bims-raghud 2026-09-13 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–09–13
seven papers selected by
Irene Sambri, TIGEM

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.
Reassembly of human kidney organoids after dissociation.
[Birt-Hogg-Dubé syndrome-associated renal tumors: a clinicopathological and molecular genetic analysis of ten cases].
An Underrecognized Cause of Recurrent Spontaneous Pneumothorax: Birt-Hogg-Dubé Syndrome With Isolated Pulmonary Manifestation.
The applications of organoids in kidney diseases: progress and challenges.
Mitochondrial extracellular vesicles in cardiorenal syndrome: emerging mediators of mitochondrial signaling and inter-organ crosstalk.

JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.

Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.

  Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.

Keywords:  Endocrinology; Muscle biology; Signal transduction

DOI:  https://doi.org/10.1172/jci.insight.210523
Autophagy. 2026 Sep 07. 1-17

Augmenting intracellular amino acid pools suppresses the phenotypes of autophagy-deficient cells.

Rubén Barrios, Rebeca Gracia-Domingo, Cristina Corral-Ramos, Élida Alechaga, Óscar J Pozo, José Ayté, Elena Hidalgo.

  TORC1 is a central regulator of cell growth whose inactivation under conditions of nutrient deprivation triggers adaptive responses, including macroautophagy/autophagy, amino acid uptake, and sexual differentiation. Autophagy-deficient fission yeast cells display mating defects and are unable to recover from amino acid starvation, even when external amino acids are available. Here, we investigate how TORC1 signaling and autophagy interact to control these processes. We show that both major phenotypes of autophagy-deficient cells - their inability to resume growth after amino acid starvation and their mating defects - stem from insufficient intracellular amino acid pools. Genetic or environmental enhancement of intracellular amino acid pools alleviates both defects. During leucine starvation, deletion of any1 rescues the growth defect of atg1Δ mutants by maintaining amino acid transporters at the plasma membrane, promoting amino acid uptake. Importantly, we uncover a previously unrecognized role for autophagy in the cell-cycle remodeling required for sexual differentiation. Nitrogen depletion-mediated TORC1 inactivation initiates these cell-cycle rearrangements required to start the mating/meiosis program, but autophagy is specifically required for the final G2-to-G1 arrest that precedes the program. This step correlates with the accumulation of the cyclin-dependent kinase inhibitor Rum1. Metabolomic analyses reveal that intracellular amino acid pools drop sharply during nitrogen starvation, especially in autophagy-deficient cells, and supplementation with trace amino acids restores their ability to complete the final G2-to-G1 transition. Together, our results reveal that autophagy sustains intracellular amino acid pools during prolonged stress, enabling TORC1 reactivation and cell-cycle remodeling necessary for successful mating and meiosis.Abbreviations: DNA: deoxyribonucleic acid; FACS: fluorescence-activated cell sorting; GATOR1: GAP activity toward Rags 1; GATOR2: GAP activity toward Rags 2; GFP: green fluorescent protein; MM: minimal medium; N: nitrogen; PCR: polymerase chain reaction; RNA: ribonucleic acid; S. cerevisiae: Saccharomyces cerevisiae; S. pombe: Schizosaccharomyces pombe; TOR: target of rapamycin; TORC1: target of rapamycin complex 1; TORC2: target of rapamycin complex 2; tRNA: transfer ribonucleic acid; YE5S: yeast extract 5 amino acid supplemented; WT: wild-type.

Keywords:  Amino acid transporters; Eif21/eIf2α; Eliminate Gcn2; G1 arrest; Rum1; TORC1; leucine starvation

DOI:  https://doi.org/10.1080/15548627.2026.2719430
Nephron. 2026 Sep 09. 1

Reassembly of human kidney organoids after dissociation.

Suzanne de Vetten, Annelot Klaassen, Dominique Yrsa Veldhoen, Thierry van den Bosch, Sander Korevaar, Ingrid Garrelds, A H Jan Danser, Jeroen van de Peppel, Sebastiaan Heidt, Martin J Hoogduijn.

INTRODUCTION: Human induced pluripotent stem cell (iPSC)-derived kidney organoids have emerged as a valuable model for studying kidney development and disease. Phenotypically, these organoids resemble kidneys of gestational week 12. Embryonic kidneys have the capacity to reassemble after dissociation, which offers the possibility to study the effect of introducing additional cell types or gene expression modification through transfection of dissociated organoids before reassembly. We examined whether human iPSC-derived kidney organoids share the property of embryonic kidneys to reassemble after dissociation. This would open new research avenues with human kidney organoids.
METHODS: Human iPSC-derived kidney organoids were dissociated into single cells by TrypLE Select and reaggregated by centrifugation. Organoids were collected 4 and 7 days after reaggregation and immunostaining was performed to assess structural organization. Restoration of endocrine activity was assessed by measurement of renin production. As a proof of principle, dissociated organoids were transfected with a GFP expressing plasmid, and expression was monitored in reaggregated organoids.
RESULTS: Kidney organoids displayed the capacity to reassemble proximal and distal tubular structures, demonstrated by reappearance of Villin-1+ and E-cadherin+ structures. Podocalyxin (PODXL)+ glomerular structures reappeared sparsely after dissociation. Reassembled organoids responded to forskolin with renin secretion, albeit at a lower level than non-dissociated organoids. Dissociated organoids that were transfected with a GFP plasmid at the cell suspension stage showed robust GFP expression after reassembly.
CONCLUSION: Human kidney organoids partially reassemble after dissociation. Dissociation and reassembly of kidney organoids offers a novel tool for kidney organoid research that allows the introduction of exogenous cell types or transfection of kidney organoid cells.

DOI: https://doi.org/10.1159/nef/adtag003
Zhonghua Bing Li Xue Za Zhi. 2026 Sep 08. 55(9): 831-838

[Birt-Hogg-Dubé syndrome-associated renal tumors: a clinicopathological and molecular genetic analysis of ten cases].

X Cheng, Y Zhan, Y J Wang, X Q Yang, H Z Zhang.

Objective: To investigate the clinicopathological features, immunophenotypic characteristics, molecular genetic profiles for an accurate diagnosis of renal tumors associated with Birt-Hogg-Dubé (BHD) syndrome. Methods: Clinicopathological data from 10 patients with BHD syndrome-associated renal tumors were collected from Ningbo Clinical Pathology Diagnosis Center (4 cases) and Ruijin Hospital, Shanghai Jiaotong University School of Medicine (5 in-house cases and 1 consultation case) from January 2015 to December 2025. Their clinical characteristics and histological features were studied and analyzed. Immunohistochemical staining and next-generation sequencing (NGS) were performed. Follow-up data were obtained and relevant literature was reviewed. Results: All 10 patients were adults, including 6 males and 4 females, with an age 57 (54, 67) years old. Seven patients had pulmonary bullae/pneumothorax and one patient had a right anterior chest wall fibroma. For the patients with renal tumor, 6 cases presented with a unilateral single tumor, 1 case with unilateral multiple tumors and 3 cases with bilateral multiple tumors (totaling 16 renal tumors). Four cases of the renal tumor were associated with multiple renal cysts. Histologically, among the 16 tumors, 10 were hybrid oncocytic/chromophobe tumors (HOCT) with the typical "mosaic" pattern, 4 with chromophobe renal cell carcinoma-like morphology, 1 with predominantly sarcomatoid morphology and focal areas of low-grade oncocytic renal tumor, and 1 renal angiomyolipoma. The immunophenotype of BHD-associated renal tumors was not specific. Immunohistochemistry revealed diffuse positive for GPNMB in all epithelial-derived renal tumors (15/15). CK7 and CD117 were focally expressed in 7/15 cases each, CD10 was focally expressed in 6/15 cases, and carbonic anhydrase Ⅸ (CAⅨ) was negative in all tumors (0/15). ALK, TFE3 and TFEB were negative. No loss of SDHB or FH expression was identified. DNA next-generation sequencing identified FLCN mutations in all cases, including 7 cases with germline FLCN mutations and 3 cases with somatic FLCN mutations. During a 9-120 months follow-up, the patient with sarcomatoid differentiation passed away 6 months after renal tumor identified, and another patient experienced relapse in the left kidney 6 years after bilateral nephron-sparing surgery. No relapse or metastasis was identified in the remaining 8 patients. Conclusions: Morphologically, BHD syndrome-associated renal tumors can mimic various low-grade oncocytic renal tumors. In addition to the classic HOCT morphology, they may also present with high-grade sarcomatoid differentiation. GPNMB is a highly sensitive marker for BHD-associated renal tumors. Molecular genetic analysis to detect FLCN mutation is the gold standard for definitive diagnosis. BHD syndrome-associated renal tumors typically show indolent biological behavior, with sarcomatoid differentiation as a morphological feature of poor prognosis.

DOI: https://doi.org/10.3760/cma.j.cn112151-20260203-00106
Respirol Case Rep. 2026 Sep;14(9): e70703

An Underrecognized Cause of Recurrent Spontaneous Pneumothorax: Birt-Hogg-Dubé Syndrome With Isolated Pulmonary Manifestation.

Chia-Ni Liu, Hsiao-Chin Shen, Yi-Chen Yeh.

  Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder characterized by a classic triad of cutaneous fibrofolliculomas, bilateral pulmonary cysts and renal tumours. Pulmonary manifestations may occur in isolation, posing a significant diagnostic challenge. We report a 50-year-old non-smoking woman with recurrent pneumothorax referred to our pulmonology clinic for dyspnoea on exertion. Chest CT revealed multiple bilateral pulmonary cysts with lower-lobe predominance. Review of prior wedge resection specimens showed subpleural and parenchymal cysts lined by flattened epithelium. Negative immunohistochemical staining for HMB-45 and GPNMB excluded lymphangioleiomyomatosis. Given the characteristic cyst pattern, germline whole-exome sequencing identified a pathogenic heterozygous FLCN frameshift variant, confirming the diagnosis. Because of the lifetime risk of renal malignancy, early recognition is important and genetic testing is recommended when BHD is suspected.

Keywords:  Birt‐Hogg‐Dubé syndrome; FLCN; folliculin; pneumothorax; pulmonary cysts

DOI:  https://doi.org/10.1002/rcr2.70703
Cytotechnology. 2026 Oct;78(5): 194

The applications of organoids in kidney diseases: progress and challenges.

Qianying Feng, Junzheng Yang.

  Kidney organoids are a type of three-dimensional cellular aggregates derived from primary tissues or stem cells cultured in vitro. Under specific induction conditions, these cell aggregates can differentiate into complex renal nephron structures, including glomeruli, proximal tubules, and distal tubules. These cells have been demonstrated to possess a remarkable capacity for self-renewal and self-organization, demonstrating a high degree of structural and functional similarity to the structure of kidney organs and the certain renal functions. Due to their ability to replicate the key renal structures and functions, they hold significant potential in various areas of kidney disease research, including novel drug development, disease modeling, personalized medicine, and therapeutic interventions for kidney diseases. In this review, we summarize the recent advancements in organoid culture technology and the applications of organoids in kidney diseases. The technical challenges and current limitations of organoid technology and possible solutions are also discussed. The aim of this review is to promote the development of organoid technology and to provide the theoretical knowledge for researchers in related fields.

Keywords:  Drug development; Kidney diseases; Organoids; Precision medicine; Regenerative medicine

DOI:  https://doi.org/10.1007/s10616-026-01064-x
Ren Fail. 2026 Dec;48(1): 2727298

Mitochondrial extracellular vesicles in cardiorenal syndrome: emerging mediators of mitochondrial signaling and inter-organ crosstalk.

Jian Hou, Xiaozhi Yang, Rui Zheng, Jianhao Li, Dayu Wang, Bo Hu, Xin Jin, Guangtao Xu.

  Cardiorenal syndrome (CRS) comprises five clinically distinct patterns of acute, chronic, or systemic heart-kidney interaction. Mitochondrial dysfunction is shared by cardiac and renal injury, but the cardiorenal setting is distinguished by the possibility that mitochondrial stress arising in one organ is externalized and transmitted to the other. Extracellular vesicles (EVs) are established mediators of intercellular communication, and EVs carrying mitochondrial DNA, proteins, lipids, RNA, or structurally preserved mitochondrial material-collectively referred to here as mitochondrial extracellular vesicles (mitoEVs)-may connect mitochondrial quality control with systemic signaling. Direct CRS-specific evidence, however, remains limited: patient-derived studies support pathogenic effects of total circulating EVs, whereas most mitoEV-specific mechanisms are inferred from related cardiovascular, renal, inflammatory, cancer, or regenerative models. Accordingly, this review presents an evidence-graded conceptual framework rather than a definitive mechanistic summary. We define and classify mitoEVs, outline methodological requirements for their isolation, same-particle identification, cargo-topology analysis, quantification, and functional validation, and map the available evidence across the five CRS subtypes. We further propose the mitoEV-mitophagy-inflammation axis as a working hypothesis in which impaired mitochondrial quality control may favor vesicular export, inflammatory activation in recipient cells, and secondary mitochondrial dysfunction. Finally, we evaluate the biomarker and therapeutic potential of mitoEVs while emphasizing the need for subtype-specific clinical validation, standardized analytical workflows, source-resolved studies, and rigorous distinction between pathological and reparative vesicle populations.

Keywords:  Cardiorenal syndrome; inter-organ communication; mitochondrial DNA; mitochondrial dysfunction; mitochondrial extracellular vesicles

DOI:  https://doi.org/10.1080/0886022X.2026.2727298