bims-raghud 2026-09-27 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–09–27
eight papers selected by
Irene Sambri, TIGEM

mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis.
mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.
TRPML1 loss disrupts lysosome-mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy.
Cardiac Organoids for Modeling Congenital Heart Disease: From Genetic Discovery to Therapeutic Screening.
The role of senescence in kidney ageing, injury and fibrosis.
Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.
Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma.
Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.

Nature. 2026 Sep 23.

mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis.

Thomas L Li, John D Blair, Taesun Yoo, Gerald A Grant, Dirk Hockemeyer, Brenda E Porter, Helen S Bateup.

Tuberous sclerosis complex (TSC) is a genetic neurodevelopmental disorder characterized by focal brain malformations called cortical tubers, which are associated with severe, intractable epilepsy1. Tubers are thought to result from somatic second-hit mutations that disrupt the TSC1 or TSC2 genes in neural progenitor cells, driving hyperactive mTORC1 signalling2. Glial abnormalities are commonly observed in tubers3; however, whether glia actively cause disease or merely result from chronic seizure activity has remained unclear. To address this question, we used human brain organoid models to track the developmental fate of mutated progenitor cells in the absence of seizures. Here we show, using single-cell transcriptomics and cyclic immunostaining across human brain organoids and resected tuber tissue from patients, that loss of TSC2 biases neural progenitors to differentiate into enlarged, pro-inflammatory reactive astrocytes in a cell autonomous manner. These mutant astrocytes show downregulated glutamate transporter expression, increased inflammatory cytokine secretion and elevated expression of neurodegenerative disease risk genes such as APOE and CLU. Our findings demonstrate that reactive astrocytes emerge as a primary consequence of TSC2 loss. These results implicate glial dysfunction as a driver of TSC pathogenesis and highlight reactive astrocytes as potential therapeutic targets for TSC-related neuropathology.

DOI: https://doi.org/10.1038/s41586-026-11054-w
Sci Adv. 2026 Sep 25. 12(39): eaee1905

mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.

Alex Zaufel, Wenfei Sun, Nunzia Pastore, Ulrike Taschler, Carina Wagner, Hubert Hackl, Judith Sommer, Dagmar Silbert-Wagner, Jan G Hengstler, Brigitte Begher-Tibbe, Rudolf Stauber, Dagmar Kolb, Martin Troetzmueller, Benjamin Gottschalk, Chelsea Thorsheim, Eva-Lena Stange, Mathias W Hornef, Olga Pivovarova-Ramich, Andreas F H Pfeiffer, Kylie P Matchett, Anne Loft, Stephan Herzig, Neil C Henderson, Andrea Ballabio, Zoltan Arany, Christian Wolfrum, Peter Fickert, Tarek Moustafa.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal cues to regulate hepatic lipid metabolism with major implications for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that altered hepatic mTORC1-TFEB/TFE3 signaling is associated with coordinated remodeling of bile acid (BA) metabolism during metabolic adaptation. Our data support a model in which cross-talk between mTORC1 and TFEB/TFE3 is associated with divergent regulation of bile acid synthesis and transformation. Depending on the mTORC1 signaling state, changes in hepatic Cyp2c70 and Cyp8b1 expression, together with altered cholesterol trafficking, were associated with shifts toward non-12-OH or 12-OH bile acid species. These effects were attenuated or reversed by Tfe3 deletion or rapamycin treatment. Furthermore, protein restriction (which inhibits mTORC1) similarly reshaped the BA profile in mice and correlated with improved metabolic outcomes in MASLD patients. Together, these findings uncover BA homeostasis as an integral component of the metabolic adaptations orchestrated by mTORC1, underscoring a link between nutrient signaling and metabolic liver disease.

DOI: https://doi.org/10.1126/sciadv.aee1905
J Biol Chem. 2026 Sep 22. pii: S0021-9258(26)02468-3. [Epub ahead of print] 113596

TRPML1 loss disrupts lysosome-mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy.

Alia K Syeda, Shekoufeh Almasi, Cory J Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Amari Delima-Baril, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Unnikrishnan B Sheela, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.

Signaling mechanisms at the lysosome-mitochondria interface form a critical network that enables cancer cells to maintain mitochondrial quality control, adapt to metabolic stress, and survive therapy. However, the incomplete understanding of the mechanisms coordinating this network has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we identify TRPML1 as an important regulator of lysosome-mitochondrial communication in MDA-MB-231 TNBC cells. We find that TRPML1 knockdown (ML1-KD) impaired mitochondrial respiration, oxidative substrate utilization, ATP production and redox balance in MDA-MB-231 cells, whereas comparable changes were not observed in non-cancerous MCF10A cells. ML1-KD reduced lysosomal acidification and impaired autophagic flux and was accompanied by reduced TFEB nuclear localization, impaired mitophagy, and alterations in mitochondrial maintenance proteins. These changes were accompanied by organellar proximity remodelling, with increased mitochondria-ER proximity and reduced mitochondria-lysosome proximity, together with altered cytosolic/mitochondrial Ca2+ responses, broad metabolic remodelling, G0/G1 arrest, and caspase-3/7-independent cell death. Importantly, ML1-KD cells showed enhanced responses to otherwise subeffective concentrations of doxorubicin and paclitaxel. Together, our findings support TRPML1-dependent lysosomal signaling as an important contributor to mitochondrial-metabolic resilience and chemotherapy responsiveness in MDA-MB-231 TNBC cells.

DOI: https://doi.org/10.1016/j.jbc.2026.113596
Curr Cardiol Rep. 2026 Sep 21. pii: 97. [Epub ahead of print]28(1):

Cardiac Organoids for Modeling Congenital Heart Disease: From Genetic Discovery to Therapeutic Screening.

Wenyan Lucy Zhang, Elizabeth G Porter, Casey A Gifford.

   PURPOSE OF REVIEW: Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant mortality. This review highlights recent advances in human stem cell-derived cardiac organoids and their applications to understand CHD etiology, with a focus on functional genomics and therapeutic discovery.
RECENT FINDINGS: Advances in cardiac organoid engineering have enabled increasingly complex models with enhanced vascularization, diverse cellular lineages, and chamber-specific features that more faithfully mimic the developing heart. Single-cell transcriptomic and epigenomic profiling of organoid differentiation has revealed gene regulatory programs governing cardiogenesis. Machine learning models trained on these datasets provide powerful frameworks for predicting genetic variant effects associated with CHD. Cardiac organoids provide scalable, human-specific platforms for investigating CHD etiology across multiple cell types and disease-relevant developmental stages. Combined with single-cell profiling and machine learning, cardiac organoids offer new opportunities for CHD mechanistic discovery, improved genetic risk prediction, and personalized therapeutic development.

Keywords:  Cardiac organoids; Congenital heart disease; Disease modeling; Drug screening; Genetics; Pluripotent stem cells

DOI:  https://doi.org/10.1007/s11886-026-02418-9
Nat Rev Nephrol. 2026 Sep 23.

The role of senescence in kidney ageing, injury and fibrosis.

Piotr P Janas, Tilly Mason, David A Ferenbach.

Despite treatment advances, chronic kidney disease (CKD) remains an incurable, progressive disease affecting ~850 million people worldwide. Kidney ageing and CKD have many common features, including capillary and epithelial cell loss, increased fibroblast numbers, interstitial fibrosis and chronic immune infiltrates. Consequently, identifying pathways driving the fibrosis and loss of homeostasis shared in both states is a major research priority. Cellular senescence, a cell state characterized by generally irreversible growth arrest with an altered secretory phenotype, is highly conserved across all multicellular organisms. 'Acute' senescence induction with prompt physiological clearance is important for development, contributes to adaptive repair in response to organ injury, and represents a defence against neoplasia. However, the increased numbers of senescent epithelial cells associated with human kidney ageing and CKD include 'chronic' senescent cells, which have been implicated as drivers of kidney dysfunction and fibrosis. Experimental evidence links chronic senescence to kidney leukocyte recruitment and myofibroblast activation. Moreover, pre-clinical studies of senescent cell depletion show extended healthy lifespan, preserved function and reduced fibrosis in multiple organs, including the kidney. Here, we examine current evidence of senescence as a driver of kidney disease and its potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41581-026-01123-8
Circulation. 2026 Sep 22.

Novel mTORC1 Booster LAPTM4A Potentiates Pathological Cardiac Hypertrophy.

Yufeng Hu, Wei Li, Manli Hu, Song Tian, Siyi Zhou, Jiayi Liu, Xu Cheng, Changjiang Zhang, Yingjie Zuo, Jiaxing Zhang, Dianyu Liu, Yang Hu, Yuanbao Chen, Xin Li, Lei Luo, Hailong Yang, Lan Bai, Hui Liu, Péter Ferdinandy, Mario Chiong, Mayarling Francisca Troncoso, Jinying Wen, Jingjing Cai, Xiao-Jing Zhang, Zhi-Gang She, Xin Zhang, Hongliang Li.

   BACKGROUND: Excessive unnecessary protein accumulation in cardiomyocyte is a leading contributor for pathological cardiac hypertrophy and has been found closely regulated by the mTORC1 (mechanistic target of rapamycin complex 1) signaling and lysosome transmembrane proteins. However, the precise regulatory mechanism stratifying mTORC1 signaling and the specific functions of lysosomal proteins in protein homeostasis of cardiomyocytes remain largely unidentified.
METHODS: We screened lysosomal genes conserved in mice, rats, and humans. Adenoviral infection of rat cardiomyocytes was used to assess the functional role of LAPTM4A (lysosome-associated protein transmembrane 4A). To evaluate its effects in vivo, adeno-associated virus 9 driven by the cardiac troponin T promoter was used for cardiomyocyte-specific expression. RNA sequencing and mass spectrometry-based proteomics were performed to elucidate the underlying molecular mechanisms. Last, a dual-luciferase reporter assay was used to screen a Food and Drug Administration-approved drug library for compounds that suppress LAPTM4A expression.
RESULTS: Lysosomal transmembrane proteins expressed in cardiomyocytes were screened for their roles in regulating hypertrophy, and LAPTM4A emerged as a potent promoter of cardiomyocyte hypertrophy and prohypertrophic gene expression. Overexpression of LAPTM4A aggravated cardiac remodeling and dysfunction by enhancing mTORC1-p70S6K (70-kDa ribosomal protein S6 kinase)/4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1)-mediated protein synthesis, without affecting lysosomal autophagy, in a NEDD4L (neural precursor cell expressed developmentally downregulated 4-like)-dependent manner. Mechanistically, LAPTM4A directly interacted with NEDD4L, facilitating K63-linked ubiquitination of AKT (protein kinase B [v-akt murine thymoma viral oncogene homolog]) and subsequent activation of mTORC1 signaling. Cardiomyocyte-specific deletion of LAPTM4A significantly attenuated myocardial hypertrophy and fibrosis induced by transverse aortic constriction in mice. Furthermore, a dual-luciferase reporter screen identified magnolol, a Food and Drug Administration-approved compound, as a suppressor of LAPTM4A expression with marked cardioprotective effects in vivo.
CONCLUSIONS: Our study identified a novel mTORC1 booster LAPTM4A and verified interrupting the LAPTM4A-mTORC1 axis can significantly inhibit excessive protein synthesis and pathological cardiac hypertrophy, which might represent an attractive therapeutic approach for this disease.

Keywords:  LAPTM4A; abnormal protein accumulation; cardiac hypertrophy; mTORC1

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.080371
Nat Commun. 2026 Aug 26. pii: 10191. [Epub ahead of print]17(1):

Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma.

Prathyusha Konda, Alexandra J Wakolbinger, Yantong Cui, Gabriel Roberti de Oliveira, Yasmin L Nabil, Cary N Weiss, Maxwell D Seager, Riva Deodhar, Jiao Li, Sayed Matar, Jinyu Wang, Jack Horst, Sabrina Y Camp, Aseman B Sheshdeh, Jonathan L Hecht, David J Einstein, Yashika Rustagi, Anwesha Nag, Aaron R Thorner, Cheng-Zhong Zhang, Eliezer M Van Allen, Sabina Signoretti, Toni K Choueiri, Srinivas R Viswanathan.

Renal cell carcinomas (RCC) comprise multiple molecularly distinct cancers but most are treated empirically with therapies designed for clear cell RCC (ccRCC), the most common subtype, due to incomplete understanding of subtype-specific biology. We analyzed single-cell transcriptomes and chromatin accessibility profiles from translocation renal cell carcinoma (tRCC), an aggressive RCC defined by oncogenic TFE3 gene fusions. We show that, despite arising from a proximal tubule cell of origin similar to ccRCC, tRCCs display distinct oncogenic programs and an immunosuppressive tumor microenvironment (TME). tRCCs exhibit six conserved tumor meta-programs, including epithelial-mesenchymal transition (EMT) and proximal tubule identity programs whose balance is regulated by TFE3 fusion activity. The fusion-driven EMT program drives a suppressive TME marked by progenitor-exhausted CD8 + T cells, anti-inflammatory SPP1+ macrophages, and matrix-associated fibroblasts. Our findings highlight unique TFE3 fusion-driven biology in tRCC, explaining its reduced immunotherapy responsiveness relative to ccRCC, and suggesting strategies for targeting fusion-driven oncogenic programs and TME reprogramming.

DOI: https://doi.org/10.1038/s41467-026-76858-w
Nat Rev Nephrol. 2026 Sep 24.

Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.

Shen Li, E Dale Abel, Zoltan Arany, Joseph A Baur, Liming Pei, Katalin Susztak.

Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem disorder in which obesity, diabetes, chronic kidney disease, and cardiovascular disease reinforce one another through shared pathobiological characteristics and bidirectional organ crosstalk. Rather than representing the mere coexistence of diseases, CKM syndrome can be understood as a mitochondrial systems disorder. In energy-intensive tissues such as the myocardium and renal tubules, chronic haemodynamic stress, substrate excess, hypoxia and neurohormonal activation converge on mitochondrial programmes governing oxidative phosphorylation, redox balance, organelle dynamics and quality control. Disruption of these programmes, including impaired fatty acid oxidation, suppressed biogenesis, defective mitophagy and mitochondrial DNA instability, reduces bioenergetic reserve and promotes reactive oxygen species generation, inflammatory signalling and progressive organ dysfunction. Mitochondrial dysfunction in other metabolic tissues further amplifies these processes. In the liver, reduced fatty acid oxidation promotes steatosis, insulin resistance and the release of lipids, whereas in skeletal muscle and adipose tissue, impaired oxidative capacity and insulin resistance increases lipid spillover and systemic inflammation. Mitochondria-derived signals - including FGF21, GDF15, succinate and circulating mitochondrial DNA - enable bidirectional communication between organs, reinforcing multi-organ decline in a positive-feedback loop. Advancing our understanding of mitochondrial dysfunction and inter-organ communication may provide new mechanistic insights into CKM syndrome progression and inform the development of mitochondria-targeted therapeutic strategies.

DOI: https://doi.org/10.1038/s41581-026-01127-4