bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–05–11
ten papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Key Mechanisms in Lysosome Stability, Degradation and Repair.
  2. Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model.
  3. Uncovering a key enzyme opens possible therapeutic avenues for lysosomal diseases.
  4. ER-to-lysosome-associated degradation.
  5. Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches.
  6. PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease.
  7. Unconventional secretion of PARK7 requires lysosomal delivery via chaperone-mediated autophagy and specialized SNARE complex.
  8. A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.
  9. Lysosomal EGFR functions as a GEF for Rheb.
  10. The role of sphingolipids in heart failure.
  1. Mol Cell Biol. 2025 May 09. 1-13
    Key Mechanisms in Lysosome Stability, Degradation and Repair.
    Rui Zhang, Marc A Vooijs, Tom Gh Keulers.
      Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.
    Keywords:  ESCRT; Lysosome stabilization; ROS; lipid peroxidation; lysophagy; lysosomal membrane permeabilization
    DOI:  https://doi.org/10.1080/10985549.2025.2494762
  2. Sci Adv. 2025 May 09. 11(19): eadr5703
    Niemann Pick C1 mistargeting disrupts lysosomal cholesterol homeostasis contributing to neurodegeneration in a Batten disease model.
    Abhilash P Appu, Maria B Bagh, Nisha Plavelil, Avisek Mondal, Tamal Sadhukhan, Satya P Singh, Neil J Perkins, Aiyi Liu, Anil B Mukherjee.
      Neurodegeneration is a devastating manifestation in most lysosomal storage disorders (LSDs). Loss-of-function mutations in CLN1, encoding palmitoyl-protein thioesterase-1 (PPT1), cause CLN1 disease, a devastating neurodegenerative LSD that has no curative treatment. Numerous proteins in the brain require dynamic S-palmitoylation (palmitoylation-depalmitoylation) for trafficking to their destination. Although PPT1 depalmitoylates S-palmitoylated proteins and its deficiency causes CLN1 disease, the underlying pathogenic mechanism has remained elusive. We report that Niemann-Pick C1 (NPC1), a polytopic membrane protein mediating lysosomal cholesterol egress, requires dynamic S-palmitoylation for trafficking to the lysosome. In Cln1-/- mice, Ppt1 deficiency misroutes NPC1-dysregulating lysosomal cholesterol homeostasis. Along with this defect, increased oxysterol-binding protein (OSBP) promotes cholesterol-mediated activation of mechanistic target of rapamycin C1 (mTORC1), which inhibits autophagy contributing to neurodegeneration. Pharmacological inhibition of OSBP suppresses mTORC1 activation, rescues autophagy, and ameliorates neuropathology in Cln1-/- mice. Our findings reveal a previously unrecognized role of CLN1/PPT1 in lysosomal cholesterol homeostasis and suggest that suppression of mTORC1 activation may be beneficial for CLN1 disease.
    DOI:  https://doi.org/10.1126/sciadv.adr5703
  3. Nature. 2025 May 07.
    Uncovering a key enzyme opens possible therapeutic avenues for lysosomal diseases.
      
    Keywords:  Cell biology; Diseases
    DOI:  https://doi.org/10.1038/d41586-025-01368-6
  4. Curr Biol. 2025 May 05. pii: S0960-9822(25)00384-7. [Epub ahead of print]35(9): R320-R322
    ER-to-lysosome-associated degradation.
    Maurizio Molinari.
      Maurizio Molinari introduces ER-to-lysosome-associated degradation - the autophagic and non-autophagic pathways that deliver ERAD-resistant misfolded proteins to the lysosome for degradation to maintain cellular proteostasis.
    DOI:  https://doi.org/10.1016/j.cub.2025.03.068
  5. Bioelectricity. 2025 Mar;7(1): 29-57
    Lysosomal Ion Channels and Transporters: Recent Findings, Therapeutic Potential, and Technical Approaches.
    Artem Kondratskyi, Andre Bazzone, Markus Rapedius, Rocco Zerlotti, Bastien Masson, Nidish Ponath Sadanandan, Joanne L Parker, Alexandre Santinho, Marine Moutia, Abdou Rachid Thiam, Arlene Kemp, Fitzwilliam Seibertz, Nicoletta Murciano, Søren Friis, Nadine Becker, Alison Obergrussberger, Maria Barthmes, Cecilia George, Michael George, David Dalrymple, Bruno Gasnier, Simon Newstead, Christian Grimm, Niels Fertig.
      In recent years, there has been a growing interest in lysosomal ion channels and transporters due to their critical role in maintaining lysosomal function and their involvement in a variety of diseases, particularly lysosomal storage diseases, cancer, and neurodegenerative disorders. Recent advancements in research techniques, including manual and automated patch clamp (APC) electrophysiology, solid-supported membrane-based electrophysiology (SSME), and fluorescence-based ion imaging, have further enhanced our ability to investigate lysosomal ion channels and transporters in both physiological and pathological conditions, spurring drug discovery efforts. Several pharmaceutical companies are now developing therapies aimed at modulating these channels and transporters to improve lysosomal function in disease. Small molecules targeting channels like transient receptor potential mucolipin (TRPML) 1 and TMEM175, as well as drugs modulating lysosomal pH, are currently in preclinical and clinical development. This review provides an overview of the role of lysosomal ion channels and transporters in health and disease, highlights the cutting-edge techniques used to study them, and discusses the therapeutic potential of targeting these channels and transporters in the treatment of various diseases. Furthermore, in addition to summarizing recent discoveries, we contribute novel functional data on cystinosin, TRPML1, and two-pore channel 2 (TPC2), utilizing both SSME and APC approaches.
    Keywords:  APC; SSME; electrophysiology; ion channels; lysosome; patch clamp; pumps; transporters
    DOI:  https://doi.org/10.1089/bioe.2025.0010
  6. Nature. 2025 May 07.
    PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease.
    Kwamina Nyame, Jian Xiong, Hisham N Alsohybe, Arthur P H de Jong, Isabelle V Peña, Ricardo de Miguel, Thijn R Brummelkamp, Guido Hartmann, Sebastian M B Nijman, Matthijs Raaben, Judith A Simcox, Vincent A Blomen, Monther Abu-Remaileh.
      Lysosomes catabolize lipids and other biological molecules, maintaining cellular and organismal homeostasis. Bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles, stimulates lipid-degrading enzymes and is altered in various human conditions, including neurodegenerative diseases1,2. Although lysosomal BMP synthase was recently discovered3, the enzymes mediating BMP turnover remain elusive. Here we show that lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that the resistance of BMP to lysosomal hydrolysis arises from its unique sn2, sn2' esterification position and stereochemistry, as neither feature alone confers resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes. Furthermore, PLA2G15 efficiently hydrolyses synthesized BMP stereoisomers with primary esters, challenging the long-held thought that BMP stereochemistry alone ensures resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate several BMP species, a phenotype reversible by supplementing wild-type PLA2G15 but not its inactive mutant. Targeting PLA2G15 reduces the cholesterol accumulation in fibroblasts of patients with Niemann-Pick disease type C1 and significantly ameliorates disease pathologies in Niemann-Pick disease type C1-deficient mice, leading to an extended lifespan. Our findings established the rules governing BMP stability in lysosomes and identified PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41586-025-08942-y
  7. Proc Natl Acad Sci U S A. 2025 May 13. 122(19): e2414790122
    Unconventional secretion of PARK7 requires lysosomal delivery via chaperone-mediated autophagy and specialized SNARE complex.
    Biplab Kumar Dash, Yasuomi Urano, Yuichiro Mita, Yuki Ashida, Ryoma Hirose, Noriko Noguchi.
      PARK7/DJ-1, a redox-sensitive protein implicated in neurodegeneration, cancer, and inflammation, exhibits increased secretion under stress. We previously demonstrated that, as a leaderless protein, PARK7 relies on an unconventional autophagy pathway for stress-induced secretion. The current study delves deeper into the mechanisms governing PARK7 secretion under oxidative stress triggered by the neurotoxin 6-hydroxydopamine (6-OHDA). Here, we revealed that 6-OHDA-induced autophagic flux is critical for PARK7 secretion. Downregulation of syntaxin 17 (STX17), a SNARE protein crucial for autophagosome-lysosome fusion and cargo degradation, hindered PARK7 secretion. Likewise, impairing lysosomal function with bafilomycin A1 (BafA1) or chloroquine (CQ) diminished PARK7 release, highlighting the importance of functional lysosomes, potentially in the form of secretory autolysosomes, in PARK7 release. We also found that 6-OHDA appeared to promote the unfolding of PARK7, allowing its selective recognition by the chaperone HSPA8 via KFERQ-like motifs, leading to PARK7 translocation to the lysosomal membrane through LAMP2 via chaperone-mediated autophagy (CMA). Additionally, a dedicated SNARE complex comprising Qabc-SNAREs (STX3/4, VTI1B, and STX8) and R-SNARE SEC22B mediates the fusion of PARK7-containing autolysosomes with the plasma membrane, facilitating the extracellular release of PARK7. Hence, this study uncovers a mechanism where 6-OHDA-induced autophagic flux drives the unconventional secretion of PARK7, involving CMA for PARK7 translocation to lysosomes and specialized SNARE complexes for membrane fusion events.
    Keywords:  PARK7/DJ-1; SNAREs; chaperone-mediated autophagy; secretory autolysosome; unconventional secretion
    DOI:  https://doi.org/10.1073/pnas.2414790122
  8. J Cell Sci. 2025 May 01. pii: jcs263907. [Epub ahead of print]138(9):
    A lipid in transit - the journey of cholesterol into the heart of mitochondrial research.
    Thomas Simmen, Luca Pellegrini.
      Mitochondrial cholesterol biology in non-steroidogenic tissues remains understudied in cell science. Although detecting cholesterol in mitochondria is challenging due to isolation difficulties, studies using mitoplasts (mitochondria stripped of their outer membrane) and imaging approaches confirm its presence in the inner mitochondrial membrane. Through analysis of published evidence and first-principles reasoning, we advance a model of cholesterol trafficking into and out of mitochondria via phospholipids at mitochondria-associated membranes (MAMs), challenging the traditional view of protein-driven transport. In this model, cholesterol enters mitochondria alongside phosphatidylserine and exits with phosphatidylethanolamine - either unchanged or in a hydroxylated form after modification by the enzyme CYP27A1. Strong cholesterol-phospholipid binding energies, ∼17 kcal/mol (71.128 kJ/mol), support this lipid-mediated mechanism, suggesting it complements protein-based pathways. Future research should explore how these mechanisms collaborate to regulate mitochondrial cholesterol trafficking. By rethinking cholesterol dynamics, we raise the possibility that cholesterol plays a larger role in mitochondrial biology, influencing membrane-dependent functions like cristae structure, respiratory efficiency and inter-organelle communication. This Perspective also highlights the potential of mitochondria to regulate both dietary and endogenous cholesterol flux and homeostasis across the cell.
    Keywords:  Lipid biology; Membrane trafficking; Organelles
    DOI:  https://doi.org/10.1242/jcs.263907
  9. Cell Res. 2025 May 07.
    Lysosomal EGFR functions as a GEF for Rheb.
    Tao Hou, Peiqiang Yan, Hiroyuki Inuzuka, Wenyi Wei.
      
    DOI:  https://doi.org/10.1038/s41422-025-01126-3
  10. Eur Heart J Open. 2025 May;5(3): oeaf035
    The role of sphingolipids in heart failure.
    Rana Hamouche, Scott A Summers, William L Holland, Sutip Navankasattusas, Stavros G Drakos, Eleni Tseliou.
      Advanced heart failure (HF) is characterized by changes in the structure, function, and metabolism of cardiac muscle. As the disease progresses, cardiomyocytes shift their ATP production from fatty acid oxidation to glycolysis. This shift results in an accumulation of lipid metabolites, particularly sphingolipids, which can disrupt normal cellular function and contribute to cardiac dysfunction. In animal models of obesity, accumulation of toxic sphingolipid metabolites in the heart has been described as cardiac lipotoxicity. In humans, HF is classified into two groups based on ejection fraction (EF): HF with reduced EF of less than 40% (HFrEF) and HF with preserved EF of greater than 50% (HFpEF). Despite shared risk factors and comorbidities, the structural and cellular differences between HFrEF and HFpEF distinguish them as separate conditions. Ceramides (Cer), a type of sphingolipid, have gained significant attention for their involvement in the development and prognosis of atherosclerotic disease and myocardial infarction, while sphingosine-1-phosphate, a downstream product of Cer, has shown cardioprotective properties. The aim of this review is to describe the role of sphingolipids in HF with reduced and preserved EF. By understanding the role of sphingolipids through animal and human studies, this review aims to pave the way for developing strategies that target abnormal signalling pathways in the failing heart, ultimately bridging the gap between scientific research and clinical applications.
    Keywords:  Ceramides; HFpEF; HFrEF; Heart failure; Sphingolipids
    DOI:  https://doi.org/10.1093/ehjopen/oeaf035
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