bims-lypmec 2025-09-21 papers

Adv Sci (Weinh). 2025 Sep 17. e13241

Gal3-CaN-Smurf1 Complex Sequestrates FLCN-FNIPs to Facilitate TFEB Activation in Response to Endomembrane Damage.

Qin Xia, Ziwan Liu, Gaoqing Feng, Wanting Xu, HuaHua Wang, Haihang Su, Jiaqian Li, Dan Liu, Jun Qu, Tonghui Yu, Lei Dong.

Smurf1 mediates lysosomal biogenesis upon endomembrane damage by interacting with lysosomal injury sensor Gal3 and phosphatase CaN to form Gal3-CaN-Smurf1 complex, which is critical for TFEB dephosphorylation. However, whether Smurf1 plays a role in the inhibition of mTOR-mediated TFEB phosphorylation is still unclear. TFEB phosphorylation by mTORC1 is strictly dependent on RagC/D GTPase activating protein FLCN. Here, we found that Smurf1 promotes the dissociation of RagC from TFEB upon lysosomal damage, selectively impairing TFEB phosphorylation. These findings suggest that the lysosomal damage-induced Gal3-CaN-Smurf1 complex sequesters FLCN-FNIPs to facilitate TFEB activation. This disruption of FLCN GAP function toward RagC/D impairs TFEB's lysosomal localization and phosphorylation. Notably, FLCNK462R and/or FNIP2K466R mutations reduce their binding affinity with the Gal3-CaN-Smurf1 complex, suggesting Smurf1-mediated poly-ubiquitylation of FLCNK462 and FNIP2K466 plays a role for pentamer formation. Indeed, sequestration of FLCN-FNIPs stabilizes the Gal3-CaN-Smurf1 complex, wherein Smurf1 directly binds and ubiquitinates TFEB. This facilitates TFEB's dephosphorylation and activation. These findings indicate that Gal3-CaN-Smurf1 complex interconnects with the FLCN-FNIPs to orchestrate TFEB localization and activity in response to lysosomal damage stress. Understanding Smurf1's regulation in the mTOR-TFEB axis, which balances tumor growth and stress-induced cell homeostasis, may provide novel therapeutic targets for tumor progression and drug resistance.

Keywords: FLCN‐FNIPs; Gal3‐CaN‐Smurf1 complex; TFEB; endomembrane damage; lysosomal stress; ubiquitylation

DOI: https://doi.org/10.1002/advs.202413241

Nature. 2025 Sep 17.

Structural basis for mTORC1 activation on the lysosomal membrane.

Zhicheng Cui, Alessandra Esposito, Gennaro Napolitano, Andrea Ballabio, James H Hurley.

The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy1,2. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB)3. Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change4. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Cryo-electron microscopy showed that RAPTOR and mTOR interact directly with the membrane. Full engagement of the membrane anchors is required for optimal alignment of the catalytic residues in the mTOR kinase active site. Converging signals from GFs and nutrients drive mTORC1 recruitment to and activation on lysosomal membrane in a four-step process, consisting of (1) RAG-Ragulator-driven recruitment to within ~100 Å of the lysosomal membrane; (2) RHEB-driven recruitment to within ~40 Å; (3) RAPTOR-membrane engagement and intermediate enzyme activation; and (4) mTOR-membrane engagement and full enzyme activation. RHEB and membrane engagement combined leads to full catalytic activation and structurally explains GF and nutrient signal integration at the lysosome.

DOI: https://doi.org/10.1038/s41586-025-09545-3

Am J Physiol Heart Circ Physiol. 2025 Sep 15.

Metabolic Modulation of Pyruvate Dehydrogenase and Glucose Oxidationin Diabetic Cardiomyopathy: Pathways, Perspectives, and Potentials.

Jordan S F Chan, Linyue Dong, John R Ussher.

Individuals living with obesity and/or type 2 diabetes (T2D) are at a disproportionately high risk of developing cardiovascular disease. This includes diabetic cardiomyopathy (DbCM), a condition characterized by left ventricular diastolic dysfunction that is often present in individuals with pre- or early-stage T2D. Although there are numerous mediators that contribute to the development of DbCM, perturbations in cardiac substrate metabolism are widely believed to play a major role in its pathogenesis. In particular, myocardial glucose oxidation is often suppressed due to decreased activity of the pyruvate dehydrogenase (PDH) complex, the rate-limiting enzyme of glucose oxidation, which is responsible for decarboxylating pyruvate to acetyl CoA, thus acting as the link between glycolysis and oxidative phosphorylation of glucose. Importantly, numerous preclinical studies suggest that restoring suppressed myocardial glucose oxidation can alleviate DbCM. In this review we will describe the major perturbations that characterize myocardial substrate metabolism is T2D, while discussing the primary pharmacological approaches that have been pursued to stimulate myocardial PDH activity and glucose oxidation. We will also highlight potential mechanisms explaining how increasing myocardial PDH activity and glucose oxidation favorably influence diastolic function. Given the increasing prevalence of DbCM in the human population, it is not only imperative to better understand its pathophysiology but to also develop novel therapies for its management, which may also have utility in the management of heart failure with preserved ejection fraction.

Keywords: diabetic cardiomyopathy; glucose oxidation; pyruvate dehydrogenase; substrate metabolism; type 2 diabetes

DOI: https://doi.org/10.1152/ajpheart.00063.2025

Nat Metab. 2025 Sep 16.

BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.

Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria-lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells.

DOI: https://doi.org/10.1038/s42255-025-01352-4

Circulation. 2025 Sep 16. 152(11): 802-835

Intensity, Duration, and Context Dependency of the Responses to Nutrient Surplus and Deprivation Signaling in the Heart: Insights Into the Complexities of Cardioprotection.

Milton Packer.

Nutrient surplus sensing through PI3K (phosphoinositide-3-kinase) and mTOR (mechanistic target of rapamycin) stimulates anabolism to expand cellular mass, whereas nutrient and energy deprivation sensing through SIRT1 (sirtuin-1) and AMPK (adenosine monophosphate-activated protein kinase) promotes catabolism to support cytoprotective quiescence. By signaling through downstream effectors (PGC-1α [peroxisome proliferator-activated receptor gamma coactivator 1-alpha], PPARα/PPARγ, FoxO1 [forkhead box protein family O1], NRF2 [nuclear factor erythroid-derived factor 2], HIF-1α [hypoxia-inducible factor-1α], and HO-1 [heme oxygenase-1]), environmental nutrients, growth factors, and cellular stress influence mitochondrial biogenesis, autophagic flux, cardiac hypertrophy, and cardiomyocyte senescence and apoptosis. Despite these canonical descriptions, the actual response to each effector is determined by the intensity and duration of signaling. Typically, transient and measured signaling produces adaptive effects, whereas continuous heightened activity yields maladaptive responses. The effects of signaling are also influenced by context; ie, the nature and intermittency of the external stress and the characteristics of the underlying substrate (eg, cardiomyopathy, obesity, or aging). PI3K signaling promotes physiological hypertrophy and is cardioprotective during abrupt cardiac stress, but its sustained activation accelerates pathological hypertrophy related to obesity and aging. Signaling through SIRT1/AMPK (and upregulation of autophagic flux) exerts favorable effects during exercise training and in chronic cardiomyopathy, obesity, and aging, but it undermines the cardiac response to abrupt stress. Intermittent FoxO1 upregulation may promote physiological hypertrophy while antagonizing pathological hypertrophy, but prolonged activation leads to cardiomyocyte apoptosis. NRF2 exerts antioxidant effects when background autophagic flux is vigorous but aggravates cellular stress when autophagy is suppressed (as in pathological hypertrophy). Sustained activation of PPARγ, NRF2, and HIF-1α in nutrient surplus states can lead to maladaptive ventricular remodeling, thus explaining the results of clinical trials with thiazolidinediones, bardoxolone, and prolyl hydroxylase inhibitors. The influence of duration, intensity, and context may be mediated (in part) by the activation or suppression of counterregulatory mechanisms, by the selective recruitment of corepressors, and by posttranslational protein modifications. These observations, considered collectively, suggest that no protein or cellular process viewed in isolation can be regarded as cardioprotective or maladaptive. Cell signals operate usefully if they are delivered as part of an orchestrated program of compartmentalized nuanced bursts, acting as elements of multifaceted oscillating systems whose periodicity is determined by the need to achieve homeostasis.

Keywords: cardiomyocytes; cardioprotection; cell signaling; nutrient deprivation signaling; nutrient surplus signaling

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.075568

Sci Adv. 2025 Sep 19. 11(38): eadv4437

Endoplasmic reticulum junctions serve as a platform for endosome-lysosome interactions through their stop-and-go motion switching.

Wenjing Li, Yuanhao Guo, Qi Wang, Mengxuan Qiu, Yudong Zhang, Yutong Yang, Junjie Hu, Ge Yang.

Endosomes and lysosomes (collectively termed "endolysosomes") traverse the cytoplasm in a stop-and-go manner, but the mechanisms underlying this motion remain poorly understood. Using deep learning-based image analyses, including particle tracking, spatial distribution, and endoplasmic reticulum (ER) morphology analysis, we found that ER junctions facilitate stop-and-go motion switching and serve as platforms for endolysosome interactions. Within the ER network, endolysosomes exhibit three dynamic states: fast movement, local slow movement, and pausing. Pauses occur mainly at ER junctions, where transient endosome-lysosome interactions often coincide with organelle fission and are followed by departure. Disruption of ER junctions impairs lysosomal motility and maturation. We further show that actin condensation around endolysosomes mediates motion switching, involving VAP-STARD3 interaction and the actin regulator YWHAH. Other organelles, such as lipid droplets and peroxisomes, also pause near ER junctions. These findings highlight ER junctions as regulatory hubs that orchestrate organelle dynamics, contributing to the spatial coordination of organelle distribution and interactions within the cytoplasm.

DOI: https://doi.org/10.1126/sciadv.adv4437