bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2026–08–02
ten papers selected by
Irene Sambri, TIGEM
  1. Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
  2. Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
  3. TFEB at the Crossroads: From Cellular Mechanism to Precision Care.
  4. Cardioprotective properties of empagliflozin and other SGLT2 inhibitors.
  5. mTOR signaling in cholangiocarcinoma: mechanistic insights and therapeutic opportunities.
  6. Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
  7. Endothelial-to-Mesenchymal Transition in Chronic Kidney Disease: Mechanisms and Therapeutic Targets.
  8. Proteomic Analysis of Hippo Pathway Protein-Protein Interactions.
  9. Epigenetic regulation of kidney development.
  10. Single-cell spatial mapping of human kidney development implicates the microenvironment in guiding cell fate decisions.
  1. Int J Mol Sci. 2026 Jul 19. pii: 6418. [Epub ahead of print]27(14):
    Autophagy-Lysosomal Dysfunction as a Converging Mechanism of Cardiomyopathy in Lysosomal Storage Disorders: From Pathobiology to Targeted Therapy.
    Chung-Lin Lee, Chih-Kuang Chuang, Ya-Hui Chang, Huei-Ching Chiu, Yuan-Rong Tu, Yun-Ting Lo, Jun-Yi Wu, Hsiang-Yu Lin, Shuan-Pei Lin.
      Cardiac disease is a leading cause of morbidity and early death across several lysosomal storage disorders (LSDs); however, the cardiomyopathies of Fabry, Pompe, and Danon disease are still largely treated as separate, substrate-specific disorders. We argue that they are better understood as variations on a single theme: the breakdown of the autophagy-lysosome system within cardiomyocytes. In the healthy heart, this system clears damaged proteins and organelles and is regulated by mTORC1 and the master regulator TFEB. Once lysosomal degradation or autophagosome-lysosome fusion fails, undegraded substrates and defective mitochondria accumulate, driving hypertrophy, interstitial fibrosis, and conduction disease. Danon disease, resulting from the loss of LAMP2, is the clearest example of a primary defect in autophagic flux, whereas the glycogen storage of Pompe disease and the globotriaosylceramide accumulation of Fabry disease impair flux through different upstream mechanisms that converge on the same downstream injury. The same framework extends to other storage disorders with cardiac involvement, such as mucopolysaccharidosis (MPS). We trace this shared pathobiology from molecule to bedside, examine biomarkers that reflect lysosomal and autophagic dysfunction rather than storage alone, and re-examine treatment in that light: why enzyme replacement therapy corrects substrate accumulation but leaves much of the autophagic and mitochondrial damage unresolved, and why gene therapy-particularly AAV9-LAMP2B for Danon disease-together with autophagy- and TFEB-directed strategies may help close that gap. Viewing these disorders through a single mechanistic lens reshapes how we monitor them and where future therapies should be directed.
    Keywords:  Danon disease; TFEB; autophagy–lysosomal dysfunction; cardiomyopathy; gene therapy; lysosomal storage disorders; mucopolysaccharidosis
    DOI:  https://doi.org/10.3390/ijms27146418
  2. Sci Adv. 2026 Jul 31. 12(31): eaef0140
    Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
    Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.
      Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.
    DOI:  https://doi.org/10.1126/sciadv.aef0140
  3. Circ Res. 2026 Jul 31. 139(4): e329311
    TFEB at the Crossroads: From Cellular Mechanism to Precision Care.
    Ivor J Benjamin, Jacek Zielonka.
      
    Keywords:  Editorials; heart failure; lysosomes; mitochondria; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329311
  4. Nat Rev Cardiol. 2026 Jul 27.
    Cardioprotective properties of empagliflozin and other SGLT2 inhibitors.
    Thomas A Zelniker, Eugene Braunwald.
      Since the publication of the landmark EMPA-REG OUTCOME trial, sodium-glucose cotransporter 2 (SGLT2) inhibitors have redefined the therapeutic landscape of cardiovascular-kidney-metabolic disease. Initially developed as glucose-lowering drugs, empagliflozin and subsequent SGLT2 inhibitors have demonstrated robust benefits in reducing hospitalization for heart failure, slowing the progression of chronic kidney disease and lowering cardiovascular mortality across diverse populations. Although the precise mechanisms underlying these effects are not completely understood, the cardioprotective effects of empagliflozin seem to be mediated by an interconnected network of pleiotropic mechanisms. Empagliflozin modulates haemodynamics, restores endothelial and vascular function, improves mitochondrial bioenergetics through increased mitochondrial activity and substrate flexibility, and attenuates maladaptive cardiac remodelling. In this Review, we synthesize the current mechanistic understanding of SGLT2 inhibitors and highlight key directions for the future of cardiovascular-kidney-metabolic disease management. The next decade of research on SGLT2 inhibitors will be shaped by efforts to close evidence gaps, including in kidney failure and cardio-oncology, as well as the integration of SGLT2 inhibitors with other guideline-directed therapies, optimization of therapeutic sequencing and broad implementation in clinical care.
    DOI:  https://doi.org/10.1038/s41569-026-01325-4
  5. Front Pharmacol. 2026 ;17 1882709
    mTOR signaling in cholangiocarcinoma: mechanistic insights and therapeutic opportunities.
    Zhenxuan Chen, Tao Peng.
      Cholangiocarcinoma (CCA) is a clinically and molecularly heterogeneous malignancy originating from the biliary epithelium. It represents the second most common primary liver cancer after hepatocellular carcinoma (HCC). Despite advances in understanding CCA pathobiology and improving diagnostic modalities, its global incidence and mortality continue to rise. Most patients are diagnosed at advanced stages, which are characterized by frequent recurrence, metastasis, and therapeutic resistance, leading to poor clinical outcomes. The mammalian target of rapamycin (mTOR) signaling pathway is a central regulator of cell growth, metabolic reprogramming, survival, and autophagy; its dysregulation significantly contributes to CCA initiation and progression. However, the precise roles of mTOR signaling across different CCA subtypes remain incompletely understood, and conflicting evidence exists regarding its context-dependent functions in tumor progression and therapeutic response. This review provides a comprehensive overview of recent advances in mTOR research in CCA, focusing on its involvement in metabolic reprogramming, malignant phenotypes, autophagy, apoptosis, and treatment resistance. Furthermore, current limitations and knowledge gaps in targeting mTOR signaling are discussed, alongside emerging therapeutic strategies, such as mTOR inhibitors, combination approaches, and natural small-molecule modulators. Finally, future research directions and the potential of mTOR-centered interventions to improve clinical outcomes in CCA are highlighted.
    Keywords:  autophagy; cholangiocarcinoma; mTOR signaling pathway; metabolic reprogramming; targeted therapy; therapeutic resistance
    DOI:  https://doi.org/10.3389/fphar.2026.1882709
  6. Science. 2026 Jul 30. 393(6810): eady0832
    Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
    Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.
      Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    DOI:  https://doi.org/10.1126/science.ady0832
  7. Kidney Blood Press Res. 2026 Jul 28. 1
    Endothelial-to-Mesenchymal Transition in Chronic Kidney Disease: Mechanisms and Therapeutic Targets.
    Abdul H Khan, Pratheesh D Mankuzhy, Linto Thomas, Adebowale Adebiyi.
      Renal fibrosis is the final common pathological outcome of chronic kidney disease (CKD) and a major driver of progression to end-stage kidney disease. Endothelial-to-mesenchymal transition (EndMT) is a phenotypic process in which endothelial cells lose their endothelial identity and acquire mesenchymal or myofibroblast-like characteristics, contributing to extracellular matrix accumulation, capillary rarefaction, microvascular dysfunction, and fibrotic remodeling. Transforming growth factor-β (TGF-β) is a central inducer of EndMT through both canonical Smad-dependent and non-canonical Smad-independent signaling pathways. Other pathways, including Wnt/β-catenin, Notch, Hedgehog, inflammatory cytokine signaling, autophagy dysregulation, oxidative stress, and metabolic reprogramming, further modulate EndMT in the diseased kidney. Despite growing evidence implicating EndMT in renal fibrosis, the quantitative contribution of EndMT to human CKD progression and the most effective therapeutic strategies to target this process remain incompletely defined. This review summarizes the cellular and molecular mechanisms of EndMT relevant to CKD, highlights key regulatory pathways and pathway crosstalk, and discusses emerging pharmacological approaches to limit EndMT, preserve microvascular integrity, and attenuate renal fibrogenesis.
    DOI:  https://doi.org/10.1159/kbr/adjag001
  8. Cold Spring Harb Perspect Biol. 2026 Jul 29. pii: a041906. [Epub ahead of print]
    Proteomic Analysis of Hippo Pathway Protein-Protein Interactions.
    Jeongmin An, Wenqi Wang.
      The Hippo pathway is a conserved signaling cascade that regulates development, regeneration, tissue homeostasis, and organ size through a network of protein-protein interactions (PPIs). Since its discovery in Drosophila, PPI studies have significantly contributed to defining its core kinase cascade and transcriptional machinery. Over the past two decades, advances in mass spectrometry (MS)-based proteomics have transformed Hippo pathway research from targeted assays to unbiased interactome mapping, largely expanding its regulatory and functional landscapes. In this work, we introduce MS-based biochemical approaches commonly used for analyzing PPIs, summarize historical and methodological progress in characterizing Hippo-related PPIs, highlight applications of the Hippo interactome for signaling and disease studies, and discuss future directions for improving Hippo interactome-based biological discoveries and therapeutic development. Collectively, these advances establish the Hippo pathway as a valuable model for demonstrating how MS-driven interactome analysis accelerates biological research.
    DOI:  https://doi.org/10.1101/cshperspect.a041906
  9. Nat Rev Nephrol. 2026 Jul 28.
    Epigenetic regulation of kidney development.
    Samir S El-Dahr, Jordan Kreidberg.
      The methylation or demethylation of genomic DNA at specific locations and the diverse array of post-translational modifications of histones associated with genomic DNA are collectively known as epigenetic modifications, so-called because they affect chromatin structure but do not affect the actual DNA sequence of the genome. Nevertheless, post-translational modifications of histones, including methylation, acetylation, phosphorylation and ubiquitination, as well as the methylation and subsequent de-methylation of genomic DNA, can profoundly affect gene expression. Nowhere has the study of epigenetically regulated gene expression had such impact as on our understanding of organism development. In the developing kidney, epigenetic-based regulation affects the cell fate decisions of stem-like nephron progenitor cells (NPCs). Changes in chromatin accessibility at the loci of genes associated with NPC self-renewal and nephron differentiation - in part driven by transcription factors known to regulate kidney development - affect the differentiation of NPCs into precursors of the nephron such as the pretubular aggregate and renal vesicle, and the subsequent differentiation of various segments of the mature nephron. Epigenetic mechanisms also contribute to the process of NPC ageing and the cessation of nephrogenesis, with consequences for nephron endowment and kidney function.
    DOI:  https://doi.org/10.1038/s41581-026-01105-w
  10. Nat Genet. 2026 Jul 30.
    Single-cell spatial mapping of human kidney development implicates the microenvironment in guiding cell fate decisions.
    Jonathan Levinsohn, Samuel Grindel, Bernhard Dumoulin, Amin Abedini, Carolina Conte, Aria Zheyuan Huang, Rena Levin-Klein, Boaz Weisz, Grace Rabinowitz, Andi M Bergeson, Eunji Ha, Konstantin A Klötzer, Nancy Zhang, Paul Titchenell, Mingyao Li, Joo-Seop Park, Juan Pablo Arroyo, Laura S Finn, Kotaro Sasaki, Pazit Beckerman, Oren Pleniceanu, Paola Romagnani, Alex J Hughes, Katalin Susztak.
      Evolution has used cell-cell communication as a strategy to coordinate organ development, enabling the reproducible generation of intricate structures. Classically, these interactions have been studied one at a time in model organisms, limiting our understanding of how cellular interplay coordinates human development. We investigated human kidney development using single-cell RNA sequencing and spatial transcriptomics, analyzing over 700,000 cells. By mapping gene expression and differentiation trajectories in space, we define the spatial organization of kidney development. Our analysis revealed unrecognized plasticity, showing that cell fate established during early patterning can be later revised. This plasticity provides a potential mechanism for how cell fate is robustly established in complex patterned tissues. Additionally, through a genome-wide, spatially aware cell-cell interaction analysis, we link localized ligand signals to cell fate decisions. We also define biologically meaningful cellular neighborhoods based on aggregated extracellular cues, providing a blueprint to understand the coordination of human development at scale.
    DOI:  https://doi.org/10.1038/s41588-026-02665-0
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒07 at 9:20.