occurrence of TFE3/TFEB altered RCCs in ESRD setting at our institution.
DESIGN: By retrospective review, we searched our pathology database for tRCC in ESRD setting over a 14-year period. We analyzed and documented the clinical, histopathological, immunohistochemical, and molecular findings in these tumors.
RESULTS: Out of 223 patients of ESRD associated with RCCs, we found 4 cases of molecularly confirmed TFE3/TFEB-altered RCCs. Three of four patients were on pharmacologic immunosuppression (2 for underlying SLE and 1 for prior liver transplant). The ages ranged from 36 to 74 years (median 48 years) with an equal sex ratio. Tumors were solitary and ranged in size from 1.3 to 4.7 cm (median 2 cm). All four cases were confined to the kidney (pT1) and did not exhibit any necrosis, small vessel invasion, or sarcomatoid/rhabdoid features. The tumors exhibited characteristic morphology (solid, nested and papillary architectures with clear and eosinophilic cytoplasm in TFE3-rearranged RCCs, and biphasic morphology with basement membrane-like material in TFEB-altered RCCs). On immunohistochemistry, tumors consistently expressed cathepsin-K (3/3) & Melan-A (3/3). On molecular studies one case was confirmed via FISH study (TFEB gene rearrangement) and three cases were confirmed via RNA fusionplex (PRCC::TFE3, MED15::TFE3 and MALAT1::TFEB fusion transcripts). The median follow-up was 13 months (range 10 to 95 months), none of the 4 patients had any local or metastatic recurrences. One patient died of other comorbidities. Background kidney in all 4 patients exhibited variable features of ESRD.
CONCLUSION: TFE3/TFEB-altered RCCs are rarely encountered in ESRD. Morphological and immunohistochemical findings of tRCC in ESRD replicate those found in sporadic settings. To the best of our knowledge, our study is the first to identify TFEB-rearranged RCCs in an ESRD setting.

Keywords:  ESRD; SLE; TFE3; TFEB; Translocation RCC; immunosuppression

DOI:  https://doi.org/10.1016/j.humpath.2025.105783
Mol Cell Biol. 2025 May 09. 1-13

Key Mechanisms in Lysosome Stability, Degradation and Repair.

Rui Zhang, Marc A Vooijs, Tom Gh Keulers.

  Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.

Keywords:  ESCRT; Lysosome stabilization; ROS; lipid peroxidation; lysophagy; lysosomal membrane permeabilization

DOI:  https://doi.org/10.1080/10985549.2025.2494762
Int J Cancer. 2025 May 02.

Exosomes, autophagy, and cancer: A complex triad.

María Guerra-Andrés, Álvaro F Fernández, Tania Fontanil.

  Cancer remains one of the leading causes of death worldwide. Despite remarkable progress in prevention, diagnosis, and therapy, the incidence of certain types of cancer persists, urging the identification of clinically relevant biomarkers and the development of novel therapeutic strategies to improve clinical outcomes and overcome treatment resistance. Exosomes, small extracellular vesicles released by diverse types of cells, have attracted interest in biomedical research due to their potential as carriers for different treatments. Moreover, exosomes play a pivotal role in intercellular communication, modulating various cellular processes. One of those is autophagy, a pro-survival pathway that is essential for human cells. Even though autophagy is traditionally described as a catabolic route, its machinery is intricately involved in various cellular responses, including vesicle formation and secretion. In this regard, the link between autophagy and exosomes is complex, bidirectional, and highly dependent on the cellular context. Interestingly, both processes have been extensively implicated in cancer pathogenesis, highlighting their potential as therapeutic targets. This review updates our understanding of how exosomes can participate in cancer development and progression, with a specific focus on their influence on tumor growth, angiogenesis, and metastasis. Additionally, the interplay between these extracellular vesicles and autophagy is minutely reviewed and discussed, as we hypothesize that this crosstalk may hold valuable clues for biomarker discovery and the development of novel therapeutic strategies.

Keywords:  angiogenesis; autophagy; cancer; exosomes; metastasis; tumor

DOI:  https://doi.org/10.1002/ijc.35388
Nature. 2025 May 07.

Activation of lysosomal iron triggers ferroptosis in cancer.

Tatiana Cañeque, Leeroy Baron, Sebastian Müller, Alanis Carmona, Ludovic Colombeau, Antoine Versini, Stéphanie Solier, Christine Gaillet, Fabien Sindikubwabo, Julio L Sampaio, Marie Sabatier, Eikan Mishima, Armel Picard-Bernes, Laurène Syx, Nicolas Servant, Bérangère Lombard, Damarys Loew, Jiashuo Zheng, Bettina Proneth, Leishemba K Thoidingjam, Laurence Grimaud, Cameron S Fraser, Krystina J Szylo, Emma Der Kazarian, Caroline Bonnet, Emmanuelle Charafe-Jauffret, Christophe Ginestier, Patricia Santofimia-Castaño, Matias Estaras, Nelson Dusetti, Juan Lucio Iovanna, Antonio Sa Cunha, Gabriella Pittau, Pascal Hammel, Dimitri Tzanis, Sylvie Bonvalot, Sarah Watson, Vincent Gandon, Aditya Upadhyay, Derek A Pratt, Florêncio Porto Freitas, José Pedro Friedmann Angeli, Brent R Stockwell, Marcus Conrad, Jessalyn M Ubellacker, Raphaël Rodriguez.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death called ferroptosis1. Defining where this chemistry occurs in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Genetic approaches have revealed suppressors of ferroptosis2-4; by contrast, small molecules can provide spatiotemporal control of the chemistry at work5. Here we show that the ferroptosis inhibitor liproxstatin-1 exerts cytoprotective effects by inactivating iron in lysosomes. We also show that the ferroptosis inducer RSL3 initiates membrane lipid oxidation in lysosomes. We designed a small-molecule activator of lysosomal iron-fentomycin-1-to induce the oxidative degradation of phospholipids and ultimately ferroptosis. Fentomycin-1 is able to kill iron-rich CD44high primary sarcoma and pancreatic ductal adenocarcinoma cells, which can promote metastasis and fuel drug tolerance. In such cells, iron regulates cell adaptation6,7 while conferring vulnerability to ferroptosis8,9. Sarcoma cells exposed to sublethal doses of fentomycin-1 acquire a ferroptosis-resistant cell state characterized by the downregulation of mesenchymal markers and the activation of a membrane-damage response. This phospholipid degrader can eradicate drug-tolerant persister cancer cells in vitro and reduces intranodal tumour growth in a mouse model of breast cancer metastasis. Together, these results show that control of iron reactivity confers therapeutic benefits, establish lysosomal iron as a druggable target and highlight the value of targeting cell states10.

DOI: https://doi.org/10.1038/s41586-025-08974-4
Front Cell Dev Biol. 2025 ;13 1564847

Podocytes in health and glomerular disease.

Joanna Cunanan, Daniel Zhang, Anna Julie Peired, Moumita Barua.

  Podocytes are highly specialized, terminally differentiated cells in the glomerulus of the kidney and these cells play a central role in blood filtration. In this review, we comprehensively describe the cell biology of podocytes under healthy conditions and in glomerular disorders wherein podocyte injury is a major pathological mechanism. First, the molecular mechanisms that maintain podocyte actin cytoskeleton structure, permanent cell cycle exit, and metabolism under healthy conditions are described. Secondly, the mechanisms of podocyte injury, including genetic alterations and external insults that ultimately disrupt podocyte actin cytoskeleton dynamics or interrupt podocyte quiescence and mitochondrial metabolism are discussed. This understanding forms the basis of described potential therapeutic agents that act by modulating dysregulated podocyte cytoskeleton organization, prevent or reverse cell cycle re-entry, and re-establish normal mitochondrial energy production. Lastly, the application of modern techniques such as single cell RNA sequencing, super resolution microscopy, atomic force microscopy, and glomerular organoids is improving the resolution of mechanistic podocytopathy knowledge. Taken together, our review provides critical insights into the cellular and molecular mechanisms leading to podocyte loss, necessary for the advancement of therapeutic development in glomerular diseases.

Keywords:  actin cytoskeleton; differentiated; glomerular disease; metabolism; podocytes; slit diaphragm; therapeutic targets

DOI:  https://doi.org/10.3389/fcell.2025.1564847