bims-raghud 2025-09-28 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–09–28
ten papers selected by
Irene Sambri, TIGEM

Coexistence of Renal Cell Carcinoma and Psoriasis in Tuberous Sclerosis Complex: A Shared mTOR Pathway Pathogenesis?
Cardiovascular Complications in ADPKD.
Late failure of Everolimus in a patient with tuberous sclerosis complex after 10 years of effective response: an illustrative case.
The Hippo Pathway in Kidney Development.
TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
Lysosomes signal through the epigenome to regulate longevity across generations.
Identification, functional insights and therapeutic targeting of EMT tumour states.
Clinical and genetic investigations of five Chinese families with Birt-Hogg-Dubé syndrome: a long-term follow-up study.
Apolipoprotein C3 Promotes Angiogenesis in an Inflammatory Mouse Model of Peripheral Artery Disease.
Isolation of functional lysosomes from skeletal muscle.

Clin Case Rep. 2025 Sep;13(9): e70938

Coexistence of Renal Cell Carcinoma and Psoriasis in Tuberous Sclerosis Complex: A Shared mTOR Pathway Pathogenesis?

Sunil Jaiswal, Shraddha Uprety, Mukesh Kumar Ranjan, Pratichya Thapa, Bigyan Paudel, Prakriti Lamichhane.

  Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder characterized by benign hamartomas in multiple organs. Although renal manifestations such as angiomyolipomas and cysts are common, the occurrence of renal cell carcinoma (RCC) in tuberous sclerosis is rare. Similarly, psoriasis, which is an immune-mediated inflammatory skin disease, is not commonly associated with tuberous sclerosis. We hereby present a 30 year old male patient, a known case of TSC, who presented with extensive plaque psoriasis and was diagnosed with RCC during evaluation. The coexistence of RCC and psoriasis in a patient with tuberous sclerosis might be due to shared mTOR signaling pathway activation, which our study emphasizes.

Keywords:  mTOR pathway; psoriasis; renal cell carcinoma; tuberous sclerosis complex

DOI:  https://doi.org/10.1002/ccr3.70938
Kidney Int Rep. 2025 Sep;10(9): 2953-2966

Cardiovascular Complications in ADPKD.

Niloufar Ebrahimi, Yasar Caliskan, Pranav S Garimella, Sol Carriazo, Fouad T Chebib, Giv Heidari Bateni, Neera K Dahl, Anjay Rastogi, Amir Abdipour, Sayna Norouzi.

  Autosomal dominant polycystic kidney disease (ADPKD), primarily caused by mutations in the PKD1 or PKD2 gene, is among the most common hereditary kidney diseases worldwide and is associated with significant extrarenal manifestations, including cardiovascular disease. In patients with ADPKD, cardiovascular disease is the major cause of mortality and is associated with a high burden of comorbidities. Cardiovascular manifestations include hypertension, which may lead to left ventricular hypertrophy (LVH) and diastolic dysfunction, as well as valvular abnormalities, aortic aneurysm, and pericardial effusion (PCE). The cardiovascular manifestations can present early as part of the ADPKD manifestation or later because of chronic kidney disease (CKD) progression. Early detection of cardiovascular manifestations can play a pivotal role in better management of these patients. Hypertension in ADPKD might start at an early age and is driven by a complex interplay of polycystin (PC) dysfunction, intracellular signaling disruptions, and activation of the renin-angiotensin-aldosterone system (RAAS), which can contribute to vascular structural changes and impaired endothelial function. Valvular involvement exhibits a bimodal pattern of age distribution, with early manifestations occurring in younger patients likely linked to genetic factors and later complications emerging as part of CKD progression. This review explores cardiovascular complications in ADPKD, emphasizing the need for early detection, and briefly provides an overview of tailored management approaches to improve outcomes in this high-risk population.

Keywords:  autosomal dominant polycystic kidney disease; cardiovascular complications; hypertension; left ventricular hypertrophy; valvular abnormalities

DOI:  https://doi.org/10.1016/j.ekir.2025.06.054
Childs Nerv Syst. 2025 Sep 25. 41(1): 294

Late failure of Everolimus in a patient with tuberous sclerosis complex after 10 years of effective response: an illustrative case.

Carla Richetta, Shlomi Constantini, Rina Dvir, Jonathan Roth.

   INTRODUCTION AND PURPOSE: Late treatment failure following an initially effective response to targeted therapy may occur. Everolimus, a targeted drug that serves as an mTOR (rapamycin) inhibitor, has been extensively studied for its efficacy and safety in treating subependymal giant cell astrocytomas (SEGA) in pediatric patients with tuberous sclerosis complex (TSC). Clinical studies have demonstrated that Everolimus leads to a sustained reduction in SEGA volume. However, TSC patients may need to continue long term or even lifelong treatment to avoid the risk of progression following termination of treatment. The case report provided here demonstrates that late failure can occur even while in treatment.
CASE REPORT: We hereby describe a 16-year-old female diagnosed with TSC and bilateral large intraventricular SEGA, who displayed sustained tumor volume reduction on Everolimus treatment for 10 years. Despite proper adjustment of dosage, confirmed by blood levels, the lesions eventually grew. This bilateral tumor growth subsequently led to symptomatic hydrocephalus. Therefore, at this point, the Everolimus treatment was stopped, and the girl was operated upon. Following subtotal surgical resection, a decision was made to simply follow the residual tumor remnant. When, after a few months, the tumor remnant was found to be slowly growing, the patient was re-started on Everolimus, which proved again to be effective in stabilizing the lesion growth.
DISCUSSION: Everolimus is a well-known treatment for patients affected by TSC-related SEGA. Maintenance therapy can be continued safely for prolonged periods with continuous tumor volume stability. Nonetheless, late failure of treatment may still occur and require surgery. Potential mechanisms of such late reduction in effectiveness are discussed.

Keywords:  Everolimus; Late failure; SEGA; TSC

DOI:  https://doi.org/10.1007/s00381-025-06959-2
Encyclopedia (Basel, 2021). 2025 Mar;pii: 15. [Epub ahead of print]5(1):

The Hippo Pathway in Kidney Development.

Caroline M Lara, Toni Castro Torres, Usaid Mazhar, Dorrian G Cohen, Rebecca A Wingert.

  The kidney, a complex organ crucial for a multitude of homeostatic functions, including the maintenance of fluid and electrolyte balance, removal of various metabolic waste products, and hormone production, undergoes intricate developmental processes to form functional nephron units. Understanding the mechanisms behind kidney development is paramount for elucidating the etiology of renal congenital disabilities and acquired diseases. The Hippo pathway is known for its involvement in various cellular functions, including cell fate determination and differentiation, and is a critical player in renal organogenesis. Here, we discuss research findings about the roles that Hippo signaling plays in kidney formation.

Keywords:  Hippo pathway; TAZ; YAP; kidney development; nephron

DOI:  https://doi.org/10.3390/encyclopedia5010015
bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]

TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.

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

Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.

DOI: https://doi.org/10.1101/2025.09.11.675705
Science. 2025 Sep 25. 389(6767): 1353-1360

Lysosomes signal through the epigenome to regulate longevity across generations.

Qinghao Zhang, Weiwei Dang, Meng C Wang.

The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. Activation of lysosomal lipid signaling and lysosomal adenosine monophosphate-activated protein kinase (AMPK) or reduction of lysosomal mechanistic target of rapamycin (mTOR) signaling increased the expression of a histone H3.3 variant and increased its methylation on K79, leading to life-span extension across multiple generations. This transgenerational prolongevity effect required intestine-to-germline transportation of histone H3.3 and a germline-specific H3K79 methyltransferase and was recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. Thus, signals from a lysosome affect the epigenome and link the soma and germ line to mediate transgenerational inheritance of longevity.

DOI: https://doi.org/10.1126/science.adn8754
Nat Rev Cancer. 2025 Sep 25.

Identification, functional insights and therapeutic targeting of EMT tumour states.

Anqi Dong, Cédric Blanpain.

Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed.

DOI: https://doi.org/10.1038/s41568-025-00873-0
Front Med (Lausanne). 2025 ;12 1613154

Clinical and genetic investigations of five Chinese families with Birt-Hogg-Dubé syndrome: a long-term follow-up study.

Xi Kang, Ting Guo, Ali Basit, Lv Liu, Hong Luo.

  Birt-Hogg-Dubé syndrome (BHDS), an autosomal dominant disease, is caused by germline mutations in the folliculin (FLCN, NM_144997) gene. This rare disorder is characterized by a clinical triad, which includes fibrofolliculomas (FFs), renal cell carcinoma (RCC), and pulmonary manifestations such as multiple pulmonary cysts (PCs) and pneumothorax. To investigate the clinical features and genetic mutations of five unrelated BHDS families in a long-term follow-up study at the Second Xiangya Hospital of Central South University, five families and their affected patients, who met the clinical and histological criteria for BHDS and were confirmed to have FLCN germline mutations, were evaluated. All participants underwent a comprehensive physical examination along with other relevant tests. Three novel mutations (c.246C > A, c.625_626insAGGCAGAGCAGTTTGGAT, and c.1542_1542delA) and one previously reported mutation (c.1429C > T) in the FLCN gene were identified. These mutations are predicted to cause truncation of the folliculin protein, likely resulting in decreased folliculin expression. Our study expands the genetic landscape associated with BHDS and provides valuable insights for future genetic counseling and the clinical management of individuals with BHDS.

Keywords:  Birt–Hogg–Dubé syndrome; fibrofolliculomas; pneumothorax; pulmonary cysts; renal cell carcinoma

DOI:  https://doi.org/10.3389/fmed.2025.1613154
FASEB J. 2025 Sep 30. 39(18): e71058

Apolipoprotein C3 Promotes Angiogenesis in an Inflammatory Mouse Model of Peripheral Artery Disease.

Jordyn M Thomas, Panashe Bamhare, Jocelyne Mulangala, Christina A Bursill, Stephen J Nicholls, Belinda A Di Bartolo, Kristen J Bubb.

  Apolipoprotein C3 (ApoC3) regulates triglyceride metabolism and is associated with accelerated atherogenesis and adverse cardiovascular outcomes. However, its role in peripheral artery disease (PAD) remains unclear. We investigated whether Apoc3 deficiency impacts key features of PAD. Vascularization was assessed using an inflammatory periarterial cuff model (21 days) and a hind limb ischemia model (14 days) in male and female Apoc3+/+ and Apoc3-/- mice. Neovascularization was also assessed in mice following extracellular matrix (ECM) plug implantation. Isolated human umbilical vein endothelial cells (HUVECs) were co-cultured with ApoC3-stimulated THP-1 monocytes, and tubule formation was assessed. Apoc3-deficient mice demonstrated less neovessel formation around the cuffed femoral artery, with endothelial cell (CD31+) staining reduced by approximately 40% compared to Apoc3+/+ mice. Twenty-four hours after cuff placement, Apoc3+/+ vessels exhibited increased expression of angiogenic (Hif1a and Vegf1) and pro-inflammatory (Cd68) markers, while Apoc3-deficient vessels did not. Confirming a role for inflammation in ApoC3-induced angiogenesis, tubulogenesis of HUVECs increased only in the presence of ApoC3 and THP-1 monocytes. Apoc3 deficiency, however, did not affect ischemia-driven angiogenesis, as there were no differences in revascularization compared to Apoc3+/+ mice, as assessed by the perfusion index (laser Doppler), fibrosis (Picrosirius red staining), or the mRNA expression of apoptotic (Bax), angiogenic (Hif1a and Vegf1), and inflammatory (Ccl2, Il6, and Vcam1) markers in the ischemic hind limb. Neovascularization following ECM plug implantation was also unaffected by Apoc3 deficiency. In conclusion, ApoC3 contributes to pathological, inflammation-driven angiogenesis, highlighting its potential as a therapeutic target for pathological angiogenesis without inhibiting physiological ischemia-driven angiogenesis.

Keywords:  apolipoprotein C‐III; endothelial cells; hypoxia‐inducible factor 1 alpha subunit (HIF‐1α); inflammation; macrophages; pathological angiogenesis; peripheral arterial disease; physiologic neovascularization; triglycerides; vascular endothelial growth factor A (VEGFA)

DOI:  https://doi.org/10.1096/fj.202502155R
Am J Physiol Cell Physiol. 2025 Sep 22.

Isolation of functional lysosomes from skeletal muscle.

Thulasi Mahendran, Anastasiya Kuznyetsova, Neushaw Moradi, David A Hood.

  Lysosomes are membrane-bound organelles responsible for the degradation of damaged or dysfunctional cellular components, including mitochondria. Their acidic internal environment and the presence of an array of hydrolytic enzymes facilitate the efficient breakdown of macromolecules such as proteins, lipids, and nucleic acids. Mitochondria play a critical role in maintaining skeletal muscle homeostasis to meet the energy demands under physiological and pathological conditions. Mitochondrial quality control within skeletal muscle during processes such as exercise, disuse, and injury is regulated by mitophagy, where dysfunctional mitochondria are targeted for lysosomal degradation. The limited understanding of quality control mechanisms in skeletal muscle necessitates the need for isolating intact lysosomes to assess organelle integrity and the degradative functions of hydrolytic enzymes. Although several methods exist for lysosome isolation, the complex structure of skeletal muscle makes it challenging to obtain relatively pure and functional lysosomes due to the high abundance of contractile proteins. Here we describe a method to isolate functional lysosomes from small amounts of mouse skeletal muscle tissue, preserving membrane integrity. We also describe functional assays that allow direct evaluation of lysosomal enzymatic activity and we provide data indicating reduced lysosomal degradative activity in lysosomes from aging muscle. We hope that this protocol provides a valuable tool to advance our understanding of lysosomal biology in skeletal muscle, supporting investigations into lysosome-related dysfunction in aging, disease, and exercise adaptations.

Keywords:  differential centrifugation; lysosomal enzymes; mitochondria; mitophagy; proteolysis

DOI:  https://doi.org/10.1152/ajpcell.00471.2025