bims-raghud 2025-11-23 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–11–23
nine papers selected by
Irene Sambri, TIGEM

Focal postnatal deletion of Tsc2 causes epilepsy.
Macrophages lacking TSC2 have mTORC1-dependent increased GPNMB and ameliorate ventricular dysfunction/remodeling after ischemia-reperfusion.
TFE3-rearranged and TFEB-altered renal cell carcinoma: from classification to real-life. Insights from a national Italian survey.
Mechanistic insights and clinical horizons of SGLT2 inhibitors in heart failure management.
Non-canonical roles of lysosomes in neurons.
Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis.
The Ets2 super-enhancer modulates endothelial-mesenchymal transition during cardiac aging.
Transcription Factor EB Inhibition in Response to Genotoxic Stress Promotes Apoptosis of Glioblastoma Cells.
A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.

Front Mol Neurosci. 2025 ;18 1686023

Focal postnatal deletion of Tsc2 causes epilepsy.

Carlie McCoy, Mary Dusing, Lilian G Jerow, Grace C Winstel, Felix Zhan, Jason L Rogers, Madison Wesley, J Brian Otten, Steve C Danzer, Candi L LaSarge.

   Introduction: Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either the TSC1 or TSC2 genes. These mutations prevent the TSC1/TSC2 protein complex from forming, resulting in hyperactivation of the mechanistic target of rapamycin (mTOR) cell growth and protein synthesis pathway. Epilepsy is one of the most common neurological symptoms in TSC patients, often associated with focal cortical lesions. However, it is not fully established whether such focal abnormalities are sufficient on their own to generate seizures and associated behavioral deficits. Here, we created a novel mouse model to test the hypothesis that a focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to induce an epileptogenic network and produce behavioral changes relevant to TSC.
Methods: Tsc2 was deleted from neurons in a focal area of the frontal cortex in Tsc2 fl/fl (fTSC2 KO) mice following neonatal bilateral AAV9-CaMKII-Cre-mCherry injections on postnatal day 2. One group of adult fTSC2 KO and Tsc2 wt/wt (control) mice was implanted with cortical electrodes for combined video-EEG monitoring. A separate group of control and fTSC2 KO mice, injected with a lower viral titer, underwent video recording and behavioral exploration analysis in a novel environment. Tissue was collected for histology.
Results: All adult fTSC2 KO mice implanted with cortical electrodes had seizures, whereas no control mice did. Histological analyses showed that virally infected cells in fTSC2 KO mice had enlarged somas and increased mTOR activation (pS6 expression). These fTSC2 KO mice also had decreased parvalbumin and somatostatin interneuron densities in the surrounding cortex. fTSC2 KO mice displayed increased anxiety-like behaviors, spending significantly less time in the center of the novel environment compared to controls.
Conclusion: A focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to cause both epilepsy and behavioral deficits in mice. This model recapitulates key phenotypes of TSC, including abnormal cell growth, reduced inhibitory cell density, and increased microglia activation. This fTSC2 KO model is advantageous for delineating the cortical changes that support epilepsy and behavioral deficits in TSC, and for investigating possible targets for therapeutic intervention.

Keywords:  cortical development; epileptogenesis; mTOR; parvalbumin; somatostatin; tuberous sclerosis complex

DOI:  https://doi.org/10.3389/fnmol.2025.1686023
Sci Rep. 2025 Nov 19. 15(1): 40891

Macrophages lacking TSC2 have mTORC1-dependent increased GPNMB and ameliorate ventricular dysfunction/remodeling after ischemia-reperfusion.

Mohammad Keykhaei, Navid Koleini, Mariam Meddeb, David J Polhemus, Masih Tajdini, Malihe Rezaee, Qiao Huang, Tegbir Panesar, Mark J Ranek, Luigi Adamo, David A Kass.

  Macrophages (MΦ) modulate myocardial inflammation and repair after ischemia-reperfusion (I/R) injury. The mechanistic target of rapamycin (mTOR) regulates MΦ phenotype and functionality, but studies conflict regarding its pro- or anti-inflammatory role. To test this, myeloid TSC2 depleted (MΦTSC2-/-) mice were generated by crossing Lys2Cre with TSC2flx/flx. In vitro, bone marrow-derived MΦTSC2-/- vs. control MΦ had greater mTORC1 and less mTORC2 activity coupled with differential responses to pro- or anti-inflammatory ligands. These disparities were eliminated by inhibiting mTORC1 with rapamycin. MΦTSC2-/- mice had substantially less cardiac dysfunction and ventricular remodeling after I/R, with reduced lung edema and activation of stress/pro fibrotic genes. These differences were eliminated by treating mice with rapamycin, supporting mTORC1 dependence. Post I/R MΦTSC2-/- myocardium had fewer pro-inflammatory (CCR2+MHC-IIhi) MΦ, LY6C+ monocytes, LY6G + neutrophils, and CD8+ T cells at 5-days post-I/R, and fewer CCR2+ but more CCR2- MΦ 2-wks after I/R. Synthesis of glycoprotein nonmetastatic melanoma protein B (GPNMB), a MΦ secreted anti-inflammatory protein was greater in MΦTSC2-/- macrophages and myocardium after I/R in an mTORC1 dependent manner. Thus, constitutive mTORC1 activation in MΦ depresses pro-inflammatory cell infiltration, increases GPNMB protein expression, and preserves heart function following I/R. This reveals beneficial effects of a MΦ-dependent mTORC1-GPNMB cascade on the post I/R heart.

Keywords:  Heart; Innate immunity; Ischemia; Mammalian target of rapamycin; Monocyte; Tuberous sclerosis

DOI:  https://doi.org/10.1038/s41598-025-24699-w
Pathologica. 2025 Sep;117(4): 384-392

TFE3-rearranged and TFEB-altered renal cell carcinoma: from classification to real-life. Insights from a national Italian survey.

Stefano Marletta, Anna Caliò, Giuseppe Nicolò Fanelli, Paola Bianco, Angelo Giovanni Bonadio, Claudia Covelli, Simona Francesconi, Mariia Ivanova, Daniele Liscia, Alessia Moro, Daniela Onnis, Maria Rosaria Raspollini, Costantino Ricci, Steno Sentinelli, Marina Valeri, Guido Martignoni.

   Objective: Ongoing discoveries in cancer research keep expanding the landscape of renal cell carcinoma classification, particularly for "molecularly-defined" tumors like TFE3-rearranged and TFEB-altered renal cell carcinoma. However, scientific updates often do not align with pathologists' daily practice and resources. Herein, we present the results from a national Italian survey assessing physicians' personal experience on TFE3-rearranged and TFEB-altered renal cell carcinomas.
Methods: An online questionnaire encompassing 26 questions was delivered to the Italian Study Group of Uropathology (GIUP) members, addressing critical concerns on their routine approach to these tumors. The answers were collected and further analyzed.
Results: Thirteen pathologists with varying uropathological experience responded to the survey. Data confirmed the rarity of these neoplasms, with 69% of participants experiencing fewer than five or none at all. Despite this, aggressive behavior was documented by half of the respondents. Unusual morphology (62%) and young age (38%) were identified as the most relevant clues for suspecting TFE3-rearranged and TFEB-altered renal cell carcinoma. However, variability was observed in the specific histological features and the age threshold. The majority of the participants (54%) agreed on the need for ancillary molecular techniques for diagnostic purposes. Regarding immunohistochemistry, all professionals relied on multiple assays, attributing a primary role to a panel including cathepsin K, melanocytic markers (HMB45 and melan-A), PAX8, cytokeratin 7, and CA9. Additionally, most (58%) reported routine TFE3 immunohistochemical staining, although generally considering it reliable as long as diffuse and intense (58%) or requiring FISH confirmation in every positive case (25%). As for this latter, variability was recorded regarding split-signals positivity cut-off.
Conclusions: The continuous evolution of renal cell carcinoma classification significantly impacts the pathologists' routine approach. Our survey underscores the importance of ongoing knowledge sharing and heightened awareness for accurately identifying TFE3-rearranged and TFEB-altered renal cell carcinoma and providing further insights on still unsolved issues.

Keywords:  TFE3-rearranged renal cell carcinoma; TFEB-altered renal cell carcinoma; immunohistochemistry; molecular tests; morphology; online survey

DOI:  https://doi.org/10.32074/1591-951X-N1518
Trends Cardiovasc Med. 2025 Nov 16. pii: S1050-1738(25)00148-3. [Epub ahead of print]

Mechanistic insights and clinical horizons of SGLT2 inhibitors in heart failure management.

Samin Sadeghi Vahid, Marziyeh Salehi Jahromi, George V Moukarbel, Jennifer W Hill.

  Sodium-glucose co-transporter-2 (SGLT2) inhibitors have become a cornerstone of heart-failure (HF) therapy, lowering hospitalization and cardiovascular mortality in patients with and without diabetes across the spectrum of ejection-fraction phenotypes. Their cardioprotective effects extend beyond glycemic control and are best explained by a hierarchy of mechanisms initiated in the kidney. Early tubular inhibition restores tubuloglomerular feedback, producing osmotic diuresis, natriuresis, and modest reductions in plasma volume and blood pressure that together relieve ventricular preload and afterload. These renal and hemodynamic actions are followed by sustained adaptations involving neurohormonal modulation, erythropoiesis, improved cortical oxygenation, and progressive anti-inflammatory, antifibrotic, and mitochondrial effects. Through these interrelated pathways, SGLT2 inhibition preserves kidney function, limits congestion, and promotes cardiac reverse remodeling. Recognizing that these mechanisms act sequentially and in parallel clarifies how SGLT2 inhibitors complement standard therapies and guides ongoing mechanistic studies to refine their role in HF management.

Keywords:  Cardiac remodeling; Cardiovascular outcomes; Heart failure; Inflammation; Myocardial metabolism; SGLT2 inhibitors

DOI:  https://doi.org/10.1016/j.tcm.2025.11.004
Trends Neurosci. 2025 Nov 18. pii: S0166-2236(25)00222-X. [Epub ahead of print]

Non-canonical roles of lysosomes in neurons.

Jonathan I Spencer, Yulia Sudarikova, Michael J Devine.

  Neurons are highly polarised and compartmentalised cells with organelles that are specialised to support their spatial and functional demands. This includes lysosomes, which are single-membrane-bound organelles enveloping acidic contents enriched with hydrolytic enzymes. While classically thought to be localised at the soma where they degrade waste, lysosomes have a range of dynamic nondegradative functions throughout neurons. Here, we review lysosomal dynamics and non-canonical functions in neurons, including axonal mRNA transport, mammalian target of rapamycin (mTOR) and Ca2+ signalling, neuronal remodelling, and interorganellar contact sites. We synthesise work across a range of model systems and species, providing insights from neurological diseases, where previous lysosomal research has focussed on proteostatic failure. This perspective highlights the need to better define lysosomal heterogeneity, compartmentalisation and specialisation in neurons.

Keywords:  autophagy; neurodegeneration; neuronal plasticity; synapse; trafficking

DOI:  https://doi.org/10.1016/j.tins.2025.10.009
Nat Commun. 2025 Nov 21.

Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis.

Kylie Klinkhammer, Rachel Warren, Joseph Knopp, Toan Nguyen, Stijn P De Langhe.

The coordination between epithelial progenitors and their mesenchymal niche is critical for organogenesis and repair, yet the mechanisms governing their competitive interactions remain unclear. Here, we reveal a paradigm of tissue-scale fitness sensing in the lung, where mesenchymal Yap levels antagonize epithelial Yap levels to dictate epithelial stem cell fate. We show that reduced fitness in alveolar fibroblasts (AF1s) via Yap/Taz or Myc deletion leads to their apoptotic elimination and a collapse of the alveolar stem cell niche. This niche collapse triggers a pathological competitive response from the epithelium, which undergoes aberrant bronchiolization that phenocopies human pulmonary fibrosis. Mechanistically, we uncovered a molecular switch that controls mesenchymal fate. During development and fibrosis resolution, Snail1/2 sequesters Yap/Taz to drive an adipogenic program, generating niche-supportive AF1s. Conversely, Yap/Taz-TEAD-Myc binding instructs a myogenic, pro-fibrotic program. Our findings demonstrate that inter-tissue cell competition, governed by a Snail/Yap rheostat, orchestrates lung architecture and provides a framework for targeting the mesenchymal niche to treat fibrotic disease.

DOI: https://doi.org/10.1038/s41467-025-66690-z
Cardiovasc Res. 2025 Nov 18. pii: cvaf242. [Epub ahead of print]

The Ets2 super-enhancer modulates endothelial-mesenchymal transition during cardiac aging.

Zhenglong Guo, Lan Li, Junwei Luo, Wei Xue, Shasha Bian, Yongchang Zhu, Dawei Huo, Wenke Yang, Jing Ma, Yibin Hao, Guanwei Fan, Bingtao Hao, Shixiu Liao.

   AIMS: Cardiac aging is characterized by endothelial dysfunction and associated cardiovascular pathologies, often involving endothelial-to-mesenchymal transition (EndoMT) in cardiac endothelial cells. While the transcription factor Ets2, a member of the Ets family, is known to regulate endothelial cell survival and function, its role in EndoMT and cardiac aging remains poorly understood.
METHODS AND RESULTS: To investigate this, we utilized single-nucleus RNA sequencing (snRNA-Seq) in Ets2-super-enhancer (Ets2-SE)-deficient mice to examine the regulation of Ets2 expression across various cardiac cell types. We assessed the relationship between Ets2 expression and heart aging, and evaluated the characteristics of cardiac aging in Ets2-SE-deficient mice. Furthermore, we generated endothelial cell-specific Ets2 knockout mice (ECKO) to investigate the role of Ets2 in EndoMT of cardiac endothelial cells both in vitro and in vivo.Our results establish a link between decreased Ets2 expression and the development of aging-associated cardiac pathological remodeling. Through data analyses, we identified a super-enhancer (Ets2-SE) that regulates Ets2 expression in the heart. Ets2-SE-deficient mice exhibited significantly lower Ets2 expression in cardiac tissues and displayed advanced aging phenotypes, including increased cardiac fibrosis and dysfunction, compared to wild-type controls. SnRNA-Seq analyses revealed a remarkable downregulation of Ets2 in endothelial cells, correlating with the activation of EndoMT. Furthermore, endothelial-specific deletion of Ets2 exacerbated aging and myocardial infarction-induced cardiac fibrosis and heart dysfunction. Mechanistic studies demonstrated that silencing ETS2 in human umbilical vein endothelial cells (HUVECs) promotes EndoMT by transcriptionally suppressing the endothelial marker gene TIE1. This transition is accompanied by endothelial cell senescence and the activation of the senescence-associated secretory phenotype (SASP), which contributes to myocardial fibrosis and cardiac aging, partially mediated by Serpine1. These findings identify Ets2 as a critical regulator of EndoMT in the context of cardiac aging.
CONCLUSIONS: Our findings reveal that the Ets2 super-enhancer regulates Ets2 expression in cardiac endothelial cells, modulating heart aging and EndoMT. Ets2's regulation of endothelial marker genes, especially TIE1, plays a pivotal role in mitigating EndoMT and preventing senescence in cardiac vascular endothelial cells, suggesting potential therapeutic targets for addressing cardiovascular aging.

Keywords:  EndoMT; Ets2; Genetic variants; Heart aging; Human vascular disease; SASP; Serpine1; Super enhancer

DOI:  https://doi.org/10.1093/cvr/cvaf242
Neurochem Int. 2025 Nov 15. pii: S0197-0186(25)00160-3. [Epub ahead of print] 106087

Transcription Factor EB Inhibition in Response to Genotoxic Stress Promotes Apoptosis of Glioblastoma Cells.

Seung-Ho Park, Minseok Jeong, Min-Jeong Kong, Kyung-Chul Choi.

  Glioblastoma multiforme (GBM), one of the most malignant brain cancers, responds poorly to chemotherapy and surgery. Transcription factor EB (TFEB) is markedly overexpressed in GBM cells. We investigated whether TFEB contributes to resistance to genotoxic stress and whether its inhibition promotes apoptosis of GBM cells and glioma stem cells (GSCs). Specifically, we examined whether combined treatment with etoposide and SAHA overcomes TFEB-mediated resistance and enhances apoptotic cell death. We examined the effects of etoposide, a topoisomerase II inhibitor, and SAHA, a histone deacetylase inhibitor, on TFEB expression and apoptotic signaling in human GBM cells and GSCs. To assess TFEB-mediated drug resistance, we measured cell viability, proliferation, and tumorsphere formation following single or combined treatments. Apoptotic signaling was analyzed by western blotting, MTT assays, and tumorsphere formation assays. Functional roles of TFEB were further investigated using overexpression and shRNA knockdown approaches. Treatment with etoposide induced apoptosis and reduced TFEB expression in GBM cells. Co-treatment with etoposide and SAHA synergistically increased cleaved PARP and phosphorylated H2AX levels, indicating enhanced apoptotic activity. In TFEB-overexpressing and knockdown GBM cells, apoptosis sensitivity varied according to TFEB expression levels. In GSCs, combination treatment significantly suppressed cell proliferation and tumorsphere formation, accompanied by reduced TFEB expression and oligomerization, and increased apoptosis. Our findings suggest that TFEB promotes the chemoresistance of GBM tumors and GSCs by suppressing apoptosis. Co-treatment with etoposide and SAHA inhibits TFEB activity and enhances apoptotic cell death, representing a promising therapeutic strategy for treating malignant brain tumors.

Keywords:  Apoptosis; Etoposide; Glioblastoma; SAHA; Transcription Factor EB

DOI:  https://doi.org/10.1016/j.neuint.2025.106087
EMBO J. 2025 Nov 20.

A unified mechanism for mitochondrial damage sensing in PINK1-Parkin-mediated mitophagy.

Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, Luiza M Gruel Budet, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.

  Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence translocase-associated import motor (PAM), blocked progression of PINK1 import through the translocase of the inner membrane (TIM23), causing it to remain bound to the translocase of the outer membrane (TOM). Ablation of TIM23 was sufficient to arrest PINK1 within TOM, irrespective of MMP. Meanwhile, TOM (including subunit TOMM5) was required for PINK1 retention on the mitochondrial surface. The energy state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Together, our findings point to a convergent mechanism of PINK1-Parkin activation by mitochondrial damage: loss of MMP stalls PINK1 import during its transfer from TOM to TIM23.

Keywords:  Autophagy; Glycolysis; Parkinson’s Disease; Unfolded Protein Response

DOI:  https://doi.org/10.1038/s44318-025-00604-z