bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–08–31
seventeen papers selected by
Satoru Kobayashi, New York Institute of Technology



  1. Autophagy. 2025 Aug 28. 1-15
      Microautophagy is a selective cellular process in which endolysosomes directly engulf cytoplasmic cargo through membrane invagination. The regulatory mechanisms governing microautophagy remain poorly understood. Here, we identified the deacetylation of ATG16L1 as a critical regulator of LC3-associated lysosomal microautophagy. We demonstrate that ATG16L1 acetylation is dynamically controlled by the acetyltransferase KAT2B and the deacetylase HDAC3. Under lysosomal osmotic stress or glucose deprivation, HDAC3-mediated deacetylation of ATG16L1 within its WD40 domain promotes its interaction with V-ATPase, facilitating ATG16L1 recruitment to lysosomal membranes. While dispensable for macroautophagy, this post-translational modification is essential for LC3 lipidation on lysosomes and enables lysosomal recovery, including the restoration of lysosomal size and degradative capacity following stress. Our results reveal a key role for ATG16L1 deacetylation in driving LC3-associated microautophagy to maintain lysosomal homeostasis.
    Keywords:  ATG16L1; Acetylation; LC3 lipidation; LC3-associated microautophagy; V-ATPase; lysosome
    DOI:  https://doi.org/10.1080/15548627.2025.2551669
  2. Science. 2025 Aug 21. 389(6762): eadz0972
      Lysosomal vacuolation is commonly found in many pathophysiological conditions, but its molecular mechanisms and functions remain largely unknown. Here, we show that the endoplasmic reticulum (ER)-anchored lipid transfer protein PDZ domain-containing 8 (PDZD8), which we propose to be renamed as lysosomal vacuolator (LYVAC), is a general mediator of lysosomal vacuolation. Using human cell lines, we found that diverse lysosomal vacuolation inducers converged on lysosomal osmotic stress, triggering LYVAC recruitment through multivalent interactions. Stress-induced lysosomal lipid signaling contributed to both the recruitment and activation of LYVAC. By directly sensing lysosomal phosphatidylserine and cholesterol, the lipid transfer domain of LYVAC mediated directional ER-to-lysosome lipid movement, leading to osmotic membrane expansion of lysosomes. These findings uncover an essential mechanism for lysosomal vacuolation with broad implications in pathophysiology.
    DOI:  https://doi.org/10.1126/science.adz0972
  3. Nat Commun. 2025 Aug 21. 16(1): 7812
      Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. We extend this concept by showing that oncogenic KRASG12D signaling can be potently inhibited by LYMTACs. Mechanistically, LYMTACs display multi-pharmacology and exert their activity through both target relocalization into the lysosome and degradation. We further generalize LYMTACs across various LMPs and thus offer a platform to access challenging membrane proteins through targeted protein relocalization and degradation.
    DOI:  https://doi.org/10.1038/s41467-025-63128-4
  4. Trends Immunol. 2025 Aug 22. pii: S1471-4906(25)00181-4. [Epub ahead of print]
      Metabolic reprogramming and signaling are key orchestrators of T cell immunity. Recent studies have illustrated important roles for intracellular organelles, especially mitochondria and lysosomes, in enforcing T cell metabolism and signaling in response to various extracellular cues. As such, mitochondrial and lysosomal function contributes to adaptive immunity by regulating T cell activation, differentiation, and functional adaptation. In this Review, we discuss how the interplay between organelle biology and metabolism instructs T cell-mediated immunity, with a particular focus on mitochondria and lysosomes. We also summarize how mitochondria and lysosomes, or their crosstalk with other organelles, orchestrate downstream signaling processes and functional reprogramming of T cells. We conclude with a discussion of the pathophysiological outcomes associated with dysregulation of these organelles.
    Keywords:  T cells; immunometabolism; lysosomes; metabolic signaling; mitochondria; organelle crosstalk
    DOI:  https://doi.org/10.1016/j.it.2025.07.014
  5. Science. 2025 Aug 21. 389(6762): 782-783
      The endoplasmic reticulum donates lipids through a tunnel-like protein to help lysosomes expand.
    DOI:  https://doi.org/10.1126/science.aea5377
  6. Cell Rep. 2025 Aug 22. pii: S2211-1247(25)00950-7. [Epub ahead of print]44(9): 116179
      ATP13A2 is an endolysosomal polyamine transporter mutated in several neurodegenerative conditions involving lysosomal defects, including Parkinson's disease (PD). While polyamines are polybasic and polycationic molecules that play pleiotropic cellular roles, their specific impact on lysosomal health is unknown. Here, we demonstrate lysosomal polyamine accumulation in ATP13A2 knockout (KO) cell lines and human induced pluripotent stem cell (iPSC)-derived neurons. Primary polyamine storage caused secondary storage of lysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP) and an age-dependent increase in the β-glucocerebrosidase (GCase) substrate glucosylsphingosine in Atp13a2 KO brains. Polyamine accumulation inhibited lysosomal GCase activity in cells, and this was reversed by lysosome reacidification or BMP supplementation. A liposome-based GCase assay utilizing physiological substrates demonstrated dose-dependent inhibition of BMP-stimulated GCase activity by polyamines, in part via a pH-independent, electrostatics-based mechanism. Therefore, excess polyamine compromises lysosomes by disrupting pH and electrostatic interactions between GCase and BMP that enable efficient substrate hydrolysis, potentially clarifying pathogenic mechanisms and suggesting convergence on PD-relevant pathways.
    Keywords:  CP: Neuroscience; Kufor-Rakeb syndrome; P-type ATPase; Parkinson’s disease; glucocerebrosidase; glycosphingolipid; lysosomal storage disorder; neuronal ceroid lipofuscinosis; polyamine; spermine
    DOI:  https://doi.org/10.1016/j.celrep.2025.116179
  7. Anal Methods. 2025 Aug 22.
      Lysosomal pH is important for regulating various physiological processes, and slight fluctuations in lysosomal pH can induce many adverse effects on cellular status, such as inflammation, aging, and tumours. Heat stroke is one of the most serious causes of morbidity and mortality. However, the relationship between heat shock and lysosomal pH values is still poorly understood. Herein, we introduced a colorimetric and turn-on fluorescent probe in the red to NIR range for monitoring lysosomal pH values. The probe can selectively accumulate in lysosomes with a high Pearson's coefficient (0.95), and the suitable pKa value (6.73 ± 0.07) enables the probe to visualize changes in lysosomal pH values during the stimulation by chloroquine and heat stroke, respectively.
    DOI:  https://doi.org/10.1039/d5ay00791g
  8. Mol Cell. 2025 Aug 19. pii: S1097-2765(25)00656-2. [Epub ahead of print]
      Ferroptosis is a form of cell death caused by iron-dependent phospholipid peroxidation and subsequent membrane rupture. Autophagic degradation of the iron-storage protein ferritin promotes ferroptosis by increasing cytosolic bioactive iron, presumably explaining how lysosomal inhibitors suppress ferroptosis. Surprisingly, we found that lysosomal inhibitors suppress cysteine-deprivation-induced (CDI) ferroptosis, even in autophagy-defective cells, and subsequently discovered that clathrin-mediated endocytosis (CME) of transferrin is essential for CDI ferroptosis. Blocking lysosomal proteolytic activity failed to inhibit ferroptosis, whereas disrupting endosomal acidification and eliminating the endocytic protein AP2M1 both impeded ferroptosis. Conversely, replenishing cellular iron with ferric ammonium citrate, but not with transferrin, restored CDI ferroptosis in endocytosis-deficient cells. Unexpectedly, abolishing endosomal acidification, CME, and the associated increase in cellular labile iron could not prevent ferroptosis triggered by direct inhibition of the ferroptosis-suppressing enzyme glutathione peroxidase-4 (GPX4). Together, this study reveals the essential role of endocytosis, specifically for CDI ferroptosis.
    Keywords:  AP2M1; GPX4; autophagy; cysteine deprivation; endocytosis; endosome; ferroptosis; iron; lysosome; transferrin
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.006
  9. Nature. 2025 Aug 20.
      The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability1-5. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. 6-9). GATOR2 forms an octagonal cage, with its distinct WD40 domain β-propellers interacting with GATOR1 and the leucine sensors Sestrin1 and Sestrin2 (SESN1 and SESN2) and the arginine sensor CASTOR1 (ref. 10). The mechanisms through which these sensors regulate GATOR2 and how they detach from it upon binding their cognate amino acids remain unknown. Here, using cryo-electron microscopy, we determined the structures of a stabilized GATOR2 bound to either Sestrin2 or CASTOR1. The sensors occupy distinct and non-overlapping binding sites, disruption of which selectively impairs the ability of mTORC1 to sense individual amino acids. We also resolved the apo (leucine-free) structure of Sestrin2 and characterized the amino acid-induced structural rearrangements within Sestrin2 and CASTOR1 that trigger their dissociation from GATOR2. Binding of either sensor restricts the dynamic WDR24 β-propeller of GATOR2, a domain essential for nutrient-dependent mTORC1 activation. These findings reveal the allosteric mechanisms that convey amino acid sufficiency to GATOR2 and the ensuing structural changes that lead to mTORC1 activation.
    DOI:  https://doi.org/10.1038/s41586-025-09428-7
  10. Cell Rep. 2025 Aug 21. pii: S2211-1247(25)00957-X. [Epub ahead of print]44(9): 116186
      Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identify regulators in glucose-starvation-induced cell death and find a group of genes in lysosomal pathway is enriched following glucose starvation. We focus on one candidate gene, Transcriptional Factor 25 (TCF25). We find TCF25 enhances lysosomal acidification by targeting V-ATPase, promoting autophagy and ATP generation under glucose starvation. However, prolonged glucose starvation constitutively activates ferritinophagy via TCF25, increasing lysosomal membrane permeability (LMP) and leading to lysosome-dependent cell death (LDCD). Knocking out TCF25 or V-ATPase components prevents cell death. Furthermore, TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury. Our findings identify TCF25 as a crucial nutrient sensor that regulates lysosomal activity, offering potential therapeutic targets for metabolic and ischemic disorders.
    Keywords:  CP: Cell biology; CP: Metabolism; TCF25; cell death; glucose starvation; lysosome; metabolic adaptation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116186
  11. Nat Commun. 2025 Aug 22. 16(1): 7811
      Mitochondria-lysosome interactions are critical for maintaining cellular homeostasis. Although genetically encoded protein based optogenetic technique is developed to regulate such interactions, it still suffers from shortcomings including complicated operation and potential interference to organelle functions. Here, we present a fast, simple, biocompatible and programmable platform via activable DNA regulators to achieve spatiotemporal regulation of mitochondria-lysosome interactions in living cells. In our system, two locked DNA regulators, OK-MLIR and DK-MLIR, that can be respectively activated with UV light (One Key) as well as UV light and endogenous glutathione (Dual Keys), are modularly designed for modulating mitochondria-lysosome contacts. We show that these DNA regulators can be used for facilitating mitochondrial fission and autophagy. Moreover, the DK-MLIR enables selective and efficient manipulation of target cell migration and proliferation with highly temporal and spatial controllability. This programmable and modular design principle provides a platform for organelle interaction study, cellular regulation and precision therapy.
    DOI:  https://doi.org/10.1038/s41467-025-63040-x
  12. Med Rev (2021). 2025 Aug;5(4): 297-317
      Macroautophagy/autophagy is a lysosome-dependent degradation process involved in cellular energy metabolism, recycling and quality control. Autophagy is a highly dynamic and precisely regulated process, which contains four major steps: autophagic membrane initiation and cargo recognition, autophagosome formation, autophagosome-lysosome fusion and lysosomal degradation. During the terminal phase of autophagy, the merging of the autophagosome and lysosome membranes is critical for the effective breakdown of sequestered cargoes. However, the participated molecules and the interplay among them have not been fully uncovered. The spatiotemporal property of these molecules is crucial for maintaining the orderly fusion of autophagosomes and lysosomes, otherwise it may lead to fusion disorders. In this article, we tend to summarize the molecules mediating autophagosome-lysosome fusion into two categories: effector molecules and regulatory molecules. The effector molecules are soluble N-ethylmaleimide-sensitive factor attachment protein receptor and tethering proteins, and the latter category contains phosphatidylinositol, Rab GTPases and ATG8-family proteins. The spatio-temporal properties of these autophagosome-lysosome fusion mediating molecules will be featured in this review.
    Keywords:  autophagosome-lysosome fusion; autophagy; sensitive factor attachment protein receptor; syntaxin 17
    DOI:  https://doi.org/10.1515/mr-2024-0095
  13. Front Endocrinol (Lausanne). 2025 ;16 1641114
       Objective: Diabetic cardiomyopathy (DCM) is a myocardial dysfunction disorder driven by diabetes-associated metabolic disorders, significantly elevating the risk of heart failure in patients with type 2 diabetes mellitus (T2DM). We aimed to develop and validate a nomogram for individualized DCM risk prediction in T2DM populations.
    Methods: This retrospective study enrolled 525 consecutive T2DM patients admitted to our hospital (June 2022-June 2024). Participants were randomly allocated to training (70%) or validation (30%) cohorts. Baseline clinical characteristics, laboratory profiles, and echocardiographic parameters were collected. Predictors were identified via univariate then multivariate logistic regression, followed by nomogram construction. Model validation included: (1) internal validation via 1000 bootstrap resamples; (2) discrimination assessed by the area under the receiver operating characteristic curve (AUC-ROC); (3) calibration evaluated using calibration plots and the Hosmer-Lemeshow goodness-of-fit test; (4) clinical utility determined by decision curve analysis (DCA) and clinical impact curves (CIC).
    Results: Six independent predictors-age, duration of type 2 diabetes mellitus (T2DM Duration), systolic blood pressure (SBP), urinary albumin-to-creatinine ratio (UACR), left atrial diameter (LAD), and left ventricular posterior wall thickness at end-diastole (LVPWd)-were incorporated. The model showed excellent discrimination: AUC 0.947 (95% CI: 0.916-0.967) in training and 0.922 (95% CI: 0.870-0.956) in validation cohorts. Calibration indicated strong agreement (Hosmer-Lemeshow χ² = 9.2119, P = 0.3247). DCA and CIC confirmed clinical utility.
    Conclusions: This nomogram integrates routine clinical/echocardiographic parameters to predict DCM risk in T2DM patients, facilitating individualized risk stratification and guiding early cardioprotective interventions in high-risk populations.
    Clinical Trial Registration: https://www.chictr.org.cn/index.html, identifier ChiCTR2400093755.
    Keywords:  diabetic cardiomyopathy; echocardiographic; nomogram; risk prediction model; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3389/fendo.2025.1641114
  14. Nature. 2025 Aug 20.
      Eukaryotic cells produce over 1,000 different lipid species that tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unclear, owing to the difficulty of imaging lipid transport in cells3. Here we measured the retrograde transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high-resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting, in contrast to the slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between energy-dependent lipid flipping and non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids, while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09432-x
  15. Nat Cell Biol. 2025 Aug 25.
      Understanding how cells mitigate lysosomal damage is critical for unravelling pathogenic mechanisms of lysosome-related diseases. Here we generate and characterize induced pluripotent stem cell (iPSC)-derived neurons (i3Neuron) bearing ceroid lipofuscinosis neuronal 4 (CLN4)-linked DNAJC5 mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosomal damages caused by lysosome-associated CLN4 mutant aggregates, as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP's lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i3Neurons and effectively alleviates lipofuscin accumulation and cell death in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, offering new insights into therapeutic development for lysosome-related neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41556-025-01738-2
  16. JACC Basic Transl Sci. 2025 Aug 21. pii: S2452-302X(25)00297-9. [Epub ahead of print]10(9): 101345
      A substantial component of the increasing global burden of cardiovascular disease is attributed to heart failure (HF), affecting over 64 million adults worldwide. Maladaptive mitochondrial respiratory alterations and oxidative stress are major contributors to HF development and progression, with subsequent downstream myocardial energetic impairment as a strong predictor of mortality. Current conventional therapeutic approaches, including renin-angiotensin-aldosterone system inhibition and β-adrenergic blockade, target neurohormonal aspects of HF and are effective in slowing disease progression. However, although these therapies may be associated with some improvement in myocardial energetics, they do not specifically address alterations in myocardial mitochondrial respiration or redox homeostasis. Targeting mitochondria has hence become a promising approach for more effective and tailored therapies. This review summarizes metabolic derangements that drive HF progression, with a specific focus on mitochondria. Importantly, here we address the essential knowledge gaps in the field, highlighting key translational strategies used to date, and the challenges associated with therapeutically targeting mitochondrial pathways, alongside recent developments seeking to deploy novel mitochondrial-targeted therapeutic approaches to treat HF.
    Keywords:  cardiomyopathy; drug discovery; myocardial metabolism; oxidative stress; pharmacotherapy; respiration
    DOI:  https://doi.org/10.1016/j.jacbts.2025.101345
  17. New Phytol. 2025 Aug 22.
      Recent studies across biological systems highlight an important function of biomolecular condensates (hereafter biocondensates) in regulating physiology. Biocondensates are membraneless organelles that compartmentalize cellular processes and allow regulatory control of key biomolecules through their assembly and disassembly. Biocondensates have been identified in molecular pathways ranging from RNA regulation to metabolism to seed germination in plants. In this review, we focus on biocondensates that control metabolism. Most of this review addresses metabolic biocondensates in bacteria, algae, and animals whose functions are involved in core metabolism relevant to plants, even if their existence as metabolic biocondensates has not yet been described in plants. We hope this review provides useful information for a broad audience and encourages new directions into previously characterized enzymes and pathways to understand how their subcellular localization could impact function.
    Keywords:  bacterial microcompartment; biomolecular condensate; membraneless organelle; metabolic biocondensate; metabolon; plant cell biology
    DOI:  https://doi.org/10.1111/nph.70474