bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–11–15
eight papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. CASM regulates lysosomal expansion and cell fate during senescence.
  2. TMEM192 is a calcineurin-regulated membrane receptor for ubiquitin-independent lysophagy.
  3. Elucidating lysosomal dysfunction in cardiac fibrosis progression: Molecular understanding and pharmacological targeting strategies.
  4. TMEM184 proteins are Ca2+ uptake transporters in lysosomes.
  5. Theoretical considerations regarding an acidic nanolayer surrounding lysosomes.
  6. Noncanonical role of copper ATPase ATP7B in cadmium detoxification via lysosomal adaptation.
  7. Animal models and lysosomal pathogenesis of atherosclerosis.
  8. Progranulin haploinsufficiency disrupts cathepsin D function, resulting in lysosomal abnormalities and elevated TDP-43 levels in the mouse brain.
  1. JCI Insight. 2026 Nov 09. pii: e207890. [Epub ahead of print]11(21):
    CASM regulates lysosomal expansion and cell fate during senescence.
    Yu-Wei Cheng, Michael Z Gao, Jay Xiaojun Tan, Jie Liu, Toren Finkel.
      Cellular senescence, a hallmark of aging, is accompanied by a striking expansion of the cell's lysosomal compartment, yet the pathway leading to increased lysosomal content remains unresolved. Here, we demonstrate that the master lysosomal transcriptional regulator TFEB is activated during senescence through a pathway that involves conjugation of ATG8 onto single membranes (CASM). Using various senescence inducers, we show that senescence induction triggers robust TFEB nuclear translocation and upregulation of TFEB target genes. In contrast, inhibition of the core CASM machinery by CRISPR-mediated deletion of either ATG16L1, ATG12, or ATG5 markedly reduced senescence-induced TFEB nuclear translocation. In ATG16L1-KO cells, reconstitution with WT ATG16L1 but not the CASM-defective ATG16L1F467A mutant restored both ATG8 lipidation on the lysosomal surface and TFEB activation. Moreover, expression of the Salmonella effector protein SopF, a previously described specific CASM inhibitor, similarly blocked senescence-induced TFEB translocation. Functionally, upon stress, CASM-deficient cells exhibited a pronounced shift away from senescence and toward a cell death fate, a phenotype reversed by expressing a constitutively active form of TFEB. Together, these findings identify CASM-dependent TFEB activation as an essential mechanism enabling senescence-associated lysosomal expansion and suggest that lysosomal capacity modulates cell fate decisions in the aftermath of acute stress.
    Keywords:  Aging; Cell biology; Lysosomes
    DOI:  https://doi.org/10.1172/jci.insight.207890
  2. Nat Cell Biol. 2026 Nov 12.
    TMEM192 is a calcineurin-regulated membrane receptor for ubiquitin-independent lysophagy.
    Xinchang Liu, Yangjun Yang, Wenchan Li, Kesong Peng, Xiangmin Qiu, Ye Xu, Sai Zeng, Dante Neculai, Qiming Sun, Tianhua Zhou, Han-Ming Shen, Wei Liu.
      Lysophagy is a selective form of autophagy responsible for clearing damaged lysosomes. Although existing models predominantly highlight ubiquitin-dependent mechanisms, here we identify the lysosomal membrane protein TMEM192 as a key ubiquitin-independent receptor for lysophagy. We demonstrate that lysophagy persists in cells even when protein ubiquitination is inhibited or autophagy adaptors are deleted. Following lysosomal damage, the efflux of calcium from lysosomes activates calcineurin, leading to the dephosphorylation of TMEM192 at Ser229. This exposes a latent LC3-interacting region and enables direct recruitment of autophagosomes. Depletion of TMEM192 or blockade of its dephosphorylation severely impairs lysophagy, resulting in the accumulation of damaged lysosomes. In a mouse model of acute hyperuricemic nephropathy, deficiency in TMEM192 exacerbates renal tubular injury. Our findings establish a ubiquitin-independent lysophagy pathway, which holds important implications for understanding and intervening lysosomal-related diseases.
    DOI:  https://doi.org/10.1038/s41556-026-02135-z
  3. Eur J Pharmacol. 2026 Nov 10. pii: S0014-2999(26)01019-8. [Epub ahead of print]1040 179537
    Elucidating lysosomal dysfunction in cardiac fibrosis progression: Molecular understanding and pharmacological targeting strategies.
    Sangita Ghosh, Mansi Vinodkumar Trivedi, Anil Bhanudas Gaikwad.
      Cardiac fibrosis is a critical pathological condition characterized by an excessive accumulation of extracellular matrix components resulting from persistent cellular stress, inflammation, oxidative stress, and organelle dysfunction. These insoluble fibers form a 3D matrix that is evident in numerous heart-related conditions, including myocardial infarction, heart failure, cardiomyopathies, and hypertension. Cardiomyocytes, unlike fibroblasts and endothelial cells, are post-mitotic and rely heavily on cellular quality-control systems to sustain their workload. Lysosomes, a single-lipid-bilayered membrane-bound organelle, are one of the important organelles that maintain cellular homeostasis by degrading and recycling cellular debris. Autophagy is one of the catabolic processes that is heavily reliant on lysosomes to form autolysosomes, which help degrade and recycle cellular components, proteins, and lipids, and maintain cellular homeostasis. Recently, lysosomal dysfunction has been found to play a critical contributing role in modulating cardiac fibrosis. The involvement of lysosomal dysfunction in mediating cardiac fibrosis progression involves several intriguing mechanisms that regulate lysosomal integrity, including V-ATPase, transcription factor EB (TFEB), lysosomal-associated membrane protein-2 (LAMP-2), cathepsin B, and chaperone-mediated autophagy, among others. The subsequent review, therefore, demonstrates the role of lysosomes in physiological and pathological heart conditions, with a particular emphasis on cardiac fibrosis, the central mechanism underlying the most aggressive stages of cardiac disease. The correlation between lysosomal dysfunction and cardiac fibrosis, as well as the interconnections and cellular pathways linking them, is discussed, along with emerging preclinical and clinical investigations that could be pursued to elucidate the role of lysosomal dysfunction in cardiac fibrosis progression.
    Keywords:  ATB2005A; Autophagy; Cardiac fibrosis; Corosolic acid; Lysosome; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179537
  4. Science. 2026 Nov 12. 394(6825): eaeh3996
    TMEM184 proteins are Ca2+ uptake transporters in lysosomes.
    Weijie Cai, Yalan Wang, Fangqian Huang, Yulou Zhang, Mingxue Gu, Chuanyan Yang, Ping Li, Wenfeng Jiang, Xiaotong Yang, Xiaodong Xu, Xiangli Li, Demin Ma, Fan Xia, Zijie Xu, Yuxin Liu, Vanity Spruill, Jiangtao Guo, Suhong Xu, Youjun Wang, Yamuna Krishnan, Liping Qiu, Meiqin Hu, Haoxing Xu.
      Lysosomal Ca2+ release from acidic stores is critical for lysosomal function, yet the molecular identity of the Ca2+ uptake conduit has remained elusive. We used a Ca2+-imaging-based genetic screen of the lysosomal membrane proteome to identify TMEM184 family proteins as lysosomal Ca2+ transporters (LyCaTs) essential for Ca2+ uptake and refilling. TMEM184 selectively transported Ca2+ while excluding monovalent cations. Loss of TMEM184B/C depleted lysosomal Ca2+ stores, diminished Ca2+ release, and disrupted lysosomal exocytosis, biogenesis, and membrane repair, thus phenocopying the release channel transient receptor potential mucolipin 1 (TRPML1) deficiency. Moreover, a human TMEM184B mutation associated with a neurodevelopmental disorder compromised lysosomal Ca2+ transport, and Tmem184b-deficient mice exhibited profound motor impairment. Thus, TMEM184 constitutes the long-sought Ca2+ uptake and refilling mechanism that governs lysosomal signaling and homeostasis.
    DOI:  https://doi.org/10.1126/science.aeh3996
  5. Nat Cell Biol. 2026 Nov 10.
    Theoretical considerations regarding an acidic nanolayer surrounding lysosomes.
    Walter F Boron, Shawn M Ferguson, Spencer Freeman, Christian Grimm, Frederick R Maxfield, Shmuel Muallem, Rajan Sah, Santiago Solé-Domènech, Sergio Grinstein, Thomas J Jentsch.
      
    DOI:  https://doi.org/10.1038/s41556-026-02125-1
  6. FEBS Lett. 2026 Nov 11.
    Noncanonical role of copper ATPase ATP7B in cadmium detoxification via lysosomal adaptation.
    Debosmita Bhattacharya, Kaustav Chakraborty, Raviranjan Pandey, Brindaban Maji, Ashima Bhattacharjee, Arnab Gupta.
      Cadmium, a highly toxic metal, disrupts cellular homeostasis by forming stable complexes with thiol-active proteins, leading to severe liver and lung damage. Despite its toxicity, the mechanisms underlying cadmium export remain poorly understood. Owing to chemical similarity between cadmium and copper, we investigated the role of copper-exporting ATPases-ATP7A and ATP7B-in cadmium handling. In hepatocytes, cadmium exposure triggers ATP7B trafficking to lysosomes via the retromer complex, accompanied by expansion of acidic lysosomal populations and function. In contrast, ATP7A in lung adenocarcinoma cells undergoes vesicular redistribution without lysosomal sequestration. ATP7B-deficient hepatocytes display heightened cadmium sensitivity. Lysosomal defective and Cu-ATPase knockout Caenorhabditis elegans exhibit similar enhanced toxicity, highlighting a noncanonical role of copper ATPase synergised with lysosomal exocytosis pathway in cadmium detoxification.
    Keywords:  ATP7B; cadmium; copper metabolism; lysosome; lysosome‐related organelle
    DOI:  https://doi.org/10.1002/1873-3468.70506
  7. Anim Adv. 2025 ;2 e005
    Animal models and lysosomal pathogenesis of atherosclerosis.
    Zhengchao Wang, Xiang Li, Alexandra K Moura, Jenny Z Hu, Yunting Wang, Yang Zhang.
      Atherosclerosis represents a leading cause of cardiovascular disease. Its onset and progression involve complex mechanisms, including inflammation, dysregulation of lipid metabolism, lysosomal dysfunction, and other contributing factors. As intracellular organelles responsible for degradation, lysosomes not only participate in lipid metabolism but also play a pivotal role in foam cell formation and the stabilization of arterial plaques. In recent years, various animal models have been employed to investigate the relationship between lysosomal dysfunction and atherosclerosis, offering novel insights into its pathogenesis and potential therapeutic strategies. This review systematically examines the types of atherosclerosis animal models, the lysosomal mechanisms underlying atherosclerosis, and the prospects and challenges associated with these models. These insights aim to facilitate a deeper understanding of the molecular pathological mechanisms of atherosclerosis and offer novel directions and a robust theoretical foundation for the prevention and treatment of cardiovascular diseases.
    DOI:  https://doi.org/10.48130/animadv-0025-0003
  8. Front Mol Neurosci. 2026 ;19 1970154
    Progranulin haploinsufficiency disrupts cathepsin D function, resulting in lysosomal abnormalities and elevated TDP-43 levels in the mouse brain.
    Raheem Fazal, Arun Kumar Tharkeshwar, Sander Beel, Annet Storm, Begga Schevenels, Sandra O Tomé, Dietmar R Thal, Ludo Van Den Bosch, Jimmy Beckers, Philip Van Damme.
       Introduction: Frontotemporal dementia (FTD) is a leading cause of early-onset neurodegeneration, frequently linked to mutations in the GRN gene, which encodes the protein progranulin (PGRN). PGRN is known to play a crucial role in lysosomal function, and its deficiency contributes to FTD pathogenesis. Here, we examined the consequences of PGRN loss on lysosomal homeostasis, focusing on the lysosomal protease cathepsin D (CTSD) and TAR DNA-binding protein 43 (TDP-43) aggregation, hallmarks of FTD and related neurodegenerative diseases.
    Methods: Using mouse models with homozygous and heterozygous GRN deletions and double knockouts for GRN and CTSD, we assessed lysosomal function, CTSD expression and activity, lysosomal-associated membrane protein (LAMP) levels and localization, TDP-43 aggregation, and survival.
    Results: PGRN deficiency resulted in significant alterations in lysosomal function. Despite significantly elevated levels of mature and immature CTSD in PGRN-deficient mice, enzymatic activity was significantly reduced. PGRN deficiency also caused accumulation of lysosomal-associated membrane protein (LAMP) and perinuclear clustering of LAMP1-positive lysosomes, suggestive of disrupted lysosomal trafficking. Correspondingly, insoluble TDP-43 levels significantly increased, implicating lysosomal impairment in defective protein degradation and aggregation. Remarkably, double-knockout mice lacking both PGRN and CTSD exhibited significantly shortened lifespans, highlighting a potential functional interaction between these proteins in maintaining neuronal health and longevity.
    Discussion: These findings underscore the importance of PGRN as a central regulator of lysosomal function and protein homeostasis. Together, the data provide mechanistic insight into PGRN-dependent lysosomal biology and identify pathways that may contribute to GRN-associated FTD and other neurodegenerative disorders.
    Keywords:  TDP-43; cathepsin D; frontotemporal dementia; lysosomes; neurodegeneration; progranulin
    DOI:  https://doi.org/10.3389/fnmol.2026.1970154
This page is being maintained by Thomas Krichel. It was last updated on 2026‒11‒15 at 5:58.