bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–11–02
ten papers selected by
Irene Sambri, TIGEM
  1. Impairment of lysosomal quality control in Huntington disease.
  2. Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives.
  3. Recent progress regarding the role of autophagy in cardiac disease.
  4. TFE3 fusion proteins promoted the progression of Xp11.2 translocation renal cell carcinoma through post-translational modification of PDL1 by upregulating CCND1/Cyclin D1.
  5. Lysosome heterogeneity and diversity mapped through its distinct cellular functions.
  6. Renoprotective effects of SGLT2 inhibitors in patients with Fabry disease.
  7. Autophagy-senescence interplay in kidney disease: mechanistic insights and therapeutic potential.
  8. Advances in Mitochondrial Dysfunction and Its Role in Cardiovascular Diseases.
  9. Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
  10. FLCN-mutated eosinophilic renal tumors: clinicopathologic and molecular analysis of five cases highlighting morphologic heterogeneity.
  1. Cell Death Dis. 2025 Oct 27. 16(1): 762
    Impairment of lysosomal quality control in Huntington disease.
    Paola Rusmini, Francesco Mina, Marta Valenza, Martina Vitali, Veronica Ferrari, Barbara Tedesco, Elena Casarotto, Marta Cozzi, Marta Chierichetti, Ali Mohamed, Paola Pramaggiore, Laura Cornaggia, Carmelo Milioto, Maria Brodnanova, Rocio Magdalena, Prashant Koshal, Margherita Piccolella, Riccardo Cristofani, Mariarita Galbiati, Valeria Crippa, Angelo Poletti.
      Huntington disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion (polyQ) in the Huntingtin protein (muHTT), which makes it prone to misfolding and aggregation. muHTT aggregates sequester a wide variety of proteins essential for cell homeostasis, including chaperones and transcription factors, and their depletion may contribute to HD pathogenesis. Lysosomes are the main hubs for degradative and signaling activities in cells, and their functionality is crucial for cell homeostasis, especially for neurons. Different forms of cellular stresses, including proteotoxic stresses, can alter lysosome integrity and induce lysosomal membrane permeabilization (LMP). Damaged lysosomes are recognized by galectins, in particular galectin-3 (LGALS3) with activation of the lysosome quality control (LQC) system responsible for repairing, degrading, or replacing leaky lysosomes. The system is transcriptionally regulated by the transcription factors EB and E3 (TFEB and TFE3, respectively). Using HD mouse and cell models, we demonstrated that TFEB and TFE3 are sequestered in muHTT aggregates, and muHTT proteins associates with LMP triggering the translocation of LGALS3 to the lumen of lysosomes, with a close relation between polyQ size and severity of these events. Moreover, we demonstrated that TFEB and TFE3 silencing or overexpression modulate muHTT aggregation. TFEB and TFE3 knockdown worsens muHTT aggregation, while their overexpression reduces muHTT inclusions and concurrently reduces LGALS3 accumulation via lysophagy and lysosome replacement. Our findings suggest that both TFEB and TFE3 are implicated in HD, and their sequestration in muHTT inclusions increase the vulnerability of neurons to lysosome injury, altering LQC and contributing to disease pathogenesis. In physiologial conditions, lysosome membrane permeabilization occurs and activates TFEB and TFE3 triggering a response to induce lysophagy and lysosome biogenesis. In HD, muHTT sequesters TFEB and TFE3 into inclusions and the reduced TFEB/TFE3 bioavailability prevents the activation of lysophagy and leading to the accumulation of damaged lysosomes. Created in BioRender.
    DOI:  https://doi.org/10.1038/s41419-025-08103-z
  2. Kidney Int Rep. 2025 Oct;10(10): 3640-3655
    Novel RRAGD Variants in Autosomal Dominant Kidney Hypomagnesemia and Therapeutic Perspectives.
    Anastasia Adella, François Jouret, Leire Madariaga, Pieter A Leermakers, Pedro Arango, Gema Ariceta, Bodo B Beck, Anna Bjerre, Detlef Bockenhauer, Paula Coccia, Radhika Dhamija, Fernando de Frutos, Alejandro Garcia-Castano, Sara B van Katwijk, Jesus Lucas, Thomas Möller, Dominik Müller, Filippo Pinto E Vairo, Melinda Raki, Jonathan Rips, Karl Peter Schlingmann, Hanka Venselaar, Matheus Vernet Machado Bressan Wilke, Tom Nijenhuis, Joost Hoenderop, Jeroen de Baaij.
       Introduction: Variants in the Ras-related GTPase D (RRAGD) gene have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy (DCM). RRAGD, which encodes for the RagD protein, is involved in the activation of the mechanistic target of rapamycin complex 1 (mTORC1). Owing to the limited characterization of patients' phenotypes, the understanding of RRAGD-associated ADKH (ADKH-RRAGD) remains incomplete. Consequently, available treatment strategies are primarily symptomatic and insufficient.
    Methods: In the present case series, 13 new patients and 3 novel RRAGD variants, that is, p.(Ser77Phe), p.(Thr91Ile), and p.(Ile100Arg), are described. To assess the pathogenicity of the novel variants, an in vitro assay of mTORC1 activity was performed. In addition, the clinical response to diuretics (furosemide and thiazide, n = 4) and Na+-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (n = 6) was evaluated in patients carrying the RRAGD p.(Thr97Pro) variant during routine.
    Results: The patients presented with kidney tubulopathies, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Five patients also exhibited DCM. In vitro assays demonstrated constitutive activation of noncanonical mTORC1 signaling caused by the p.(Ser77Phe) and p.(Ile100Arg) variants. Clinically, patients remained sensitive to diuretic challenges, whereas dapagliflozin treatment increased serum magnesium (Mg2+) levels by 0.04 mM but exacerbated hypokalemia.
    Conclusion: To date, 37 patients with ADKH-RRAGD have been identified. Kidney tubulopathy is the most prominent feature within the phenotypic spectrum of ADKH-RRAGD. Molecularly, constitutive activation of noncanonical mTORC1 is present in most RRAGD variants. From a therapeutic perspective, dapagliflozin may increase serum Mg2+ levels in patients with RRAGD variants.
    Keywords:  RRAGD; dapagliflozin; dilated cardiomyopathy; kidney tubulopathy; mTORC1; magnesium
    DOI:  https://doi.org/10.1016/j.ekir.2025.07.035
  3. Cardiovasc Res. 2025 Oct 27. pii: cvaf203. [Epub ahead of print]
    Recent progress regarding the role of autophagy in cardiac disease.
    Yasuhiro Maejima, Allen Sam Titus, Daniela Zablocki, Junichi Sadoshima.
      Autophagy is a lysosomal-dependent mechanism of cellular degradation characterized by the presence of double membraned vesicles called autophagosomes. Increasing lines of evidence suggest that both non-selective autophagy and cargo-specific forms of autophagy, such as the mitochondria-specific form of autophagy, termed mitophagy, are activated in the heart in response to stress. However, their activation is often transient and insufficient during the chronic phase of cardiac conditions, including both pressure and volume overload, heart failure with preserved ejection fraction, obesity and diabetic cardiomyopathy and aging cardiomyopathy. Indeed, interventions to restore the levels of autophagy and mitophagy often alleviate cardiac dysfunction in animal models of heart failure. It is, therefore, important to understand the molecular mechanisms that inhibit or activate autophagy and mitophagy during the chronic phase of heart failure. Under some conditions, autophagy can become dysregulated in the heart and induce cellular dysfunction and death. For example, lysosomal function is attenuated through multiple mechanisms. Autosis, a specific form of cell death caused by autophagy dysregulation, is characterized by unique morphologies, including perinuclear space, and sensitivity to cardiac glycoside, and contributes to the late phase of myocardial ischemia/reperfusion injury. Over the past decade, previously unrecognized functions of autophagy have been discovered, including organelle- and protein-specific degradation, and even inter-cellular communication through secretion of extracellular vesicles, which may also contribute to the pathogenesis of heart disease. The purpose of this review is to highlight recent progress in autophagy research in the heart, with a particular focus on underlying signaling mechanisms, cargo-specific autophagy and pharmacological interventions.
    DOI:  https://doi.org/10.1093/cvr/cvaf203
  4. Cell Oncol (Dordr). 2025 Oct 31.
    TFE3 fusion proteins promoted the progression of Xp11.2 translocation renal cell carcinoma through post-translational modification of PDL1 by upregulating CCND1/Cyclin D1.
    Yanwen Lu, Yi Chen, Xinghe Pan, Wenliang Ma, Ning Liu, Lei Yang, Xiang Dong, Hongqian Guo, Dongmei Li, Weidong Gan.
       BACKGROUND: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a very rare and aggressiveness malignancy with poor outcome. Previous studies suggested that programmed cell death protein-1 ligand 1 (PDL1) was characterized with high mRNA and low protein in Xp11.2 tRCC, however, the potential mechanism is still blurry.
    METHODS: Immunohistochemistry was conducted to verify Cyclin D1 and PDL1 expression in Xp11.2 tRCC. ChIP and dual-luciferase reporter gene assay were applied to evaluate transcriptional-regulation of TFE3 fusion proteins on CCND1/Cyclin D1 and NR1D1, we used RNA-seq to detect the regulation role of NR1D1 on CCND1/Cyclin D1, half-life experiment and autophagy flux were employed to demonstrate Cyclin D1-CDK4 speeded PDL1 degradation.
    RESULTS: Here, we demonstrated that CCND1/Cyclin D1 was not only a direct target gene for positive regulation of TFE3 fusion proteins, but also up-regulated by nuclear receptor subfamily 1 group D member 1 (NR1D1) which was positively transcriptional regulation of TFE3 fusion proteins. Besides, TFE3 fusion proteins reduced the degradation of Cyclin D1 by activating the AKT/mTOR pathway. As a result, the high-expression of CCND1/Cyclin D1 mediated degradation of PDL1 protein through ubiquitin-proteasome system and autophagy pathway.
    CONCLUSION: This research found that CCND1/Cyclin D1 was upregulated in Xp11.2 tRCC through three mechanisms, high-expression CCND1/Cyclin D1 inducing PDL1 degradation. Overall, the study provided a theoretical basis for sequentially using CDK4 inhibitors and anti-PDL1 for Xp11.2 tRCC treatment.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:   CCND1/Cyclin D1; CDK4 inhibitors; PDL1; TFE3 fusion proteins; Xp11.2 tRCC
    DOI:  https://doi.org/10.1007/s13402-025-01125-x
  5. Cell Mol Life Sci. 2025 Oct 30. 82(1): 380
    Lysosome heterogeneity and diversity mapped through its distinct cellular functions.
    Indira Chavan, Arindam Bhattacharjee.
      Lysosomes respond to cellular nutrient availability and diverse oncoming vesicle traffic such as endocytosis and autophagy by switching between anabolic signaling or catabolic hydrolase activity, which coincides with a drastic shift in their cellular distribution, organelle contacts, ion homeostasis, membrane proteome and lipidome. Emerging evidence now reveals a dynamic remodeling of lysosomal membrane to counter membrane damage, acting via extensive lipid transfer from the endoplasmic reticulum or by localized membrane repair. Functionally, lysosomes play a key role in lipid metabolism and intracellular calcium signaling. Unsurprisingly, disease-associated lysosomes are either often hyperactive- thus promoting abnormal tissue growth, or hypoactive, promoting storage. Taken together, this presents an incredible functional diversity among the cellular population of lysosomes. Here, we discuss this intracellular heterogeneity and intercellular diversity in context of lysosomal function in health and disease.
    Keywords:  Lipid storage disorders; Lysosome plasticity; Lysosome quality control; Lysosome subpopulations; Phosphoinositides
    DOI:  https://doi.org/10.1007/s00018-025-05883-7
  6. Mol Genet Metab Rep. 2025 Dec;45 101271
    Renoprotective effects of SGLT2 inhibitors in patients with Fabry disease.
    Hayaki Okamoto, Shunsuke Goto, Mika Fujita, Hideki Fujii.
       Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterized by globotriaosylceramide (Gb3) accumulation, resulting in kidney and cardiac dysfunction. Although enzyme replacement therapy (ERT) and chaperone therapy are the standard therapies, progression of renal decline persists. Sodium-glucose co-transporter 2 (SGLT2) inhibitors exert renoprotective effects in chronic kidney disease (CKD), but their efficacy in FD remains unknown.
    Methods: We retrospectively analyzed data of 10 patients with FD treated with SGLT2 inhibitors and compared their renal outcomes to 18 patients with CKD without FD. The estimated glomerular filtration rate (eGFR) slope, urinary albumin-to-creatinine ratio (UACR), and plasma brain natriuretic peptide (BNP) levels were assessed 1 year before and after initiating SGLT2 inhibitor therapy. Linear mixed-effects models were employed for statistical analysis.
    Results: In patients with FD, the annual eGFR decline significantly improved from -4.38 mL/min/1.73 m2/year (IQR: -10.57 to 0.59) before treatment to 1.25 (IQR: -4.16 to 9.74) after treatment (p < 0.05). This improvement remained significant after adjusting for confounding factors. In contrast, the annual eGFR decline in patients with CKD without FD also tended to improve, albeit without significance. Notably, the initial eGFR decline usually seen with SGLT2 inhibitors in CKD was not observed in the FD cohort. UACR and plasma BNP levels remained unchanged after SGLT2 inhibitor therapy.
    Conclusions: SGLT2 inhibitors substantially attenuated the decline in eGFR in patients with FD. These findings support their potential as a renoprotective adjunct in the management of FD.
    Keywords:  Chronic kidney disease; Fabry disease; Sodium–glucose co-transporter 2 inhibitors; eGFR slope
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101271
  7. Mol Biol Rep. 2025 Oct 29. 53(1): 22
    Autophagy-senescence interplay in kidney disease: mechanistic insights and therapeutic potential.
    Jiajun Sang, Kexin Zhang, Qiming Fan, Chengxia Kan, Ruiyan Pan, Xiaodong Sun, Zhentao Guo.
      Autophagy and cellular senescence are intimately linked processes that play pivotal roles in renal homeostasis, aging, and disease progression. Autophagy preserves intracellular integrity by degrading damaged organelles, misfolded proteins, and metabolic waste through lysosomal pathways, thereby maintaining energy balance and delaying senescence. However, with advancing age or persistent stress, autophagic activity declines, leading to the accumulation of senescent cells, mitochondrial dysfunction, and chronic inflammation. In the kidney, a metabolically demanding organ, this imbalance contributes to the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI). Senescent cells secrete a senescence-associated secretory phenotype, which amplifies inflammation, fibrosis, and tissue remodeling. The bidirectional interplay between impaired autophagy and cellular senescence exacerbates renal tubular atrophy, glomerulosclerosis, and interstitial fibrosis, thereby promoting CKD progression and maladaptive repair following AKI. Emerging therapeutic strategies, including autophagy activators, senolytics, antioxidants, and stem cell based interventions, have shown promise in restoring cellular homeostasis and delaying renal aging. Nonetheless, challenges remain in achieving cell type specific modulation while avoiding the deleterious effects of excessive activation. This review highlights recent advances in understanding the mechanistic interplay between autophagy and senescence in renal physiology and disease, outlines their contributions to CKD and AKI, and explores evolving therapeutic strategies aimed at restoring autophagic flux and eliminating senescent cells. Targeting the autophagy senescence axis represents a compelling avenue for precision therapy in kidney disease and may redefine future approaches in nephrology.
    Keywords:  AKI; Autophagy; CKD; Cellular senescence
    DOI:  https://doi.org/10.1007/s11033-025-11180-0
  8. Cells. 2025 Oct 17. pii: 1621. [Epub ahead of print]14(20):
    Advances in Mitochondrial Dysfunction and Its Role in Cardiovascular Diseases.
    Yan Qiu, Shuo Chang, Ye Zeng, Xiaoqi Wang.
      Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide and is attributed to complex pathophysiological mechanisms that surpass the traditional risk factors. Emerging evidence indicates that mitochondrial dysfunction plays a central role in CVD progression, linking impaired bioenergetics, oxidative stress imbalance, and defective mitochondrial quality control to endothelial dysfunction, myocardial injury, and adverse cardiac remodeling. However, the mechanistic interplay between mitochondrial dysfunction and CVD pathogenesis remains unclear. This review provides a comprehensive synthesis of recent knowledge, focusing on the dysregulation of mitochondrial energy metabolism, alterations in mitochondrial membrane potential, and disruptions in mitochondrial dynamics, including the balance of fusion and fission, mitophagy, and biogenesis. Furthermore, we critically evaluated emerging mitochondria-targeted therapeutic strategies, including pharmacological agents, gene therapies, and regenerative approaches. By bridging fundamental mitochondrial biology with clinical cardiology, this review underscores the critical translational challenges and opportunities in developing mitochondria-focused interventions. A deeper understanding of the mitochondrial mechanisms in CVD pathophysiology will offer novel diagnostic biomarkers and precision-targeted therapeutics, thereby transforming CVD management.
    Keywords:  cardiovascular disease; mitochondria dynamics; mitochondrial dysfunction; mitophagy; oxidative stress; targeted therapy
    DOI:  https://doi.org/10.3390/cells14201621
  9. Nat Cell Biol. 2025 Oct 31.
    Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
    Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe.
      The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine-GCN2-SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.
    DOI:  https://doi.org/10.1038/s41556-025-01799-3
  10. Virchows Arch. 2025 Oct 30.
    FLCN-mutated eosinophilic renal tumors: clinicopathologic and molecular analysis of five cases highlighting morphologic heterogeneity.
    Ming Zhao, Jing Song, Jiayun Xu, Guoqing Ru, Lin Ye, Huizhi Zhang, Suying Wang.
      Eosinophilic/oncocytic renal cell neoplasms represent a diagnostically challenging group of tumors with overlapping morphologic and immunophenotypic features. Recent advances in molecular genetics have expanded the spectrum of FLCN-mutated renal tumors, including both Birt-Hogg-Dubé (BHD) syndrome-associated and sporadic cases. This study aimed to characterize the clinicopathologic and molecular features of five FLCN-mutated eosinophilic renal tumors, emphasizing their diagnostic pitfalls and heterogeneity. The cohort included three male and two female patients (median age: 61 years) with solitary renal masses (median size: 3 cm), all incidentally detected and managed surgically (partial/radical nephrectomy). All patients lacked clinical stigmata of BHD syndrome (cutaneous fibrofolliculomas, pulmonary cysts) or relevant family history. Histologically, tumors exhibited diverse patterns (solid-nested, tubuloacinar, trabecular) with uniform eosinophilic cytoplasm, low-grade nuclei, hemorrhagic and edematous stroma, and prominent branching dilated vasculature, along with distinctive features such as intraluminal foamy histiocytes, psammomatous calcification, and thyroid follicle-like secretions (all classified as non-conventional FLCN-mutated tumors). None of the cases showed renal oncocytosis in the surrounding renal parenchyma. Immunohistochemically, all cases showed diffuse GPNMB expression, while TFE3 was weakly expressed in one case. Molecular profiling identified pathogenic/likely pathogenic FLCN mutations (truncating mutations in four cases, missense variant in one) without concurrent alterations in TSC1/2, MTOR, FH, SDHx, or MiT family genes. Over a median follow-up of 38 months, no recurrence or metastasis occurred, suggesting an indolent behavior. These findings highlight the morphologic mimicry of FLCN-mutated tumors with a spectrum of renal neoplasms characterized by low-grade eosinophilic features, particularly TSC/MTOR-altered or MiT family renal neoplasms, underscoring the necessity of integrated immunohistochemical (GPNMB) and molecular testing for accurate diagnosis. Despite their heterogeneity, FLCN-mutated tumors typically follow a benign clinical course, though rare aggressive variants warrant vigilance.
    Keywords:   FLCN ; Eosinophilic renal tumor; GPNMB; Molecular pathology
    DOI:  https://doi.org/10.1007/s00428-025-04289-x
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