bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2026–08–30
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. From plasma membrane to lysosomes: expanding roles of TMEM63/OSCA channels in mechanosensation and intracellular signaling.
  2. Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling.
  3. TFEB and MCOLN1 are important for Coxiella burnetii egress via lysosomal exocytosis.
  4. Endolysosomal remodeling and acidity dictates ferroptosis sensitivity to iron oxide nanoparticles.
  5. Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.
  6. Lipid-manager autophagy proteins ATG2 and ATG9 regulate extracellular vesicle secretion via amphisome biogenesis and cell lipidome modulation.
  7. Organelle network dysfunction in primary cardiomyopathy: An integrated perspective on pathogenesis and therapeutics.
  1. Front Pharmacol. 2026 ;17 1909797
    From plasma membrane to lysosomes: expanding roles of TMEM63/OSCA channels in mechanosensation and intracellular signaling.
    Serap Erdogmus, Gurkan Mollaoglu, Ursula Storch.
      Mechanosensation enables cells to detect physical forces, including membrane stretch, pressure, shear stress, and osmotic stress, and to convert them into biochemical and electrical signals that regulate cellular function. Among the emerging families of mechanosensitive proteins, TMEM63/OSCA channels have recently been recognized as evolutionarily conserved mechanically activated ion channels with important roles in cellular and organellar physiology. While mechanosensation has traditionally been studied at the plasma membrane, increasing evidence suggests that intracellular organelles also experience and respond to mechanical cues. Lysosomes are particularly exposed to membrane tension, curvature changes, osmotic fluctuations, and cytoskeletal forces generated during trafficking, fusion-fission dynamics and cargo loading. These observations support an emerging view of lysosomes as dynamic hubs of mechano-responsive signaling in addition to their established degradative functions. Recent studies have identified TMEM63 proteins at both the plasma membrane and lysosomes, where they are proposed to couple mechanical and osmotic stimuli to ion flux, membrane remodeling, and stress-adaptive signaling pathways. In this review, we summarize current advances in the structural biology, gating mechanisms, and physiological functions of TMEM63/OSCA channels with particular emphasis on their emerging roles in lysosomal mechanobiology. We further discuss evidence linking TMEM63/OSCA dysfunction to human channelopathies and highlight key questions regarding mechanosignaling across cellular compartments. By integrating recent findings from mechanobiology, organelle physiology, and disease genetics, this review positions TMEM63 channels as an important molecular link between membrane mechanics, lysosomal function, and cellular homeostasis.
    Keywords:  OSCA; TMEM63; ion channel; lipid scramblase; lysosome; mechanosensation; mechanotransduction
    DOI:  https://doi.org/10.3389/fphar.2026.1909797
  2. Sci Adv. 2026 Aug 28. 12(35): eaec4519
    Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling.
    Kohta Takahashi, Nario Tomishige, Mitsuhiro Abe, Gašper Šolinc, James Rae, Toshiyuki Yamaji, Frédéric Przybilla, Ludovic Richert, Nicolas Humbert, Takefumi Uemura, Thomas Wollert, Satoshi Waguri, Kentaro Hanada, Yasushi Sako, Gregor Anderluh, Robert G Parton, Yves Mély, Catherine Tomasetto, Fabien Alpy, Toshihide Kobayashi.
      The physiological role of lipid asymmetry in intracellular membranes remains poorly understood. Here, we show that sphingomyelin (SM), typically confined to the lumen of the trans-Golgi network (TGN), is exposed on its cytoplasmic surface by the action of the Golgi-associated protein, Golgi-associated gamma-adaptin ear-containing adenosine 5'-diphosphate-ribosylation factor-binding protein 1 (GGA1). This exposure is driven by the GGA1 GAT domain, which induces lipid scrambling in a manner dependent on membrane curvature and cholesterol. SM exposure coincides with the exit of mannose 6-phosphate receptors from the TGN, a process essential for lysosomal enzyme trafficking. Furthermore, SM is transferred to autophagic membranes, where it facilitates autophagosome-lysosome fusion. These findings reveal a previously unrecognized role for lipid remodeling in membrane trafficking and autophagy.
    DOI:  https://doi.org/10.1126/sciadv.aec4519
  3. Front Cell Infect Microbiol. 2026 ;16 1835140
    TFEB and MCOLN1 are important for Coxiella burnetii egress via lysosomal exocytosis.
    Sven Rinkel, Jan Schulze-Luehrmann, Bhavyalakshmi Kadavil Baburaj, Fiona Weber, Elisabeth M Liebler-Tenorio, Anja Lührmann.
      Coxiella burnetii is a Gram-negative, obligate intracellular pathogen and the causative agent of the zoonotic disease Q fever. Resident alveolar macrophages are the first target cells, but C. burnetii spreads to other cell types. While we have information about C. burnetii uptake and the establishment of the replication-competent phagolysosomal-like C. burnetii-containing vacuole (CCV), it is not well studied how C. burnetii exits its host cell. Here, we show that an infection with C. burnetii also triggers the activation of TFEB, a master regulator of autophagy and lysosomal development. The activation occurs in a time-dependent manner and depends on the size of the CCV. Crucially, TFEB activation during C. burnetii infection depends on MCOLN1, which channels Ca2+ across the lysosomal membrane into the cytosol. Knock-down of MCOLN1 resulted in reduced TFEB activation and smaller CCVs, while MCOLN1 activation boosted bacterial egress. Indeed, peripheral CCVs are positive for LAMP1/2 and release bacteria, without inducing host cell death. Importantly, LAMP1/2 and C. burnetii were stainable in non-permeabilized cells at sites of bacterial release, demonstrating fusion of the lysosome with the plasma membrane. Crucially, while replication of C. burnetii is not inhibited in cells lacking LAMP1/2, egress is impaired. Taken together, our data indicates that with increasing CCV size, TFEB is activated by the release of Ca2+ from lysosomes via the MCOLN1 channel, which in turn enables further CCV development and damage of the CCV membrane. This triggers lysosomal exocytosis and egress of C. burnetii without cell death induction.
    Keywords:  Coxiella burnetii; Egress; LAMP; MCOLN1; Q fever; TFEB; lysosomal exocytosis; type IV secretion system
    DOI:  https://doi.org/10.3389/fcimb.2026.1835140
  4. Biomed Pharmacother. 2026 Aug 25. pii: S0753-3322(26)00911-X. [Epub ahead of print]203 119875
    Endolysosomal remodeling and acidity dictates ferroptosis sensitivity to iron oxide nanoparticles.
    Neus Daviu, Alberto Irigaray-Moreno, Carla Graciano-Casero, Domingo F Barber.
      Iron oxide nanoparticles (IONPs) exhibit remarkable anti-tumoral activity, largely mediated by the generation of reactive oxygen species (ROS). Although certain IONPs can induce ferroptosis, the determinants underlying cell-type-specific sensitivity remain poorly understood. Here, we provide novel mechanistic insight by demonstrating that lysosomal acidity and plasticity critically regulate iron mobilization, ROS compartmentalization, and the ferroptotic response triggered by dimercaptosuccinic acid-coated IONPs (DMSA‑IONPs) in MDA‑MB‑231 breast cancer and U87MG glioma cells. DMSA-IONPs generate ROS in both cell models, however, their subcellular localization markedly differed. In MDA-MB-231 cells, highly acidic lysosomes retained redox-active iron (Fe2+), leading to localized ROS accumulation, lysosomal enlargement and pronounced lipid peroxidation, ultimately inducing ferroptosis, which was reverted by the anti-ferroptosis drug Ferrostatin-1. In contrast, the less acidic lysosomes of U87MG cells released iron into the cytosol and mitochondria, resulting in diffuse ROS production without lipid peroxidation and conferring resistance to ferroptosis despite higher nanoparticle uptake. While IONP‑mediated ROS generation via iron mobilization and Fenton‑like reactions is well established, our findings identify lysosomes as critical determinants of cellular responses to IONPs exposure. Specifically, lysosomal acidity and endolysosomal trafficking govern ferroptotic sensitivity to IONPs by controlling the site of ROS accumulation. Our results demonstrate that IONP-induced ferroptosis depends not only on total ROS levels but also on ROS subcellular distribution, with ROS accumulated in lysosomes triggering lipid peroxidation of these organelles. These insights highlight the importance of evaluating lysosomal physiology across tumor type to optimize nanoparticle-based ferroptosis therapies, particularly for tumors resistant to apoptosis.
    Keywords:  Cancer cell death; Ferroptosis; Lipid peroxidation; Lysosomal damage; Lysosome-dependent cell death; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.biopha.2026.119875
  5. iScience. 2026 Sep 18. 29(9): 117203
    Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.
    Maria Sakurai, Tomoki Kuwahara, Shoichi Suenaga, Sho Takatori, Taisuke Tomita, Tammy Shalit, Elizabeth Tengstrand, Frank Hsieh, Takeshi Iwatsubo.
      LRRK2, the Parkinson's disease-associated kinase, phosphorylates a subset of Rab GTPases and regulates membrane dynamics. We previously reported that lysosomal stress activates LRRK2 and thereby induces the exocytic secretion of lysosomal contents, but the detailed secretion mechanism remained unclear. Here we found that, under lysosomal stress, endolysosomal luminal and membrane components were secreted with extracellular vesicles (EVs) via LRRK2. Bis(monoacylglycerol)phosphate, an endolysosomal lipid and a urinary marker of LRRK2 activity, was similarly secreted via LRRK2, whereas CD9-positive EVs were not involved. Further dissection of the secreted EVs revealed that Alix-positive EVs were secreted via Rab8a as well as the ESCRT component VPS4, whereas LAMP1/cathepsin B-positive EVs were secreted via Rab10/Rab35, and SNARE proteins syntaxin 2 and VAMP8 regulated the secretion of both EV subtypes. These findings suggest a distinctive stress-induced secretory mechanism whereby LRRK2 facilitates the secretion of multiple EV subtypes by controlling Rab GTPases involved in each pathway.
    Keywords:  LRRK2; Parkinson’s disease; extracellular vesicles; lysosomal stress; rab
    DOI:  https://doi.org/10.1016/j.isci.2026.117203
  6. Nat Commun. 2026 Jul 22. pii: 8948. [Epub ahead of print]17(1):
    Lipid-manager autophagy proteins ATG2 and ATG9 regulate extracellular vesicle secretion via amphisome biogenesis and cell lipidome modulation.
    Asmita Singh, Dylan J Johnson, Jeffrey Kuhn, Katina L Johnson, Jason G Williams, Ricardo Vancini, Deloris Sutton, Kedar Sharma, Jadranka Loncarek, Mario J Borgnia, Carlos M Guardia.
      Autophagy intersects with endocytic trafficking to regulate extracellular vesicle (EV) biogenesis, but how upstream lipid-handling autophagy proteins influence this crosstalk is unclear. Here we show that the autophagy lipid-supply proteins ATG9A and ATG2A/B restrain small EV (sEV) secretion by promoting amphisome formation and controlling cellular lipid composition. Deletion of ATG9A or ATG2A/B in cells, which abolishes autophagosome biogenesis, causes a RAB27A-dependent increase in secretion of CD63-enriched, smaller sEVs, and accumulation of intraluminal vesicles within multivesicular endosomes. Under lysosomal inhibition, wild-type cells release LC3- and autophagy cargo receptor-positive sEVs, whereas ATG9A- and ATG2A/B-deficient cells, despite hypersecretion of sEVs, fail to load LC3 or canonical cargo receptors, indicating a block in amphisome-mediated export. Proteomics reveals selective depletion of autophagy receptors and ferritinophagy factors and enrichment of RNA-binding proteins and endosomal trafficking regulators in sEVs from ATG9A- and ATG2A/B-deficient cells. Whole-cell lipidomics uncovers extensive rewiring of the lipidome, with accumulation of ceramides and neutral lipids, altered phospholipid balance, and transcriptional remodeling of lipid metabolic enzymes, while neutral sphingomyelinase inhibition normalizes sEV output. These findings identify ATG9A and ATG2A/B as lipid-dependent gatekeepers that couple autophagosome and amphisome formation, regulating membrane partition between degradative autophagy and exosome-mediated secretion.
    DOI:  https://doi.org/10.1038/s41467-026-75742-x
  7. J Mol Cell Cardiol Plus. 2026 Sep;17 100864
    Organelle network dysfunction in primary cardiomyopathy: An integrated perspective on pathogenesis and therapeutics.
    Shixin Pu, Pan Yang.
      Primary (genetic) cardiomyopathy comprises a heterogeneous group of predominantly monogenic (genetically determined) myocardial diseases-principally hypertrophic (HCM), dilated (DCM) and restrictive (RCM) phenotypes-and must be distinguished from secondary/acquired cardiomyopathies attributable to ischaemia, valvular disease, pressure overload, diabetes, infection or toxins. This review is restricted to primary cardiomyopathy; because organelle biology has been characterised far more extensively in secondary or acquired settings, evidence derived from such models (ischaemia-reperfusion, pressure overload, diabetes, sepsis, drug toxicity, neurodegenerative or non-cardiac injury models) is explicitly identified as such and treated as indirect, hypothesis-generating support rather than as direct evidence in primary cardiomyopathy. The pathophysiology of primary cardiomyopathy is tightly related to abnormal energy metabolism, protein homeostasis and calcium homeostasis. An increasing body of evidence suggests that organelle malfunction and abnormal inter-organelle interactions play a role in primary cardiomyopathy development. This review focuses on key organelles: mitochondrial dysfunction results in energy deprivation and oxidative imbalance; endoplasmic reticulum stress (ERS) impairs protein folding and calcium homeostasis; defects in the lysosome-mediated autophagy pathway exacerbate the accumulation of intracellular damaged material; Golgi fragmentation affects protein processing and trafficking; and cytoskeletal disruption compromises the structural integrity of myocardium. Furthermore, organelles create complex regulatory networks via structures like mitochondrial-associated ER membranes (MAMs), where imbalances such as aberrant calcium signalling and stress pathway cross-activation exacerbate pathological damage. While previous studies focus on individual proteins or organelles, the heart's high energy consumption and synchronized contraction require understanding cardiomyocytes as a dynamic, interdependent organelle ecosystem. Treating primary cardiomyopathy as a 'organelle network disease', in which organelles constitute a dynamic, interdependent ecosystem, provides a useful integrative paradigm for comprehending the causes. This review lays the groundwork for targeted therapy in primary cardiomyopathy by clarifying the functions of organelles.
    Keywords:  Autophagic flux; Endoplasmic reticulum stress; Mitochondria-associated membranes; Organelle network; Primary cardiomyopathy
    DOI:  https://doi.org/10.1016/j.jmccpl.2026.100864
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