bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–10–26
six papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. Roles of lysosomal small-molecule transporters in metabolism and signaling.
  2. ATG9 assists lipid replenishment for lysosome membrane repair.
  3. TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.
  4. STX1A localizes to the lysosome and controls its exocytosis.
  5. TFEB Dysfunction Mediates Lysosomal Membrane Permeabilization-Induced Pyroptosis in Deoxynivalenol-Exposed Intestinal Epithelium.
  6. Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.
  1. Trends Cell Biol. 2025 Oct 17. pii: S0962-8924(25)00222-3. [Epub ahead of print]
    Roles of lysosomal small-molecule transporters in metabolism and signaling.
    Markus Damme, Océane Guelle, Christian Löw, Bruno Gasnier.
      Lysosomes degrade damaged or unwanted cell/tissue components and recycle their building blocks through small-molecule transporters of the lysosomal membrane. They also act as signaling hubs that sense and signal internal cues, such as amino acids, to coordinate cell responses. Recently, the activity of several lysosomal metabolite transporters has been elucidated, bringing new insights into lysosomal functions. Cell biological and structural studies of lysosomal transporters have also highlighted their roles in recruiting signaling complexes to lysosomes and delineated how their substrates gate such hybrid transporter/receptor, or 'transceptor', function. In this review, we summarize recent progress in our understanding of lysosomal transporters, with a focus on the export of lysosomal degradation intermediates, the existence of lysosomal amino acid shuttles that regulate the redox state and pH of the lysosomal lumen, and the role of lysosomal transceptors in nutrient and immune signaling.
    Keywords:  lysosomes; metabolism; signaling; transceptor; transporter
    DOI:  https://doi.org/10.1016/j.tcb.2025.09.004
  2. Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00570-2. [Epub ahead of print]60(20): 2701-2702
    ATG9 assists lipid replenishment for lysosome membrane repair.
    Hemmo Meyer, Bojana Kravic.
      Lysosomal membranes can be permeabilized under various conditions with detrimental consequences for the cell. In this issue, de Tito et al. report that the lipid scramblase ATG9, best known for its role in autophagosome formation, helps distribute lipids from the ER to reseal the limiting membrane and restore lysosomal function.
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.010
  3. J Cell Biol. 2026 Jan 05. pii: e202501145. [Epub ahead of print]225(1):
    TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.
    Erika Riederer, Vedrana Mikusevic, Tuoxian Tang, Lillian Martin, Joseph A Mindell, Dejian Ren.
      The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is remarkably small, ∼0.02 fA, strongly arguing against major contributions from an ion channel. The predominant effect of TMEM175 deficiencies is lysosomal alkalinization in challenged cells, which is further evidence arguing against TMEM175 as a H+-selective channel and can be explained by K+ conductance through TMEM175. Also, lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Our studies clarify a basic lysosomal biological problem and provide insights into the working mechanism of TMEM175 and its contribution to PD pathology.
    DOI:  https://doi.org/10.1083/jcb.202501145
  4. Mol Biol Cell. 2025 Oct 22. mbcE25040196
    STX1A localizes to the lysosome and controls its exocytosis.
    Anshul Milap Bhatt, Bishal Singh, Prince Singh, Subba Rao Gangi Setty.
      Lysosome exocytosis is one of the critical functions of lysosomes in maintaining cellular homeostasis and plasma membrane repair. At the basal level, the SNAREs regulating the lysosome fusion with the cell surface have been poorly defined. Here, we identified a Qa-SNARE STX1A, localized majorly to lysosomes and a cohort to the plasma membrane in HeLa cells. Overexpression of GFP-STX1A in HeLa cells causes decreased lysosome number and their peripheral dispersion. However, STX1A knockdown in HeLa cells displayed an accumulation of lysosomes beneath the cell surface with reduced lysosome exocytosis. Consistently, TIRF imaging microscopy demonstrated an enhanced enrichment of LAMP1-positive vesicles at the cell surface in STX1A depleted compared to control cells. Moreover, STX1A depletion reduces proteolytic activity without affecting the lysosome content or acidity. Additionally, these cells showed enhanced lysosome dispersion and autolysosome accumulation. Functionally, GFP-STX1A also localizes to LLOMe-induced GAL3-positive damaged lysosomes and reduces their number by enhancing exocytosis. Biochemically, STX1A forms a SNARE complex with SNAP23 or SNAP25 (Qbc) and VAMP2 (R), and their knockdown in HeLa cells mimics the STX1A-depletion phenotypes. Overall, these studies demonstrate a unique function of STX1A in regulating lysosomal exocytosis by localizing to these degradative organelles. [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-04-0196
  5. J Agric Food Chem. 2025 Oct 22.
    TFEB Dysfunction Mediates Lysosomal Membrane Permeabilization-Induced Pyroptosis in Deoxynivalenol-Exposed Intestinal Epithelium.
    Chun Zeng, Zhenyu Zou, Xinyi Cheng, Yang Hu, Yu Huang, Zhongtao Li, Xiaoquan Guo, Huabin Cao, Caiying Zhang, Guoliang Hu, Yu Zhuang.
      Deoxynivalenol (DON), a prevalent mycotoxin in cereals, triggers lysosomal membrane permeabilization (LMP) in intestinal epithelial cells, resulting in Transcription Factor EB (TFEB) dysfunction and subsequent pyroptosis. Both in vivo porcine jejunum and in vitro IPEC-J2 monolayer experiments revealed that DON exposure induced jejunal villus atrophy, tight junction disruption, mucin2 downregulation, cathepsin B/D leakage, and impaired TFEB nuclear translocation. LMP-mediated TFEB suppression activated NLRP3 inflammasome and gasdermin D (GSDMD)-dependent pore formation, culminating in caspase-1-driven pyroptosis. Pharmacological TFEB activation restored lysosomal integrity and attenuated pyroptosis, whereas TFEB knockdown exacerbated lysosomal instability. Mechanistically, TFEB maintained lysosomal homeostasis through LAMP1/LAMP2 upregulation. Notably, although NLRP3 inhibition by MCC950 mitigated pyroptotic markers, it failed to rescue lysosomal integrity in TFEB-deficient cells. Our findings establish TFEB as a pivotal regulator connecting lysosomal function to pyroptosis, revealing its therapeutic potential for DON-induced intestinal injury.
    Keywords:  NLRP3 inflammasome; deoxynivalenol; lysosomal membrane permeabilization; pyroptosis; transcription factor EB
    DOI:  https://doi.org/10.1021/acs.jafc.5c10855
  6. Sci Immunol. 2025 Oct 24. 10(112): eads9456
    Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.
    Jordy Saravia, Nicole M Chapman, Yu Sun, Xiaoxi Meng, Isabel Risch, Wei Li, Cliff Guy, Hao Shi, Haoran Hu, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil Kc, Seon Ah Lim, Jana L Raynor, Sharad Shrestha, Erienne G Norton, Sarah E La Grange, Camenzind G Robinson, Peter Vogel, Hongbo Chi.
      Immunotherapies targeting regulatory T (Treg) cells often trigger inflammation and autoimmunity. How Treg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates Treg cell metabolic and functional fitness. Treg cell-specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of Treg cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate-activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, Treg cell-specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency-associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient Treg cells were enriched in a terminal "metabolic quiescence reset" state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria-lysosome interplay control Treg cell differentiation and function.
    DOI:  https://doi.org/10.1126/sciimmunol.ads9456
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