bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–03–30
eleven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
  2. ESCRT iii-mediated lysosomal repair improve renal tubular cell injury in cisplatin-induced AKI.
  3. Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity.
  4. From Molecular Therapies to Lysosomal Transplantation and Targeted Drug Strategies: Present Applications, Limitations, and Future Prospects of Lysosomal Medications.
  5. Lysosomes' fallback strategies: more than just survival or death.
  6. Calorie restriction plugs lithocholic bile acid into the lysosomal AMPK pathway.
  7. DA-1241, a GPR119 agonist, ameliorates fatty liver through the upregulation of TFEB-mediated autophagy.
  8. Programmed enhancement of endogenous iron-mediated lysosomal membrane permeabilization for tumor ferroptosis/pyroptosis dual-induction.
  9. Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins.
  10. Overexpression of Cx43: Is It an Effective Approach for the Treatment of Cardiovascular Diseases?
  11. Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
  1. Nat Commun. 2025 Mar 21. 16(1): 2815
    Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
    Zhenhua Wang, Jingjing He, Yufan Yang, Yonglin He, Hongwu Qian.
      The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway.
    DOI:  https://doi.org/10.1038/s41467-025-58087-9
  2. Autophagy. 2025 Mar 28.
    ESCRT iii-mediated lysosomal repair improve renal tubular cell injury in cisplatin-induced AKI.
    Zhangyu Tian, Yiming Wu, Bin Yi, Ling Li, Yan Liu, Hao Zhang, Aimei Li.
      The chemotherapeutic agent cisplatin is widely utilized for the treatment of various solid tumors. However, its clinical utility is limited by nephrotoxicity. Although numerous studies have demonstrated the potential of enhancing macroautophagy/autophagy in alleviating cisplatin-induced acute kidney injury (AKI), the dynamics of the autophagic process during renal tubular injury remain to be elucidated. In our investigation, we observed that cisplatin treatment leads to increased expression of LC3-II, GABARAPL1, SQSTM1/p62 and NBR1 in mouse renal tubular epithelial cells and BUMPT cells. Moreover, ultrastructurally, there is extensive accumulation of autophagic vacuoles in AKI mice. These findings imply that cisplatin-induced AKI results in impaired autophagic flow within renal tubular cells. Furthermore, LGALS3 (galectin 3) was found to be enriched in lysosomes after cisplatin treatment, revealing a close association between autophagy dysfunction and impaired lysosomal membrane integrity. Given the damaging contents of lysosomes, lysosomal membrane permeabilization must be rapidly resolved. Our findings showed that ESCRT III subunit CHMP4A-mediated lysosomal membrane repair significantly ameliorates autophagic defects and protects against lysosomal damage-induced cell death in a cisplatin-induced AKI model. In conclusion, our study indicates that ESCRT III-mediated lysosomal repair can relieve cisplatin-induced cell apoptosis and restore normal autophagy function in renal tubular epithelial cells. This mechanism plays a protective role against cisplatin-induced AKI.
    Keywords:  Apoptosis; Cisplatin-induced AKI; ESCRT III; autophagy; lysosomal damage; lysosomal repair
    DOI:  https://doi.org/10.1080/15548627.2025.2483598
  3. Clin Exp Nephrol. 2025 Mar 25.
    Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity.
    Takeshi Yamamoto.
      Autophagy, a critical intracellular degradation and recycling pathway mediated by lysosomes, is essential for maintaining cellular homeostasis through the quality control of proteins and organelles. Our research focused on the role of proximal tubular autophagy in the pathophysiology of aging, obesity, and diabetes. Using a novel method to monitor autophagic flux in kidney tissue, we revealed that age-associated high basal autophagy supports mitochondrial quality control and delays kidney aging. However, an impaired ability to upregulate autophagy under additional stress accelerates kidney aging. In obesity induced by a high-fat diet, lysosomal dysfunction disrupts autophagy, leading to renal lipotoxicity. Although autophagy is initially activated to repair organelle membranes and maintain proximal tubular cell integrity, this demand overwhelms lysosomes, resulting in "autophagic stagnation" characterized by phospholipid accumulation. Similar lysosomal phospholipid accumulation was observed in renal biopsies from elderly and obese patients. We identified TFEB-mediated lysosomal exocytosis as a mechanism to alleviate lipotoxicity by expelling accumulated phospholipids. Therapeutically, interventions such as the SGLT2 inhibitor empagliflozin and eicosapentaenoic acid restore lysosomal function and autophagic activity. Based on these findings, we propose a novel disease concept, "Obesity-Related Proximal Tubulopathy." This study underscores autophagic stagnation as a key driver of kidney disease progression in aging and obesity, offering insights into the pathophysiology of kidney diseases and providing a foundation for targeted therapeutic strategies.
    Keywords:  Kidney aging; Lipid overload; Lysosomal dysfunction; Obesity-related proximal tubulopathy; TFEB
    DOI:  https://doi.org/10.1007/s10157-025-02653-4
  4. Biomolecules. 2025 Feb 24. pii: 327. [Epub ahead of print]15(3):
    From Molecular Therapies to Lysosomal Transplantation and Targeted Drug Strategies: Present Applications, Limitations, and Future Prospects of Lysosomal Medications.
    Adel A Alhowyan, Gamaleldin I Harisa.
      Lysosomes are essential intracellular organelles involved in plentiful cellular processes such as cell signaling, metabolism, growth, apoptosis, autophagy, protein processing, and maintaining cellular homeostasis. Their dysfunction is linked to various diseases, including lysosomal storage disorders, inflammation, cancer, cardiovascular diseases, neurodegenerative conditions, and aging. This review focuses on current and emerging therapies for lysosomal diseases (LDs), including small medicines, enzyme replacement therapy (ERT), gene therapy, transplantation, and lysosomal drug targeting (LDT). This study was conducted through databases like PubMed, Google Scholar, Science Direct, and other research engines. To treat LDs, medicines target the lysosomal membrane, acidification processes, cathepsins, calcium signaling, mTOR, and autophagy. Moreover, small-molecule therapies using chaperones, macro-therapies like ERT, gene therapy, and gene editing technologies are used as therapy for LDs. Additionally, endosymbiotic therapy, artificial lysosomes, and lysosomal transplantation are promising options for LD management. LDT enhances the therapeutic outcomes in LDs. Extracellular vesicles and mannose-6-phosphate-tagged nanocarriers display promising approaches for improving LDT. This study concluded that lysosomes play a crucial role in the pathophysiology of numerous diseases. Thus, restoring lysosomal function is essential for treating a wide range of conditions. Despite endosymbiotic therapy, artificial lysosomes, lysosomal transplantation, and LDT offering significant potential for LD control, there are ample challenges regarding safety and ethical implications.
    Keywords:  LDT; engineered lysosome; enzyme replacement therapy; gene therapy; lysosomal diseases; proteopathy
    DOI:  https://doi.org/10.3390/biom15030327
  5. Front Cell Dev Biol. 2025 ;13 1559504
    Lysosomes' fallback strategies: more than just survival or death.
    Quan Wang, Ruolin Wang, Haihui Hu, Xiaoqing Huo, Fulong Wang.
      Lysosomes are heterogeneous, acidic organelles whose proper functionality is critically dependent on maintaining the integrity of their membranes and the acidity within their lumen. When subjected to stress, the lysosomal membrane can become permeabilized, posing a significant risk to the organelle's survival and necessitating prompt repair. Although numerous mechanisms for lysosomal repair have been identified in recent years, the progression of lysosome-related diseases is more closely linked to the organelle's alternative strategies when repair mechanisms fail, particularly in the contexts of aging and pathogen infection. This review explores lysosomal responses to damage, including the secretion of lysosomal contents and the interactions with lysosome-associated organelles in the endolysosomal system. Furthermore, it examines the role of organelles outside this system, such as the endoplasmic reticulum (ER) and Golgi apparatus, as auxiliary organelles of the endolysosomal system. These alternative strategies are crucial to understanding disease progression. For instance, the secretion and spread of misfolded proteins play key roles in neurodegenerative disease advancement, while pathogen escape via lysosomal secretion and lysosomotropic drug expulsion underlie cancer treatment resistance. Reexamining these lysosomal fallback strategies could provide new perspectives on lysosomal biology and their contribution to disease progression.
    Keywords:  autophagy; endoplasmic reticulum; exosome; golgi apparatus; lysosomal damage; secretion
    DOI:  https://doi.org/10.3389/fcell.2025.1559504
  6. Life Metab. 2025 Apr;4(2): loaf005
    Calorie restriction plugs lithocholic bile acid into the lysosomal AMPK pathway.
    Benoit Viollet.
      
    DOI:  https://doi.org/10.1093/lifemeta/loaf005
  7. Diabetes. 2025 Mar 28. pii: db240370. [Epub ahead of print]
    DA-1241, a GPR119 agonist, ameliorates fatty liver through the upregulation of TFEB-mediated autophagy.
    Jin Yoo, Ji Eun Jun, In-Kyung Jeong, Kyu Jeung Ahn, Ho Yeon Chung, Myung-Shik Lee, You-Cheol Hwang.
      G protein-coupled receptor 119 (GPR119) is predominantly expressed in pancreatic β-cells, enteroendocrine cells, and the liver. It is a novel therapeutic for dyslipidemia and type 2 diabetes. DA-1241, a GPR119 agonist, improves glucose tolerance by inhibiting gluconeogenesis and enhancing insulin secretion. It mitigates hepatic inflammation by inhibiting NFĸB signaling. However, the mechanism by which DA-1241 ameliorates nonalcoholic fatty liver disease (NAFLD) remains unknown. We hypothesized that DA-1241 improves liver steatosis by inducing autophagy in a TFEB-dependent manner. It induced autophagy and TFEB nuclear translocation, and decreased lipid content in liver cell lines. Lysotracker staining and DQ-Red BSA assay revealed it increased lysosomal activity. Furthermore, DA-1241 increased the colocalization of mRFP-LC3 and lipid droplets, which were completely abolished by GPR119 knockdown. DA-1241 treatment improved glucose tolerance and insulin sensitivity, and decreased liver enzymes activity and hepatic triglyceride levels, and the NAFLD activity score with increased number of autophagosomes and lysosomes in high-fat diet-fed mice. Despite DA-1241 treatment, lysosomal activity and subsequent lipid content reduction were not induced in tfeb knockout HeLa cells. DA-1241 treatment failed to produce favorable metabolic effects, including reduced hepatic triglyceride levels, in liver-specific Tfeb knockout mice. Thus, DA-1241 attenuates hepatic steatosis through TFEB-mediated autophagy induction.
    DOI:  https://doi.org/10.2337/db24-0370
  8. Nat Commun. 2025 Mar 28. 16(1): 3017
    Programmed enhancement of endogenous iron-mediated lysosomal membrane permeabilization for tumor ferroptosis/pyroptosis dual-induction.
    Luwen Zhu, Jiahao Hu, Xiaochuan Wu, Jucong Zhang, Xinyi Xu, Xiajie Huang, Bing Tian, Chun-Xia Zhao, Yongzhong Du, Liming Wu.
      Ferroptosis and pyroptosis, as emerging regulated forms of cell death capable of overcoming apoptotic resistance, demonstrate promising potential in tumor therapy. Given that iron manipulation and reactive oxygen species elevation serve as common stimuli for both processes, inducing lysosomal membrane permeabilization (LMP) with ensuing release of lysosomal contents (including iron ions and cathepsins) is anticipated to realize dual induction of ferroptosis/pyroptosis. Herein, we report a folic acid and croconaine molecule-functionalized upconversion nanoparticle (UCNP-Cro/FA) that is able to mobilize intracellular stores of endogenous iron and spatiotemporally control the lysosome-intrinsic Fenton chemistry, thereby triggering LMP-associated cell death. The process of endogenous iron mobilization occurs through two key steps: Cro-mediated coordination of abundant Fe3+ ions within lysosomes, followed by UV-emitting upconversion core-mediated photoreduction, resulting in Fe2+ ions release. Both in vitro and in vivo experiments show that UCNP-Cro/FA + NIR treatment effectively boost LMP by endogenous iron-mediated •OH production, ultimately triggering irreversible tumor cell death via ferroptosis and Caspase-1/GSDMD-dependent pyroptosis pathways. Moreover, this process potentiates tumor immunogenicity, holding promise for tumor immunotherapy. Overall, this work proposes a feasible tumor therapy strategy that integrates ferroptosis and pyroptosis through the efficient application and activation of endogenous iron.
    DOI:  https://doi.org/10.1038/s41467-025-58124-7
  9. Science. 2025 Mar 28. 387(6741): eadq8331
    Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins.
    Aakriti Jain, Isaac Heremans, Gilles Rademaker, Tyler C Detomasi, Peter Rohweder, Dashiell Anderson, Justin Zhang, Grace A Hernandez, Suprit Gupta, Teresa von Linde, Mike Lange, Martina Spacci, Jiayi Luo, Y Rose Citron, James A Olzmann, David W Dawson, Charles S Craik, Guido Bommer, Rushika M Perera, Roberto Zoncu.
      Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain-containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.
    DOI:  https://doi.org/10.1126/science.adq8331
  10. Biomolecules. 2025 Mar 04. pii: 370. [Epub ahead of print]15(3):
    Overexpression of Cx43: Is It an Effective Approach for the Treatment of Cardiovascular Diseases?
    Kerstin Boengler, Beatrice Mantuano, Shira Toledano, Ofer Binah, Rainer Schulz.
      In the heart, Connexin 43 (Cx43) is involved in intercellular communication through gap junctions and exosomes. In addition, Cx43-formed hemichannels at the plasma membrane are important for ion homeostasis and cellular volume regulation. Through its localization within nuclei and mitochondria, Cx43 influences the function of the respective organelles. Several cardiovascular diseases such as heart failure, ischemia/reperfusion injury, hypertrophic cardiomyopathy and arrhythmias are characterized by Cx43 downregulation and a dysregulated Cx43 function. Accordingly, a putative therapeutic approach of these diseases would include the induction of Cx43 expression in the damaged heart, albeit such induction may have both beneficial and detrimental effects. In this review we discuss the consequences of increasing cardiac Cx43 expression, and discuss this manipulation as a strategy for the treatment of cardiovascular diseases.
    Keywords:  cardiac disease; connexin; gap junction; hemichannel; mitochondria
    DOI:  https://doi.org/10.3390/biom15030370
  11. Cell Death Dis. 2025 Mar 27. 16(1): 214
    Tracking spatiotemporal distribution of organelle contacts in vivo with SPLICS reporters.
    Lucia Barazzuol, Tetiana Tykhonenko, Tia L Griffiths, Alessio Vagnoni, Marisa Brini, Tito Calì.
      Organelle contact sites are crucial for cellular function, enabling the exchange of lipids, ions, and other molecules between different organelles. The ability to track these contact sites in vivo has been significantly advanced by the development of SPLICS (Split-GFP-based Contact Site Sensors) reporters, which have provided unprecedented insights into the intricate network of organelle communication. This innovative and powerful tool allows the real-time visualization of different organelle interactions in living cells and in vivo thus unraveling the complexity of their dynamic in the context of cellular homeostasis. Recent studies highlighted the dynamic nature of organelle contact sites either in terms of tethering/untethering and of movement of the contact itself in time and space: whether unique temporal behaviors and contact site-specific dynamics of different organelle interactions exist is currently unknown. In this study, we investigated the spatiotemporal distribution of various organelle contact sites using time-lapse in vitro and in vivo imaging and discovered an evolutionarily conserved dynamic pattern among different contact sites, influenced by the specific partner organelles involved. These findings highlight the importance of spatial and temporal regulation at organelle contact sites, which may underlie their diverse physiological functions. The discovery of contact site-specific dynamics opens new avenues for understanding the regulation of organelle interactions in health and disease, with potential implications for developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-025-07511-5
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