bims-lypmec 2025-02-09 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–02–09
seven papers selected by
Satoru Kobayashi, New York Institute of Technology

VPS41 recruits biosynthetic LAMP-positive vesicles through interaction with Arl8b.
Glucuronidase-Instructed Glycopeptide Self-Assembly for Selective Killing of Cancer Cells through Lysosomal Membrane Permeabilization.
Microenvironment-Specific Enrichment Strategy Enables Lysosomal Proteomic Dynamics Analysis.
Moving the fat: Emerging roles of rab GTPases in the regulation of lipid droplet contact sites.
Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.
Molecular Pathways in Diabetic Cardiomyopathy and the Role of Anti-hyperglycemic Drugs Beyond Their Glucose Lowering Effect.
Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting.

J Cell Biol. 2025 Apr 03. pii: e202405002. [Epub ahead of print]224(4):

VPS41 recruits biosynthetic LAMP-positive vesicles through interaction with Arl8b.

Paolo Sanzà, Jan van der Beek, Derk Draper, Cecilia de Heus, Tineke Veenendaal, Corlinda Ten Brink, Ginny G Farías, Nalan Liv, Judith Klumperman.

Vacuolar protein sorting 41 (VPS41), a component of the homotypic fusion and protein sorting (HOPS) complex for lysosomal fusion, is essential for the trafficking of lysosomal membrane proteins via lysosome-associated membrane protein (LAMP) carriers from the trans-Golgi network (TGN) to endo/lysosomes. However, the molecular mechanisms underlying this pathway and VPS41's role herein remain poorly understood. Here, we investigated the effects of ectopically localizing VPS41 to mitochondria on LAMP distribution. Using electron microscopy, we identified that mitochondrial-localized VPS41 recruited LAMP1- and LAMP2A-positive vesicles resembling LAMP carriers. The retention using selective hooks (RUSH) system further revealed that newly synthesized LAMPs were specifically recruited by mitochondrial VPS41, a function not shared by other HOPS subunits. Notably, we identified the small GTPase Arl8b as a critical factor for LAMP carrier trafficking. Arl8b was present on LAMP carriers and bound to the WD40 domain of VPS41, enabling their recruitment. These findings reveal a unique role of VPS41 in recruiting TGN-derived LAMP carriers and expand our understanding of VPS41-Arl8b interactions beyond endosome-lysosome fusion, providing new insights into lysosomal trafficking mechanisms.

DOI: https://doi.org/10.1083/jcb.202405002
Angew Chem Int Ed Engl. 2025 Feb 05. e202420596

Glucuronidase-Instructed Glycopeptide Self-Assembly for Selective Killing of Cancer Cells through Lysosomal Membrane Permeabilization.

Zhongxin Xu, Changdong He, Xinyu Li, Lu Huang, Bo Cheng, Suwei Dong.

  Current cancer treatments face significant challenges, including limited tumor specificity and drug resistance. Enzyme-instructed supramolecular peptide assembly targeting lysosomes offers a promising strategy to address these issues; however, self-assembling units that withstand lysosomal conditions are still scarce. In this study, we present a versatile glycopeptide incorporating glucuronic acid and glucose that undergoes glucuronidase-triggered self-assembly to form nanofibers, leading to lysosomal membrane permeabilization (LMP) in cancer cells. Mechanistic studies revealed that in glucuronidase-overexpressing HepG2 cells, glycopeptide assembly induces cytoskeletal disruption and apoptosis. The involvement of carbohydrate-binding receptor in enhancing the cellular entry of glycopeptides and improving proteolytic stability highlights the importance of glycan modification. Notably, combining this glycopeptide with cisplatin or adriamycin results in synergistic cytotoxicity, including in drug-resistant cancer lines. These findings establish a novel, LMP-inducing glycopeptide scaffold for developing targeted approaches for cancer treatment.

Keywords:  Cytotoxicity; glucuronidase; glycopeptides; lysosomal membrane permeabilization; self-assembly

DOI:  https://doi.org/10.1002/anie.202420596
Anal Chem. 2025 Feb 03.

Microenvironment-Specific Enrichment Strategy Enables Lysosomal Proteomic Dynamics Analysis.

Yuwen Chen, Zhiying Li, Yongbao Mao, Hui Pan, Zhen Liang, Yukui Zhang, Qun Zhao, Lihua Zhang.

Lysosomes are vital organelles for degradation, recycling, and cellular homeostasis, impacting signaling and metabolism. Analyzing the lysosomal proteome dynamics is key to understanding these roles, but the acidic environment and low abundance of lysosomes make proteomic analysis challenging. Herein, we developed a lysosome-localizable reactive diazirine molecule MDA and demonstrated its enhanced labeling capability in the lysosomal microenvironment. Furthermore, we introduced a novel microenvironment-specific enrichment (MiSE) strategy for profiling the lysosomal proteome, combining MDA-based labeling with affinity enrichment. We successfully applied MiSE to profile the lysosomal proteome in living SH-SY5Y cells, achieving coverage of 132 lysosome-annotated proteins. Moreover, by coupling MiSE with data-independent acquisition (DIA) analysis, we explored dynamic changes in the lysosomal proteome upon inhibition of the ubiquitin-proteasome system using four proteasome inhibitors. Our results reveal 117 UPS-inhibition-related lysosomal proteins, highlighting their involvement in stress response and cell cycle regulation. Notably, we observe distinct proteomic signatures for each inhibitor, suggesting unique mechanisms of lysosomal response to UPS inhibition. Therefore, MiSE offers a powerful tool for investigating the dynamic lysosomal proteome, providing insights into cellular homeostasis and disease pathogenesis. This approach holds significant potential for advancing the understanding of lysosomal function and developing novel therapeutic strategies.

DOI: https://doi.org/10.1021/acs.analchem.4c05797
Curr Opin Cell Biol. 2025 Feb 01. pii: S0955-0674(25)00004-3. [Epub ahead of print]93 102466

Moving the fat: Emerging roles of rab GTPases in the regulation of lipid droplet contact sites.

Mariano Alonso-Bivou, Albert Pol, Harriet P Lo.

Lipid droplets (LDs) play crucial roles in lipid metabolism, energy homeostasis, and cellular stress. Throughout their lifecycle, LDs establish membrane contact sites (MCSs) with the endoplasmic reticulum, mitochondria, peroxisomes, endosomes, lysosomes, and phagosomes. LD MCSs are dynamically generated in response to metabolic or immune cues to ensure that LD lipids (and proteins) are timely delivered to optimize valuable substrates and avoid lipotoxicity. It is increasingly evident that many Rab GTPases are involved in LD dynamics. Here, we summarize our current understanding of how and when Rab proteins dynamically drive the generation of LD MCSs and regulate a variety of LD functions.

DOI: https://doi.org/10.1016/j.ceb.2025.102466
Nat Aging. 2025 Feb 05.

Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.

Rabia R Khawaja, Adrián Martín-Segura, Olaya Santiago-Fernández, Rebecca Sereda, Kristen Lindenau, Mericka McCabe, Adrián Macho-González, Maryam Jafari, Aurora Scrivo, Raquel Gomez-Sintes, Bhakti Chavda, Ana Rosa Saez-Ibanez, Inmaculada Tasset, Esperanza Arias, Xianhong Xie, Mimi Kim, Susmita Kaushik, Ana Maria Cuervo.

Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.

DOI: https://doi.org/10.1038/s43587-024-00799-6
J Lipid Atheroscler. 2025 Jan;14(1): 54-76

Molecular Pathways in Diabetic Cardiomyopathy and the Role of Anti-hyperglycemic Drugs Beyond Their Glucose Lowering Effect.

Jie-Eun Lee, Byung Gyu Kim, Jong Chul Won.

  Epidemiological evidence has shown that diabetes is associated with overt heart failure (HF) and worse clinical outcomes. However, the presence of a distinct primary diabetic cardiomyopathy (DCM) has not been easy to prove because the association between diabetes and HF is confounded by hypertension, obesity, microvascular dysfunction, and autonomic neuropathy. In addition, the molecular mechanisms underlying DCM are not yet fully understood, DCM usually remains asymptomatic in the early stage, and no specific biomarkers have been identified. Nonetheless, several mechanistic associations at the systemic, cardiac, and cellular/molecular levels explain different aspects of myocardial dysfunction, including impaired cardiac relaxation, compliance, and contractility. In this review, we focus on recent clinical and preclinical advances in our understanding of the molecular mechanisms of DCM and the role of anti-hyperglycemic agents in preventing DCM beyond their glucose lowering effect.

Keywords:  Diabetic cardiomyopathy; Diastolic heart failure; Hypoglycemic agent

DOI:  https://doi.org/10.12997/jla.2025.14.1.54
Nat Commun. 2025 Feb 04. 16(1): 1330

Non-canonical lysosomal lipolysis drives mobilization of adipose tissue energy stores with fasting.

G V Naveen Kumar, Rui-Sheng Wang, Ankit X Sharma, Natalie L David, Tânia Amorim, Daniel S Sinden, Nandini K Doshi, Martin Wabitsch, Sebastien Gingras, Asim Ejaz, J Peter Rubin, Bradley A Maron, Pouneh K Fazeli, Matthew L Steinhauser.

Physiological adaptations to fasting enable humans to survive for prolonged periods without food and involve molecular pathways that may drive life-prolonging effects of dietary restriction in model organisms. Mobilization of fatty acids and glycerol from adipocyte lipid stores by canonical neutral lipases, including the rate limiting adipose triglyceride lipase (Pnpla2/ATGL), is critical to the adaptive fasting response. Here we discovered an alternative mechanism of lipolysis in adipocytes involving a lysosomal program. We functionally tested lysosomal lipolysis with pharmacological and genetic approaches in mice and in murine and human adipocyte and adipose tissue explant culture, establishing dependency on lysosomal acid lipase (LIPA/LAL) and the microphthalmia/transcription factor E (MiT/TFE) family. Our study establishes a model whereby the canonical pathway is critical for rapid lipolytic responses to adrenergic stimuli operative in the acute stage of fasting, while the alternative lysosomal pathway dominates with prolonged fasting.

DOI: https://doi.org/10.1038/s41467-025-56613-3