bims-raghud 2026-05-17 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–05–17
seven papers selected by
Irene Sambri, TIGEM

Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.
Mitochondrial metabolism and dynamics in the development of diabetic kidney disease.
The emerging role of the Hippo signaling pathway in interorgan crosstalk.
Modelling kidney cystogenesis using human kidney tubuloid cultures.
Pharmacological restoration of mitochondrial permeability transition pore flickering by high-content drug repurposing.
MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
New developments and applications of human organoids.

Nat Chem Biol. 2026 May 14.

Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.

Yanghao Zhong, Ayse Z Sahan, Zhengyao Shao, Qian-Yi Zhang, Xin Zhou, Jack G Haggett, Keiichi Koshizuka, Samuel A Myers, J Silvio Gutkind, Jin Zhang.

Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient sensor that integrates diverse inputs to regulate protein translation and cell growth. While mTORC1 is activated on the lysosome in the classical model, it has become increasingly clear that this multifaceted signaling complex is active at various subcellular locations, such as the nucleus. However, what specific functions mTORC1 serves at these locations and how its signaling is compartmentalized are unclear. To interrogate subcellular pools of mTORC1, we developed TerminaTOR, a genetically encodable inhibitor of mTORC1 that can be targeted to specific subcellular locations. When TerminaTOR is directed to the lysosome, it inhibits canonical lysosomal mTORC1 and induces autophagy. Furthermore, TerminaTOR targeted to the nucleus specifically inhibits nuclear mTORC1, uncovering noncanonical roles of nuclear mTORC1 in regulating the transcription of CCAAT motif-containing genes. Thus, mTORC1 exhibits functional spatial compartmentalization and TerminaTOR serves as a powerful tool for unraveling spatially regulated functions of mTORC1 across different scales.

DOI: https://doi.org/10.1038/s41589-026-02188-z
Kidney Res Clin Pract. 2026 May 11.

Mitochondrial metabolism and dynamics in the development of diabetic kidney disease.

Gerry George Mathew.

  Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide, affecting over 40% of individuals with diabetes. Despite advances in glycemic control and renin-angiotensin system blockade, effective therapeutic strategies remain limited. A narrative review was synthesized from research papers using PubMed, Wiley Online Library, ScienceDirect, Cochrane Library, Springer, and other sources, published between 2000 and 2025 with logical combinations of appropriate keywords and Medical Subject Headings. Emerging evidence implicates mitochondrial dysfunction as the central pathogenic mechanism underlying DKD progression. Mitochondria govern critical cellular processes, comprising energy metabolism, reactive oxygen species homeostasis, and cell survival. In DKD, hyperglycemia-induced metabolic stress compromises mitochondrial oxidative phosphorylation, enhances reactive oxygen species production, damages mitochondrial DNA, as well as disrupts mitochondrial dynamics through aberrant fission, fusion, and mitophagy processes. These alterations occur early in the pathogenesis of disease and affect multiple renal cell types, particularly proximal tubular epithelial cells and podocytes. Recent studies have identified key molecular regulators of mitochondrial quality control, including PTEN-induced putative kinase 1/Parkin-mediated mitophagy, dynamin-related protein 1-driven fission, and peroxisome proliferator-activated receptor gamma coactivator 1-αlpha-dependent biogenesis, as potential therapeutic targets. Novel therapies targeting mitochondrial dysfunction, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, mitochondria-targeted antioxidants, and metabolic modulators, have shown promise in preclinical and clinical studies. This paper synthesizes recent understanding of mitochondrial metabolism and dynamics in DKD pathogenesis and evaluates emerging mitochondria-directed therapeutic strategies. This review concludes that only SGLT2 inhibitors are the only class of drugs with robust randomized controlled trial evidence to date and other emerging therapeutic options require further clinical validation.

Keywords:  Diabetic kidney disease; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Oxidative phosphorylation; Sodium-glucose transporter 2 inhibitors

DOI:  https://doi.org/10.23876/j.krcp.25.413
FEBS J. 2026 May 14.

The emerging role of the Hippo signaling pathway in interorgan crosstalk.

Gahyeon Song, Chaerin Lee, Eek-Hoon Jho.

  Interorgan communication has emerged as a fundamental mechanism for maintaining systemic homeostasis, and its disruption contributes to the development of metabolic diseases, chronic inflammation, and cancer. The Hippo signaling pathway, traditionally known for controlling organ size, has recently been redefined as a context-dependent coordinator of systemic cues. By translating hormonal, metabolic, and microbial signals into coordinated cellular responses, Hippo signaling serves as a bidirectional communication hub that not only interprets systemic inputs but also generates "outputs" that connect multiple organ systems. In this review, we summarize how Hippo signaling integrates diverse stimuli within key interorgan axes (e.g., gut-liver, gut-pancreas, and adipose-peripheral organs), and how organ-specific Hippo activity, particularly in adipose tissue and skeletal muscle, generates systemic outputs influencing metabolism. This integration occurs through context-specific mechanisms, allowing Hippo signaling to adapt cellular programs to physiological or pathological conditions. Despite recent progress, the mechanisms by which Hippo signaling prioritizes and integrates multiple systemic inputs and transmits its effects across organs remain incompletely understood. Elucidating these processes will be crucial to establishing Hippo signaling as a unifying framework of interorgan communication and understanding its broader implications in systemic physiology and disease.

Keywords:  YAP/TAZ; cancer progression; hippo signaling; interorgan communication; systemic homeostasis

DOI:  https://doi.org/10.1111/febs.70587
BMC Mol Cell Biol. 2026 May 11. pii: 26. [Epub ahead of print]27(1):

Modelling kidney cystogenesis using human kidney tubuloid cultures.

Jana Rohe, Arsila Palliyulla Kariat Ashraf, Melina Kehl, Xenia Thielmann, Jörg Ellinger, Glen Kristiansen, Dagmar Wachten, Marieta Ioana Toma.

   BACKGROUND: Renal cyst formation, as observed in autosomal dominant polycystic kidney disease (ADPKD), is a life-threatening condition with no effective cure yet. The molecular mechanisms underlying primary cilia dysfunction, which causes cyst formation and disease development, are not well understood. Human kidney tubuloids offer a promising model system to investigate the disease mechanisms of PKD in physiologically relevant 3D structures. However, their inherent cystic morphology poses a challenge in effectively modelling kidney cystogenesis. Therefore, our study aims to refine the culture method of tubuloids and assess the efficacy of these modified cultures in modeling cyst formation and development.
RESULTS: We developed human kidney tubuloid models derived from adult kidney tubular cells using different methods for 3D in-vitro cultures. Tubuloids cultured in suspension or an extracellular matrix scaffold manifested distinctly polarized epithelial structures. Bulk RNA sequencing and immunohistochemistry revealed differential transcriptional profiles, highlighting variations in cellular composition and cellular fate within the kidney epithelium between the two types of tubuloids. Notably, the experimental activation of chronic cAMP signalling promoted cyst formation in vitro, validating the suitability of these tubuloids for studying kidney cystogenesis. Furthermore, we demonstrate that tubuloids are amenable to genetic modification through recombinant adeno-associated virus transduction.
CONCLUSIONS: Our study identifies different in-vitro tubuloid cultures as relevant model systems for examining the molecular and cellular changes involved in kidney cystogenesis in humans. These models will enhance our capability to discover novel pathogenetic mechanisms underlying ADPKD and validate candidate drugs for clinical application.

Keywords:  ADPKD; Cilia; Dome tubuloids; Kidney cyst; Kidney epithelial cells; Organoids; Suspension tubuloids; cAMP signalling

DOI:  https://doi.org/10.1186/s12860-026-00591-x
Pharmacol Res. 2026 May 07. pii: S1043-6618(26)00149-0. [Epub ahead of print]229 108234

Pharmacological restoration of mitochondrial permeability transition pore flickering by high-content drug repurposing.

Emanuela Franchini, Matteo Bulloni, Anna Sorgente, Katarina Paulikova, Laura Cassina, Ilaria Marafelli, Irene Sambri, Linda Pattini, Giorgio Casari.

  The mitochondrial permeability transition pore (mPTP) is a voltage‑ and calcium‑regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from SPG7 patient cells and healthy control confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation.

Keywords:  Berberine; Hereditary spastic paraplegia; High content screening; MPTP; Mitochondrial permeability transition pore; SPG7

DOI:  https://doi.org/10.1016/j.phrs.2026.108234
Nat Metab. 2026 May 13.

MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.

Henry M Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Elena Berezhnaya, Joanne F Garbincius, Adyson Johnson, Tyler L Stevens, Jordan E Howe, Hailey Lesniak, Anna Schmidt, Jennyfer Ngo, Emily Megill, Dhanendra Tomar, Nathaniel W Snyder, Wolfgang F Graier, John W Elrod.

Mitochondrial matrix Ca2+ concentration ([Ca2+]m) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. Here we demonstrate that MICU proteins, the reported gatekeepers of mtCU, function in coordination to impart calcium-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independently of the mtCU and [Ca2+]m. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Using an equimolar expression platform coupled with unbiased proteomics, we reveal unique interactomes for MICU1/MICU2 versus MICU1/MICU3 heterodimers and demonstrate that MICU proteins control coupling of mitochondrial glycerol-3-phosphate dehydrogenase and succinate dehydrogenase/complex II and impart calcium-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological calcium signaling mechanism regulating homeostatic energetics, not mtCU-dependent changes in [Ca2+]m.

DOI: https://doi.org/10.1038/s42255-026-01513-z
Nat Rev Mol Cell Biol. 2026 May 11.

New developments and applications of human organoids.

Amanda Andersson-Rolf, Hans Clevers.

Organoid technology offers unique opportunities for studying human biology and disease in vitro. Organoids are self-organizing 3D structures, derived from pluripotent or tissue-resident stem cells that recapitulate key aspects of primary tissues. Compared with classical cell lines, organoids provide distinct advantages. They can be derived from both healthy tissues and diseased tissues, enabling the investigation of disease mechanisms and the development of personalized therapies, and they better recapitulate the cellular heterogeneity of the native tissue, allowing for better modelling of human (patho)physiology. Although current organoids have provided valuable insights, these insights are inherently reductionist and do not fully capture the complexity of human tissues. The research field is, therefore, moving towards next-generation models that more accurately represent the intricate cellular interactions, tissue architecture and microenvironmental cues that underlie human biology and disease. In this Review, we outline the limitations and challenges of current organoid systems, highlight recent advances aimed at increasing their complexity, and discuss innovations that support their translation into clinical applications. The focus is on human tissue stem cell-derived organoids, with comparisons to pluripotent stem cell-derived organoids where relevant. We conclude by identifying key factors and remaining challenges for developing the next generation of organoids.

DOI: https://doi.org/10.1038/s41580-026-00974-0