bims-raghud 2025-03-23 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–03–23
eleven papers selected by
Irene Sambri, TIGEM

Investigation of dynamic regulation of TFEB nuclear shuttling by microfluidics and quantitative modelling.
mTORC1 activation drives astrocyte reactivity in cortical tubers and brain organoid models of TSC.
Targeting autophagy in autoimmune glomerular diseases.
Molecular mechanism on autophagy associated cardiovascular dysfunction in Drosophila melanogaster.
Pharmacological regulators of Hippo pathway: Advances and challenges of drug development.
A Case of Multiple Myeloma in a Patient with Birt-Hogg-Dube Syndrome.
Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
Nephron progenitor fate is modulated by angiotensin type 1 receptor signaling in human kidney organoids.
Sex-specific cardiac dysfunction in mice with chronic kidney disease.
Wnt/β-catenin pathway induces cardiac dysfunction via AKAP6-mediated RyR2 phosphorylation and sarcoplasmic reticulum calcium leakage.
TFE3 and HIF1α regulates the expression of SHMT2 isoforms via alternative promoter utilization in ovarian cancer cells.

Commun Biol. 2025 Mar 15. 8(1): 443

Investigation of dynamic regulation of TFEB nuclear shuttling by microfluidics and quantitative modelling.

Iacopo Ruolo, Sara Napolitano, Lorena Postiglione, Gennaro Napolitano, Andrea Ballabio, Diego di Bernardo.

Transcription Factor EB (TFEB) controls lysosomal biogenesis and autophagy in response to nutritional status and other stress factors. Although its regulation by nuclear translocation is known to involve a complex network of well-studied regulatory processes, the precise contribution of each of these mechanisms is unclear. Using microfluidics technology and real-time imaging coupled with mathematical modelling, we explored the dynamic regulation of TFEB under different conditions. We found that TFEB nuclear translocation upon nutrient deprivation happens in two phases: a fast one characterised by a transient boost in TFEB dephosphorylation dependent on transient calcium release mediated by mucolipin 1 (MCOLN1) followed by activation of the Calcineurin phosphatase, and a slower one driven by inhibition of mTORC1-dependent phosphorylation of TFEB. Upon refeeding, TFEB cytoplasmic relocalisation kinetics are determined by Exportin 1 (XPO1). Collectively, our results show how different mechanisms interact to regulate TFEB activation and the power of microfluidics and quantitative modelling to elucidate complex biological mechanisms.

DOI: https://doi.org/10.1038/s42003-025-07870-x
bioRxiv. 2025 Mar 05. pii: 2025.02.28.640914. [Epub ahead of print]

mTORC1 activation drives astrocyte reactivity in cortical tubers and brain organoid models of TSC.

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 associated with early onset epilepsy, intellectual disability and neuropsychiatric disorders. A hallmark of the disorder is cortical tubers, which are focal malformations of brain development that contain dysplastic cells with hyperactive mTORC1 signaling. One barrier to developing therapeutic approaches and understanding the origins of tuber cells is the lack of a model system that recapitulates this pathology. To address this, we established a genetically mosaic cortical organoid system that models a somatic "second-hit" mutation, which is thought to drive the formation of tubers in TSC. With this model, we find that loss of TSC2 cell-autonomously promotes the differentiation of astrocytes, which exhibit features of a disease-associated reactive state. TSC -/- astrocytes have pronounced changes in morphology and upregulation of proteins that are risk factors for neurodegenerative diseases, such as clusterin and APOE. Using multiplexed immunofluorescence in primary tubers from TSC patients, we show that tuber cells with hyperactive mTORC1 activity also express reactive astrocyte proteins, and we identify a unique population of cells with expression profiles that match the those observed in organoids. Together, this work reveals that reactive astrogliosis is a primary feature of TSC that arises early in cortical development. Dysfunctional glia are therefore poised to be drivers of pathophysiology, nominating a potential therapeutic target for treating TSC and related mTORopathies.

DOI: https://doi.org/10.1101/2025.02.28.640914
J Nephrol. 2025 Mar 19.

Targeting autophagy in autoimmune glomerular diseases.

Ponticelli Claudio, Moroni Gabriella.

  Autophagy is a natural process whereby damaged or dying parts of a cell are eliminated and recycled. The term autophagy usually refers to macroautophagy, which is one of three types of autophagy, alongside microautophagy and chaperone-mediated autophagy. Autophagy is activated by adenosine monophosphate-activated protein kinase (AMPK) and inhibited by mammalian target of rapamycin (mTOR) through their interference with Unc-51-like kinase 1 (ULK1). Dysregulated autophagy is deeply involved in autoimmune glomerular diseases. Upregulated autophagy can induce inflammation and activate innate and adaptive immunity. However, autophagy may also exert a protective role on podocytes, enhance endothelial cell function, and preserve proximal tubular epithelial cells during ischemic or endotoxic acute kidney injury (AKI). Hydroxychloroquine (HCQ) can downregulate increased autophagy and is widely used in lupus nephritis. HCQ causes alkalinization, which results in vacuolization of lysosomes and inhibition of their functions. By inhibiting autophagic activity, HCQ may reduce inflammation and innate immunity, inhibit the activation of T cells, restore the T helper 17/T regulator balance, restrict the production of pro-inflammatory cytokines, and modulate co-stimulatory molecules. This reduces the risk of flares, spares the dosage of glucocorticoids, improves lupus activity, and prevents the thrombotic effects of anti-phospholipid antibodies. Recent studies showed that HCQ can also reduce proteinuria in IgA nephropathy (IgAN) and membranous nephropathy (MN). Drugs that improve mitochondrial function or enhance autophagy, such as metformin, sodium-glucose co-transporter 2 (SGLT2) inhibitors or mTOR inhibitors, may exert protective effects on podocytes and reduce proteinuria in MN or focal segmental glomerulosclerosis (FSGS).

Keywords:  Autophagy; Glomerulonephritis; Hydroxychloroquine; Lupus nephritis; Podocyte

DOI:  https://doi.org/10.1007/s40620-025-02267-9
Front Cell Dev Biol. 2025 ;13 1512341

Molecular mechanism on autophagy associated cardiovascular dysfunction in Drosophila melanogaster.

Wei Zhang, Rong Zhou, Xinjuan Lei, Mofei Wang, Qinchun Duan, Yuanlin Miao, Tingting Zhang, Xinjie Li, Zhang Zutong, Liyang Wang, Odell D Jones, Mengmeng Xu, Joseph Bryant, Jianjie Ma, Yingli Liu, Xuehong Xu.

  As a highly conserved cellular process, autophagy has been the focus of extensive research due to its critical role in maintaining cellular homeostasis and its implications in cardiovascular pathogenesis. The decline in muscular function, along with the neuronal system, and increased sensitivity to stress have been recognized in multiple animal models. Autophagic defects in cardiovascular architecture and cellular dysfunction have been linked to both physiological and pathological conditions of the heart in mammals and Drosophila. In this review, we systematically analyze the autophagy-associated pathways in the hearts of fruit flies and aim to provide a comprehensive understanding for developing potential treatments for patients and effective strategies for agricultural applications. This analysis elucidates the molecular mechanisms of autophagy in cardiovascular function under both physiological and pathological conditions in Drosophila, offering significant insights into the development of cardiovascular diseases. The loss of key autophagy-associated proteins, including the transmembrane protein Atg9 and its partners Atg2 or Atg18, along with DmSestrin, leads to cardiac hypertrophy and structural abnormalities in Drosophila, resembling the age-dependent deterioration of cardiac function. Members of the autophagy-related (Atg) gene family, cellular or nuclear skeletal lamins, and the mechanistic or mammalian target of rapamycin (mTOR) signaling pathways are critically influential in heart function in Drosophila, with autophagy activation shown to suppress cardiac laminopathy. The mTORC1/C2 complexes, along with axis of Atg2-AMPK/Sirt1/PGC-1α pathway, are essential in the hearts of both mammals and fruit flies, governing cardiac development, growth, maturation, and the maintenance of cardiac homeostasis. The beneficial effects of several interventions that enhance cardiac function, including exercise and cold stress, can influence autophagy-dependent TOR activity of the serine/threonine protein kinase signaling in both mammals and Drosophila. Exercise has been shown to increase autophagy when it is deficient and to inhibit it when it is excessive, highlighting the dual role of autophagy in cardiac health. This review evaluates the functional significance of autophagy in the heart, particularly in the context of Drosophila, in relation to mTORC-associated autophagy and the axis of Atg2-AMPK/Sirt1/PGC-1α pathways. It systematically contrasts the molecular mechanisms underlying autophagy-related cardiovascular physiological and pathological conditions in both fruit flies and mammals. The evolutionary conservation of autophagy underscores the value of Drosophila as a model for understanding broader mechanisms of autophagy across species. This study not only deepens our understanding of autophagy's role in cardiovascular function but also provides a theoretical foundation for the potential application of autophagy in agricultural pest control.

Keywords:  Autophagy; Cardiovascular dysfunction; Drosophila melanogaster; cardiac laminopathy; interference; mTOR pathway

DOI:  https://doi.org/10.3389/fcell.2025.1512341
FASEB J. 2025 Mar 31. 39(6): e70438

Pharmacological regulators of Hippo pathway: Advances and challenges of drug development.

Zhaobai Lao, Xin Chen, Bin Pan, Bin Fang, Wanlei Yang, Yu Qian.

  The Hippo signaling pathway is crucial in regulating organ size, tumor progression, tissue regeneration, and bone homeostasis. Inactivation of the Hippo pathway results in the nuclear translocation and activation of YAP/TAZ. This activation not only promotes tumor progression but also enhances tissue regeneration, wound healing, and maintenance of bone stability Although its discovery occurred over two decades ago, developing effective inhibitors or activators for the Hippo pathway remains challenging. Recently, however, the pace of advancements in developing Hippo signaling-related agonists and antagonists has accelerated, with some drugs that target TEAD advancing to clinical trials and showing promise for treating related diseases. This review summarizes the progress in research on Hippo signaling-related agonists and inhibitors, offering an in-depth analysis of their regulatory mechanisms, pharmacological properties, and potential in vivo applications.

Keywords:  Hippo pathway; LATS1/2; MST1/2; TEADs; YAP/TAZ; agonist; inhibitor

DOI:  https://doi.org/10.1096/fj.202401895RR
Intern Med. 2025 Mar 15.

A Case of Multiple Myeloma in a Patient with Birt-Hogg-Dube Syndrome.

Fumiaki Matsumura, Tatsuhiro Sakamoto, Hirayasu Kai, Toshiaki Usui, Kunio Kawanishi, Ryota Matsuoka, Kantaro Ishitsuka, Kenichi Makishima, Sakurako Suma, Yumiko Maruyama, Takayasu Kato, Naoki Kurita, Keiichiro Hattori, Yasuhito Suehara, Hidekazu Nishikii, Naoshi Obara, Joichi Usui, Daisuke Matsubara, Kunihiro Yamagata, Mamiko Sakata-Yanagimoto.

  Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant disease caused by germline folliculin (FLCN) mutations and it is characterized by skin folliculomas, pulmonary cysts, and renal cell carcinomas (RCC). We herein report the first case of a female patient with BHDS who was diagnosed with multiple myeloma. Daratumumab-based treatment was effective, and the patient remained responsive for over three years. Whole-exome sequencing confirmed an FLCN germline mutation and nine somatic mutations, including an MPDZ mutation, which is a component of the tumor-suppressive Hippo-YAP pathway. Considering the reported association between the Hippo-YAP pathway and RCC with BHDS, an MPDZ mutation may contribute to carcinogenesis in patients with BHDS.

Keywords:  Birt-Hogg-Dube syndrome; daratumumab; folliculin; hippo-YAP pathway; multiple myeloma

DOI:  https://doi.org/10.2169/internalmedicine.4985-24
Nat Rev Cardiol. 2025 Mar 20.

Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.

Rishith Ravindran, Åsa B Gustafsson.

Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.

DOI: https://doi.org/10.1038/s41569-025-01142-1
Stem Cells. 2025 Mar 20. pii: sxaf012. [Epub ahead of print]

Nephron progenitor fate is modulated by angiotensin type 1 receptor signaling in human kidney organoids.

Hyunjae Chung, Waleed Rahmani, Sarthak Sinha, Aysa Imanzadeh, Alexander Pun, Rohit Arora, Arzina Jaffer, Jeff Biernaskie, Justin Chun.

  The renin-angiotensin system (RAS) is essential for normal kidney development. Dysregulation of the RAS during embryogenesis can result in kidney abnormalities. To explore how angiotensin type 1 receptor (AT1R) signaling modulates nephron progenitor (NP) fate specification, we used induced pluripotent stem cell (iPSC) derived human kidney organoids treated with angiotensin II (Ang II) or the AT1R blocker losartan during differentiation. Ang II promoted NP proliferation and differentiation preferentially towards a podocyte fate, depleted the podocyte precursor population and accelerated glomerular maturation. By contrast, losartan expanded the podocyte precursor population, delayed podocyte differentiation and regressed the transcriptional signature to more immature fetal state. Overall, using various in silico approaches with validation by RNAscope, we identified a role for AT1R signaling in regulating NP fate during nephrogenesis in kidney organoids. Our work supports the use of RAS modulators to improve organoid maturation and suggests that RAS may be a determinant of nephron endowment in vivo.

Keywords:  angiotensin II; kidney organoids; losartan; nephrogenesis; single cell RNA sequencing

DOI:  https://doi.org/10.1093/stmcls/sxaf012
Nephrol Dial Transplant. 2025 Mar 21. pii: gfaf056. [Epub ahead of print]

Sex-specific cardiac dysfunction in mice with chronic kidney disease.

Yitong Zhao, Karen Yang, Christy M Nguyen, Hongmei Wu, Han Liu, Leandro M Velez, Jin Kyung Kim, Marcus Seldin, Wei Ling Lau.

   BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death among patients with chronic kidney disease (CKD). Rodent models are widely used to study uremic CVD pathophysiology. We compared cardiac function parameters in male and female animals from 2 established mouse CKD models and examined associations between gut-derived uremic toxins and echocardiogram findings.
METHODS: Male and female adult C57Bl/6J mice were randomly assigned to control, adenine-induced CKD and 5/6 nephrectomy CKD groups. Echocardiography was performed on all mice at age 17 weeks (5 weeks after CKD induction). Serum creatinine, cystatin C and gut-derived uremic toxins were analyzed at study termination, and RNA sequencing of left ventricle tissue was performed and analyzed.
RESULTS: Markers of kidney dysfunction were elevated in both CKD models. The gut-derived uremic toxin indoxyl sulfate was increased in both CKD models, while trimethylamine N-oxide was increased in adenine CKD mice and p-cresyl sulfate in nephrectomy animals. Left ventricular volume was increased in nephrectomy animals. Cardiac output was decreased in male CKD animals from both models compared to controls, and ejection fraction was decreased in male 5/6 nephrectomy mice. Female controls had lower stroke volume and cardiac output than male counterparts, and female CKD animals had preserved cardiac output and ejection fraction when compared to female controls. The gut-derived uremic toxins trimethylamine N-oxide and indoxyl sulfate correlated with decreased cardiac output in male animals. Transcriptomics of cardiac tissue revealed sex-based variations in matrix metalloproteinase and mitochondrial pathways associated with cardiac dysfunction.
CONCLUSIONS: Our work highlights sex differences in cardiac function and serum chemistries in two established preclinical CKD models. Gut-derived uremic toxins may impact cardiorenal pathophysiology and low cardiac output in male CKD animals.

Keywords:  adenine; cardiac function; chronic kidney disease; echocardiogram; mouse models; nephrectomy

DOI:  https://doi.org/10.1093/ndt/gfaf056
J Mol Cell Biol. 2025 Mar 17. pii: mjaf002. [Epub ahead of print]

Wnt/β-catenin pathway induces cardiac dysfunction via AKAP6-mediated RyR2 phosphorylation and sarcoplasmic reticulum calcium leakage.

Ang Li, Yuanyuan Shen, Zhenyan Li, Lin Li.

  The Wnt signaling pathway plays important roles in cardiomyocyte proliferation and cardiac regeneration after heart injury. Abnormal activation of the Wnt pathway causes a reduction of cardiomyocyte function, leading to hypertrophy, fibrosis, and heart failure. However, the mechanism through which Wnt signaling affects cardiomyocyte function during cardiac diseases is still unclear. In this study, we observed that activation of the Wnt/β-catenin pathway, but not the Wnt/Ca2+ pathway, leads to significant cytosol calcium enrichment. Such an effect can be inhibited by cycloheximide that blocks the downstream gene expression. By analyzing the transcriptome data, we found that activation of the Wnt/β-catenin pathway significantly upregulates the expression level of muscle-selective A kinase anchoring protein (mAKAP, also called AKAP6), a scaffold protein that can improve the interaction between PKA and its substrate ryanodine receptor 2 (RyR2) in cardiomyocytes. We further identified that AKAP6 is a target gene of the canonical Wnt pathway and increasing AKAP6 expression can enhance RyR2 phosphorylation by PKA, causing the sarcoplasmic reticulum calcium leakage and finally heart dysfunction. Our finding that the Wnt/β-catenin pathway affects cardiac calcium regulation via AKAP6 and RyR2 provides profound insights into heart diseases and sheds light on potential therapeutic strategies.

Keywords:  AKAP6; RyR2; canonical Wnt pathway; cardiac calcium homeostasis

DOI:  https://doi.org/10.1093/jmcb/mjaf002
Cell Death Dis. 2025 Mar 17. 16(1): 178

TFE3 and HIF1α regulates the expression of SHMT2 isoforms via alternative promoter utilization in ovarian cancer cells.

Si-Qi Wang, Ning Liu, Qi Zhang, Bai-Qiang Li, Fu-Ying Zhao, Chao Li, Hua-Qin Wang, Chuan Liu.

Ovarian cancer ranks first lethally among gynecological malignancies. Platinum-based chemotherapy constitutes the first-line therapeutic regime. However, primary or acquired resistance seriously affects the survival rate of patients with ovarian cancer. Serine hydroxy methyltransferase (SHMT) catalyzes conversion of serine to glycine and is responsible for production of S-adenosylmethionine (SAM) for methylation. There are cytosolic SHMT1 and mitochondrial SHMT2 in human. Alternative promoter usage is a proteome-expanding mechanism that allows multiple pre-mRNAs to be transcribed from a single gene. The current study demonstrated that cisplatin-sensitive and cisplatin-resistant ovarian cancer cells expressed discrete SHMT2 isoforms, which was ascribed to the selective utilization of SHMT2 alternative promoters. SHMT2 isoforms exerted somewhat paradoxical roles in ovarian cancer cells, with tumor-suppressive role of isoform 1, and tumor-promotive role of isoform 3. In addition, the current study demonstrated that SHMT2 alternative promoter usage mediated by HIF1α and TFE3 might represent adaptive response of ovarian cancer cells to metabolic stress. Collectively, regulation of SHMT2 isoform expression via alternative promoter usage by transcription factors HIF1α and TFE3 provides a novel basis and potential drug targets for the clinical treatment of platin-resistant ovarian cancer.

DOI: https://doi.org/10.1038/s41419-025-07445-y