bims-lypmec 2025-11-09 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–11–09
eight papers selected by
Satoru Kobayashi, New York Institute of Technology

Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in C. elegans.
Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells.
Cell Surface LAMP-2C Is Internalized in a Clathrin-Dependent Manner and Transported to the Recycling and Lysosomal Pathways.
TORC1-dependent sorting of PI(3,5)P2 is required for vacuole membrane remodeling and signaling endosome formation.
Sphk2 suppresses ferroptosis in ischemic hearts by promoting HSP90AA1-mediated TFEB nuclear translocation, lysosome biogenesis and lysosome-autophagy pathway-dependent lipid-ROS clearance.
Secretome translation shaped by lysosomes and lunapark-marked ER junctions.
Targeting Ferroptosis: New Insights and Therapeutic Advances in MAFLD Complicating T2DM.
Sphingosine-1-Phosphate Lyase Inhibition Increases Glycolysis in Adult Cardiomyocytes and Restores Glycolytic Flux in Diabetic Cardiomyopathy.

Mol Biol Cell. 2025 Nov 05. mbcE25040182

Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in C. elegans.

Yuan Li, Jie Zhang, Meijiao Li, Lujia Yang, Xiaochen Wang.

The maintenance of lysosome membrane integrity is vital for cell homeostasis and viability, but the underlying mechanisms are not well understood. In this study, we identified a novel role of SPHK-1, the sole C. elegans sphingosine kinase, in protecting lysosome membrane integrity. Loss of SPHK-1 affects lysosomal integrity and degradative function, causing cargo accumulation and lysosome membrane rupture. sphk-1(lf) mutants show severe defects in embryonic and larval development and have significantly shortened lifespan. We found that sphk-1(lf) mutants accumulate high levels of sphingosine, predominantly in lysosomes. Accordingly, sphingosine supplementation leads to appearance of damaged lysosomes in wild-type worms. We identified sptl-1 and sptl-3 mutations that fully suppress the lysosomal integrity defects in sphk-1(lf) mutants. sptl-1 and sptl-3 encode serine palmitoyltransferases that catalyze the first and rate-limiting step of de novo sphingolipid synthesis. Loss of sptl-1 alleviates sphingosine accumulation, reverses lysosomal integrity and degradation defects, and restores normal development and longevity in sphk-1(lf) mutants. Our study indicates that sphingolipid metabolism via sphingosine kinase is important for maintaining lysosome membrane integrity and function, and is essential for animal development and longevity.

DOI: https://doi.org/10.1091/mbc.E25-04-0182
Biochem Biophys Res Commun. 2025 Oct 29. pii: S0006-291X(25)01603-1. [Epub ahead of print]790 152887

Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells.

Lorenzo Barrella, María Pilar Ramírez-Ponce, Victoria Vázquez-Román, Marta San Millán-Huang, Juan Antonio Flores-Cordero, Eva Alés.

  Mast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence in MCs from 2-month-old mice, consistent with immature granules. As MCs matured, quinacrine signal increased, reflecting expansion of the secretory lysosome pool; however, from 15 to 17 months, fluorescence progressively declined, indicating gradual deacidification. Chronic ketotifen treatment restored and amplified the quinacrine signal, enlarged granules, and reduced late-life MC expansion. Acute pharmacological assays revealed that ketotifen's effect requires V-ATPase activity and dynamin-dependent endocytosis. FM1-43 uptake confirmed enhanced endocytic activity with ketotifen. In the brain, ageing led to hypertrophy of toluidine blue-positive MCs without major changes in cell number; five months of ketotifen treatment reversed these morphometric alterations toward a youthful profile. These findings identify lysosomal deacidification as a hallmark of ageing MCs and demonstrate that ketotifen reacidifies secretory lysosomes via V-ATPase and endocytosis-dependent mechanisms, highlighting lysosomal pH control as a tractable strategy to mitigate MC-driven components of inflammaging.

Keywords:  Ageing; Endocytosis; Ketotifen; Lysosomal acidification; Mast cells; V-ATPase

DOI:  https://doi.org/10.1016/j.bbrc.2025.152887
Genes Cells. 2025 Nov;30(6): e70063

Cell Surface LAMP-2C Is Internalized in a Clathrin-Dependent Manner and Transported to the Recycling and Lysosomal Pathways.

Hiroshi Sakane, Yuna Takeda, Ikuto Okuda, Kanae Michihara, Kenji Akasaki.

  Lysosomes are acidic organelles that degrade a diverse range of substrates, and lysosome-associated membrane protein (LAMP)-1 and LAMP-2 are the major lysosomal membrane components. Three LAMP-2 splice variants have been identified, namely, LAMP-2A, LAMP-2B, and LAMP-2C. We previously demonstrated that when mouse LAMP-2C was stably expressed in HEK293 cells, a portion of it was present on the plasma membrane. LAMP-2C possesses a tyrosine-based motif that functions as a signal for lysosomal targeting and clathrin-mediated endocytosis (CME). However, whether cell surface LAMP-2C is indeed internalized via CME has not been clearly defined. If this occurs, it is unknown whether internalized LAMP-2C returns to the cell surface and/or moves to lysosomes from early endosomes. In this study, we found that cell surface LAMP-2C was internalized, and its internalization was impaired by knockdown of the clathrin heavy chain or the medium subunit of adaptor protein complex 2. Internalized LAMP-2C was transported to early endosomes, and a portion of the internalized LAMP-2C was recycled back to the plasma membrane. Furthermore, immunofluorescence and subcellular fractionation showed that the internalized LAMP-2C was transported to lysosomes. These results suggest that cell surface LAMP-2C is internalized by CME and that internalized LAMP-2C enters the recycling and lysosomal pathways.

Keywords:  LAMP‐2; clathrin; lysosome; recycling

DOI:  https://doi.org/10.1111/gtc.70063
Mol Biol Cell. 2025 Nov 05. mbcE25100498

TORC1-dependent sorting of PI(3,5)P2 is required for vacuole membrane remodeling and signaling endosome formation.

Frederik Brinks, Annabel Arens, Rainer Kurre, Jacob Piehler, Lars Langemeyer, Christian Ungermann.

Lysosomes, as central organelles of the endolysosomal system, support cell growth by releasing nutrients derived from hydrolytic digestion of macromolecules. Additionally, they serve as storage organelles for ions and amino acids and must respond to changes in osmolarity by adjusting their membrane to maintain membrane integrity. The nutrient-sensing target of rapamycin complex 1 (TORC1) and the lipid kinase Fab1 (PIKfyve in mammals) are key regulators of these processes on yeast vacuoles. TORC1 phosphorylates Fab1, yet how their activities are functionally coupled is unknown. Here, we show that yeast TORC1 is essential for the sorting of Fab1-derived phosphatidylinositol-3,5-bisphosphate (PI(3,5)P₂) from vacuoles to signaling endosomes (SEs), whose formation depends on the CROP membrane remodeling complex. TORC1 phosphorylation activates Fab1, presumably to maintain elevated PI(3,5)P₂ levels on SEs toward cell growth. In mutants defective in endosome-vacuole fusion, PI(3,5)P₂ accumulates on endosomes adjacent to the vacuole, indicating that its hydrolysis primarily occurs on the vacuolar membrane. Our findings reveal that synthesis and spatial distribution of the vacuolar signaling lipid PI(3,5)P₂ are directly coordinated by TORC1, coupling nutrient sensing to membrane remodeling and endosomal signaling.

DOI: https://doi.org/10.1091/mbc.E25-10-0498
Metabolism. 2025 Nov 05. pii: S0026-0495(25)00297-5. [Epub ahead of print] 156428

Sphk2 suppresses ferroptosis in ischemic hearts by promoting HSP90AA1-mediated TFEB nuclear translocation, lysosome biogenesis and lysosome-autophagy pathway-dependent lipid-ROS clearance.

Ting Gong, Danru Wang, Yawei Jin, Liming Chen, Nan Qiu, Wenyan Qiu, Na Zheng, Yang Lv, Suling Ding, Jie Yuan, Jian Wu, Ling Lin, Chunjie Yang, Miyesaier Abudureyimu, Xiang Wang, Gulinazi Yesitayi, Lei Xu, Peng Zhang, Wei Hu, Gang Zhao, Leilei Ma, Yunzeng Zou, Shijun Wang.

   BACKGROUND: Lipid peroxidation and iron overload-mediated cardiac ferroptosis play a critical role in myocardial ischemic injury and remodeling. Sphingosine kinase 2 (Sphk2) is implicated in lipid metabolism and cell survival, yet its role in myocardial infarction (MI) remains elusive. Given the critical function of ferroptosis in ischemic injury, we investigated whether Sphk2 protects the heart by regulating this novel cell death pathway.
METHODS: Sphk2 expression was assessed in human failing hearts and a murine MI model. Sphk2-/- mice and AAV9-mediated cardiac-specific Sphk2 overexpression were used to assess cardiac function by echocardiography, remodeling by Masson's trichrome staining and molecular events.
RESULTS: Sphk2 was significantly downregulated in human and murine failing hearts. Sphk2-/- mice exhibited exacerbated cardiac dysfunction, fibrosis and ferroptosis post-MI. Inhibition of CD36 signaling attenuated lipid uptake and ischemia-induced ferroptosis in Sphk2-/- mice, whereas pharmacological activation of TFEB restored autophagosome-lysosome function and further suppressed ferroptosis. Mechanistically, Sphk2 deficiency impaired the interaction with and stability of HSP90, leading to suppressed TFEB nuclear translocation, lysosomal biogenesis, and autophagic clearance of lipid peroxides. This exacerbated ferroptosis and ischemic injury via lipid-ROS accumulation and oxidative stress. Crucially, cardiac-specific overexpression of Sphk2 in knockout mice restored HSP90-TFEB signaling, ameliorated ferroptosis, and fully rescued cardiac function and remodeling after MI.
CONCLUSION: Our study unveils a novel role of Sphk2 in stabilizing HSP90 to activate TFEB-dependent lysosomal function, thereby mitigating lipid peroxidation and ferroptosis following ischemic injury. Our findings establish a direct causal link between Sphk2 deficiency and ischemic heart failure, which highlights the therapeutic potential of Sphk2 restoration in treating ischemic heart disease.

Keywords:  Autophagy; Ferroptosis; Lipid metabolism disorder; Lysosome biogenesis; Myocardial infarction (MI)

DOI:  https://doi.org/10.1016/j.metabol.2025.156428
Nature. 2025 Nov 05.

Secretome translation shaped by lysosomes and lunapark-marked ER junctions.

Heejun Choi, Ya-Cheng Liao, Young J Yoon, Jonathan Grimm, Nan Wang, Luke D Lavis, Robert H Singer, Jennifer Lippincott-Schwartz.

The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome density and translation efficiency of secretome mRNAs near lysosomes, an effect that was dependent on eIF2-mediated initiation and was reversed by the integrated stress response inhibitor ISRIB. Lysosome-associated translation was further modulated by nutrient status: amino acid deprivation enhanced lysosome-proximal translation, whereas lysosomal pH neutralization suppressed it. These findings identify a mechanism by which ER junctional proteins and lysosomal activity cooperatively pattern secretome mRNA translation, linking ER architecture and nutrient sensing to the production of secretory and membrane proteins.

DOI: https://doi.org/10.1038/s41586-025-09718-0
Front Biosci (Landmark Ed). 2025 Oct 30. 30(10): 39735

Targeting Ferroptosis: New Insights and Therapeutic Advances in MAFLD Complicating T2DM.

Fang Yao, Gaochao Wang, Fan Ning, Yanbo Shi.

  Epidemiological data show a strong connection between type 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD). In recent years, the prevalence of both conditions has been rising simultaneously. When T2DM and MAFLD occur together, patients face a significantly higher risk of glucose and lipid metabolic disorders, with fatty liver more likely to progress to fibrosis or even malignancy. The underlying mechanisms are complex, involving multiple factors such as inflammatory responses, insulin resistance (IR), and cellular aging. Ferroptosis, a newly identified form of programmed cell death characterized by iron accumulation and lipid peroxidation, plays a crucial role in the development of T2DM and MAFLD, drawing significant attention. Current research suggests that ferroptosis contributes to the progression of these two diseases. However, the exact mechanisms of ferroptosis in T2DM-related MAFLD remain unclear. This review summarizes recent advances in ferroptosis research related to T2DM and MAFLD and highlights several potential therapeutic drugs and compounds targeting ferroptosis, aiming to provide a theoretical basis for their clinical application. Additionally, intracellular iron overload, elevated reactive oxygen species levels, and lipid peroxidation are closely associated with ferroptosis. Studies have shown that certain antidiabetic medications (e.g., metformin, pioglitazone, and liraglutide) may slow the progression of MAFLD by inhibiting ferroptosis. Furthermore, experimental studies targeting FerroTerminator1 (FOT1) have demonstrated promising therapeutic value for MAFLD and insulin resistance, suggesting that targeting ferroptosis could be an effective strategy for treating T2DM-related MAFLD.

Keywords:  ferroptosis; insulin resistance; iron metabolism; metabolically associated fatty liver disease; type 2 diabetes mellitus

DOI:  https://doi.org/10.31083/FBL39735
J Cell Mol Med. 2025 Nov;29(21): e70924

Sphingosine-1-Phosphate Lyase Inhibition Increases Glycolysis in Adult Cardiomyocytes and Restores Glycolytic Flux in Diabetic Cardiomyopathy.

Jens Vogt, Melissa Kim Nowak, Marcel Benkhoff, Hao Hu, Philipp Wollnitzke, Lisa Dannenberg, Amin Polzin, Bodo Levkau.

  Sphingosine-1-phosphate (S1P) is a bioactive lipid that affects cardiac contractility and calcium homeostasis and exerts potent cardioprotective properties in myocardial infarction, heart failure, preconditioning. Whether and how it may affect energy metabolism in the heart is still unknown. Here, we examined S1P effects on glycolysis of adult cardiomyocytes (ACM) using Seahorse technology and observed that intracellular S1P rather than extracellular S1P potently potentiates basal glycolysis and increases glycolytic capacity. Accordingly, ACM from mice administered a S1P lyase inhibitor to prevent S1P degradation featured 3-fold higher S1P levels and a 30%-40% increase in basal glycolysis and glycolytic capacity, whereas acute S1P stimulation had no effect. Cardiomyocyte-specific GLUT4-deficient ACM were resistant to this increase, whereas ACM from S1P lyase-inhibited mice featured a 3-fold higher glucose uptake, suggesting that higher glycolysis may be a function of increased glucose influx through GLUT4. Comparing glycolysis in ACM from normal chow-fed mice with ACM from pre-diabetic mice following long-term feeding of a high caloric diet revealed a rapid and progressive loss of glycolytic potential without yet affecting cardiac function despite a beginning hypertrophy on echocardiography. Most importantly, both could be reconstituted to normal by S1P lyase inhibition. As the levels of bioactive lipids such as S1P are altered in obesity and diabetes, understanding their effects on metabolism may help reveal novel aspects of lipid biology in metabolic diseases of the heart.

Keywords:  cardiomyocyte; diabetic cardiomyopathy; glycolysis; hypertrophy; metabolism; sphingosine‐1‐phosphate

DOI:  https://doi.org/10.1111/jcmm.70924