bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–03–16
nine papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Mechanisms and functions of lysosomal lipid homeostasis.
  2. Cellular homeostatic responses to lysosomal damage.
  3. The TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for Lysophagy.
  4. ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells.
  5. Two-Color Single-Molecule Blinking Ratiometricity: A Functional Super-Resolution Imaging Approach for Resolving Lysosomal pH and Dynamics.
  6. Sorting of complex sphingolipids within the cellular endomembrane systems.
  7. TFEB promotes Ginkgetin-induced ferroptosis via TRIM25 mediated GPX4 lysosomal degradation in EGFR wide-type lung adenocarcinoma.
  8. Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.
  9. Advances in incretin therapies for targeting cardiovascular disease in diabetes.
  1. Cell Chem Biol. 2025 Feb 28. pii: S2451-9456(25)00035-2. [Epub ahead of print]
    Mechanisms and functions of lysosomal lipid homeostasis.
    Michael Ebner, Florian Fröhlich, Volker Haucke.
      Lysosomes are the central degradative organelle of mammalian cells and have emerged as major intersections of cellular metabolite flux. Macromolecules derived from dietary and intracellular sources are delivered to the acidic lysosomal lumen where they are subjected to degradation by acid hydrolases. Lipids derived from lipoproteins, autophagy cargo, or autophagosomal membranes themselves constitute major lysosomal substrates. Dysregulation of lysosomal lipid processing, defective export of lipid catabolites, and lysosomal membrane permeabilization underly diseases ranging from neurodegeneration to metabolic syndromes and lysosomal storage disorders. Mammalian cells are equipped with sophisticated homeostatic control mechanisms that protect the lysosomal limiting membrane from excessive damage, prevent the spillage of luminal hydrolases into the cytoplasm, and preserve the lysosomal membrane composition in the face of constant fusion with heterotypic organelles such as endosomes and autophagosomes. In this review we discuss the molecular mechanisms that govern lysosomal lipid homeostasis and, thereby, lysosome function in health and disease.
    Keywords:  contact sites; lipids; lysosomes; membrane homeostasis; phosphoinositides; signalling
    DOI:  https://doi.org/10.1016/j.chembiol.2025.02.003
  2. Trends Cell Biol. 2025 Mar 10. pii: S0962-8924(25)00041-8. [Epub ahead of print]
    Cellular homeostatic responses to lysosomal damage.
    Jingyue Jia, Suttinee Poolsup, Jay E Salinas.
      Lysosomes are essential membrane-bound organelles that control cellular homeostasis by integrating intracellular functions with external signals. Their critical roles make lysosomal membranes vulnerable to rupture under various stressors, leading to cellular dysfunction. However, the mechanisms by which cells respond to lysosomal damage have only recently begun to be explored. In this review, we summarize the cellular mechanisms activated by lysosomal damage, emphasizing those that restore lysosomal integrity and sustain homeostasis, including recognition, repair, removal, replacement, and remodeling. Drawing on our expertise, we provide an in-depth focus on the remodeling process involved in these responses, including metabolic signaling and stress granule formation. Finally, we discuss the implications of lysosomal damage in human diseases, underscoring potential therapeutic strategies to preserve lysosomal function and alleviate related disorders.
    Keywords:  damaged lysosomes; recognition; remodeling; removal; repair; replacement
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.007
  3. Autophagy. 2025 Mar 13.
    The TBK1-SCFFBXO3-TMEM192-TAX1BP1 axis: a novel regulatory mechanism for Lysophagy.
    Na Yeon Park, Dong-Hyung Cho.
      Lysophagy, the selective macroautophagic/autophagic clearance of damaged lysosomes, is a critical mechanism for maintaining cellular homeostasis. Our recent study identified a novel regulatory axis involving TBK1, SCFFBXO3, TMEM192, and TAX1BP1 that orchestrates lysophagic flux following lysosomal damage. We demonstrated that TBK1-dependent phosphorylation of FBXO3 facilitates its interaction with TMEM192, promoting its ubiquitination and subsequent recognition by the autophagy receptor TAX1BP1. Perturbing this pathway significantly reduces lysophagic flux and results in accumulation of damaged lysosomes. These findings establish a previously unrecognized mechanistic link between ubiquitination, receptor recruitment, and lysophagic degradation, broadening our understanding of lysosomal quality control.
    Keywords:  FBXO3; TAX1BP1; TBK1; TMEM192; lysophagy; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2025.2479669
  4. Autophagy. 2025 Mar 13.
    ATG2A acts as a tether to regulate autophagosome-lysosome fusion in neural cells.
    Ze Zheng, Cuicui Ji, Hongyu Zhao, Yan G Zhao.
      The macroautophagy/autophagy proteins ATG2A and ATG2B transfer lipids for phagophore membrane growth. They also form stable complexes with WDR45 and WDR45B. Our previous study demonstrated that WDR45 and WDR45B mediate autophagosome-lysosome fusion in neural cells. Given the defective autophagosome formation in cells lacking both ATG2s, their role in later autophagy stages is hard to explore. Here, we report that in neuroblastoma-derived Neuro-2a (N2a) cells, knocking down (KD) Atg2a, but not Atg2b, results in significant accumulation of SQSTM1/p62 and MAP1LC3/LC3-II, indicating impaired autophagy. Atg2a deficiency does not affect autophagosome formation, but reduces colocalization of autophagosomal LC3 with late endosomal/lysosomal RFP-RAB7, suggesting impaired autophagosome-lysosome fusion. ATG2A interacts with the SNARE proteins STX17, SNAP29, and VAMP8, facilitating their assembly. Overexpression of ATG2A partially rescues the autophagosome-lysosome fusion defects in Wdr45- and Wdr45b-deficient cells. ATG2 and another tether protein, EPG5, function partially redundantly in mediating autophagosome-lysosome fusion. Thus, ATG2A plays a key role in neural autophagy by tethering autophagosomes with lysosomes for fusion.
    Keywords:  ATG2A; WDR45; autophagosome; autophagy; lysosome; tether
    DOI:  https://doi.org/10.1080/15548627.2025.2479427
  5. Angew Chem Int Ed Engl. 2025 Mar 08. e202503916
    Two-Color Single-Molecule Blinking Ratiometricity: A Functional Super-Resolution Imaging Approach for Resolving Lysosomal pH and Dynamics.
    Qinglong Qiao, Wenting Yin, Xia Wu, Shaowei Wu, Yiyan Ruan, Ning Xu, Jin Li, Zhong-Shuai Wu, Xiaogang Liu, Zhaochao Xu.
      Fluorescence super-resolution microscopy has enabled nanoscale imaging of intracellular structures, but it remains challenging to simultaneously achieve structural imaging and quantitative functional characterization, such as pH measurement, within the same region. Here, we introduce Two-Color Single-Molecule Blinking Ratiometricity (2C-SMBR), a novel method that integrates structural and functional imaging with single-molecule precision. By loading lysosomes with two pH-dependent spontaneously blinking fluorophores of distinct colors, 2C-SMBR leverages single-molecule localization of either fluorophore to achieve nanoscale structural imaging of lysosomes, while the ratiometric analysis of blinking dynamics between the two fluorophores provides quantitative pH measurement at the single-lysosome level. This dual-color ratiometric approach at the single-molecule level enables precise quantification of lysosomal pH with exceptional spatiotemporal resolution. Using 2C-SMBR, we reveal that lysosomal pH is highly heterogeneous at the single-lysosome level, with distinct subpopulations exhibiting diverse pH values. Our measurements show a pH range of 4.0 to 6.0 within lysosomes, with perinuclear lysosomes averaging a pH of approximately 4.88, while peripheral lysosomes average around 5.64. Crucially, 2C-SMBR enables real-time correlation between lysosomal dynamics and pH changes, overcoming a key limitation of super-resolution imaging. This approach not only advances nanoscale organelle characterization but also provides mechanistic insights into lysosomal physiology and function.
    Keywords:  Lysosomal pH; Ratiometric; Spontaneously Blinking; Super-Resolution Imaging; Two-Color Single-Molecule Blinking Ratiometricity(2C-SMBR)
    DOI:  https://doi.org/10.1002/anie.202503916
  6. Front Cell Dev Biol. 2024 ;12 1490870
    Sorting of complex sphingolipids within the cellular endomembrane systems.
    Victor O Svistunov, Kigumbi J Ehrmann, Wayne I Lencer, S S Schmieder.
      Cells contain a plethora of structurally diverse lipid species, which are unevenly distributed across the different cellular membrane compartments. Some of these lipid species require vesicular trafficking to reach their subcellular destinations. Here, we review recent advances made in the field that contribute to understanding lipid sorting during endomembrane trafficking.
    Keywords:  complex sphingolipids; endocytosis; membrane curvature; membrane nanodomains; membrane rafts; membrane trafficking
    DOI:  https://doi.org/10.3389/fcell.2024.1490870
  7. Theranostics. 2025 ;15(7): 2991-3012
    TFEB promotes Ginkgetin-induced ferroptosis via TRIM25 mediated GPX4 lysosomal degradation in EGFR wide-type lung adenocarcinoma.
    Hao-Jie Wang, Ling-Feng Dong, Li-Li Ding, Xiu-Yuan Miao, Yu-Wen Zhang, Li-Ping Zhao, Li-Hua Yu, Zhen-Rong Guan, Ya-Ping Jiang, Xiao-Qi Tang, Ya-Xin Yan, Jian-Shu Lou.
      Rationale: TFEB activation is associated with prolonged survival in LUAD patients, suggesting potential benefits of TFEB agonists in LUAD treatment. In this study, we identify ginkgetin (GK), derived from Ginkgo folium, as a natural TFEB agonist, which has demonstrated promising anticancer effects in our previous research. TFEB activation has been shown to promote GPX4 degradation, inducing ferroptosis; however, the specific E3 ligases, deubiquitinating enzymes (DUBs), and types of polyubiquitination chains involved remain unclear. The unique mechanisms associated with natural compounds like GK may help elucidate the underlying biological processes. Here, we describe a novel biological event involved in the lysosomal degradation of GPX4 induced by TFEB activation through the utilization of GK. Methods: TFEB activation was induced with GK, and TFEB knockout cells were generated using CRISPR-Cas9. The activity of TFEB and its relationship with ferroptosis were assessed by immunoprecipitation, labile iron pool and lysosomal activity assays. The types of polyubiquitination chains, E3 ligases, and DUBs involved in GPX4 degradation were analyzed using LC-MS, immunoprecipitation, and immunofluorescence. These findings were further validated in an orthotopic xenograft SCID mouse model. Results: GK binds to and activates TFEB, leading to TFEB-mediated lysosomal activation and GPX4 degradation, which induces ferroptosis in LUAD cells. These effects were impaired in TFEB knockout cells. Mechanistically, K48-linked polyubiquitination of GPX4 was required for GK induced GPX4 lysosomal translocation. TFEB knockout reduced both K48-linked ubiquitination and lysosomal translocation of GPX4. Additionally, GK promotes the binding of TFEB and TRIM25. TRIM25 and USP5 were found to competitively bind to GPX4, with TFEB activation favoring TRIM25 binding to GPX4 and reducing the interaction of USP5 and GPX4. These findings were confirmed in a xenograft SCID mouse model using TFEB knockout LUAD cells. Conclusion: This study identifies, for the first time, GK as a promising TFEB agonist for LUAD treatment. TFEB activation promotes TRIM25-mediated K48-linked polyubiquitination and lysosomal degradation of GPX4, driving ferroptosis. This ferroptosis-driven mechanism offers a novel strategy to enhance ferroptosis-based anti-LUAD therapies.
    Keywords:  LUAD; TFEB; ferroptosis; ginkgetin; lysosome; ubiquitination
    DOI:  https://doi.org/10.7150/thno.106469
  8. Cell Death Dis. 2025 Mar 08. 16(1): 163
    Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.
    Jun-Bo Yuan, Gui-Xin Gu, Bang-Ming Jin, Qing Han, Bing-Hui Li, Li Zhang, Bin Xu, Xuan Zhu, Guang-Hui Jin.
      Lysosome-mediated autophagy (including mitophagy) is crucial for cell survival and homeostasis. Although the mechanisms of lysosome activation during stress are well recognized, the epigenetic regulation of lysosomal gene expression remains largely unexplored. Menin, encoded by the MEN1 gene, is a chromatin-related protein that is widely involved in gene transcription via histone modifications. Here, we report that menin regulates the transcription of specific lysosomal genes, such as CTSB, CTSE, and TFE3, through MLL-mediated H3K4me3 reprogramming, which is necessary for maintaining lysosomal homeostasis. Menin also directly controls the expression of SQSTM1 and MAP1LC3B to maintain autophagic flux in a manner independent of AMPK/mTORC1 pathways. Furthermore, loss of menin led to mitochondrial dysfunction, elevated levels of reactive oxygen species (ROS), and genome instability. In genetically engineered mouse models, Men1 deficiency resulted in severe lysosomal and mitochondrial dysfunction and an impaired self-clearance ability, which further led to metabolite accumulation. SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal and mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis.
    DOI:  https://doi.org/10.1038/s41419-025-07489-0
  9. J Mol Cell Cardiol. 2025 Mar 12. pii: S0022-2828(25)00047-1. [Epub ahead of print]
    Advances in incretin therapies for targeting cardiovascular disease in diabetes.
    Timothy D Roberts, Dana S Hutchinson, Denise Wootten, Miles J De Blasio, Rebecca H Ritchie.
      The global prevalence of obesity is skyrocketing at an alarming rate, with recent data estimating that one-in-eight people are now living with the disease. Obesity is a chronic metabolic disorder that shares underlying pathophysiology with other metabolically-linked diseases such as type 2 diabetes mellitus, cardiovascular disease and diabetic cardiomyopathy. There is a distinct correlation between type 2 diabetes status and the likelihood of heart failure. Of note, there is an apparent sexual dimorphism, with women disproportionately affected with respect to the degree of severity of the cardiac phenotype of diabetic cardiomyopathy that results from diabetes. The current pharmacotherapies available for the attenuation of hyperglycaemia in type 2 diabetes are not always effective, and have varying degrees of efficacy in the setting of heart failure. Insulin can worsen heart failure prognosis whereas metformin, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and more recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs), have demonstrated cardioprotection with their administration. This review will highlight the advancement of incretin therapies for individuals with diabetes and heart failure and explore newly-reported evidence of the clinical usefulness of GLP-1R agonists in this distinct phenotype of heart failure.
    Keywords:  Cardiomyopathy; Diabetes; GLP-1R agonists; Heart failure; Incretin therapies; Obesity; Sex-differences
    DOI:  https://doi.org/10.1016/j.yjmcc.2025.03.007
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