bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2025–04–06
seven papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. HEATR3 recognizes membrane rupture and facilitates xenophagy in response to Salmonella invasion.
  2. RAF1 kinase contributes to autophagic lysosome reformation.
  3. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis.
  4. Retromer promotes the lysosomal turnover of mtDNA.
  5. Mucopolysaccharidosis Type IIIA Presenting as Hypertrophic Cardiomyopathy.
  6. PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth.
  7. Vps41 functions as a molecular ruler for HOPS tethering complex function.
  1. Proc Natl Acad Sci U S A. 2025 Apr 08. 122(14): e2420544122
    HEATR3 recognizes membrane rupture and facilitates xenophagy in response to Salmonella invasion.
    Masashi Arakawa, Keiya Uriu, Koki Saito, Mai Hirose, Kaoru Katoh, Krisana Asano, Akio Nakane, Tatsuya Saitoh, Tamotsu Yoshimori, Eiji Morita.
      Bacterial invasion into the cytoplasm of epithelial cells triggers the activation of the cellular autophagic machinery as a defense mechanism, a process known as xenophagy. In this study, we identified HEATR3, an LC3-interacting region (LIR)-containing protein, as a factor involved in this defense mechanism using quantitative mass spectrometry analysis. HEATR3 localizes intracellularly invading Salmonella, and HEATR3 deficiency promotes Salmonella proliferation in the cytoplasm. HEATR3 also localizes to lysosomes damaged by chemical treatment, suggesting that Salmonella recognition is facilitated by damage to the host cell membrane. HEATR3 deficiency impairs LC3 recruitment to damaged membranes and blocks the delivery of the target to the lysosome. These phenotypes were rescued by exogenous expression of wild-type HEATR3 but not by the LIR mutant, indicating the crucial role of the HEATR3-LC3 interaction in the receptor for selective autophagy. HEATR3 is delivered to lysosomes in an autophagy-dependent manner. Although HEATR3 recruitment to the damaged membrane was unaffected by ATG5 or FIP200 deficiency, it was markedly impaired by treatment with a calcium chelator, suggesting involvement upstream of the autophagic pathway. These findings suggest that HEATR3 serves as a receptor for selective autophagy and is able to identify damaged membranes, facilitate the removal of damaged lysosomes, and target invading bacteria within cells.
    Keywords:  HEATR3; NOD2 signaling; autophagy; salmonella infection; xenophagy receptor
    DOI:  https://doi.org/10.1073/pnas.2420544122
  2. Cell Rep. 2025 Apr 03. pii: S2211-1247(25)00261-X. [Epub ahead of print]44(4): 115490
    RAF1 kinase contributes to autophagic lysosome reformation.
    Stefanie Toifl, Sebastian Didusch, Karin Ehrenreiter, Enrico Desideri, Coralie Dorard, Manuela Baccarini.
      Autophagic lysosome reformation (ALR) is crucial for lysosomal homeostasis and therefore for different autophagic processes. Despite recent advances, the signaling mechanisms regulating ALR are incompletely understood. We show that RAF1, a member of the RAS/RAF/MEK/ERK pathway initiated by growth factors, has an essential, kinase-dependent role in lysosomal biology. RAF1 ablation impairs autophagy, and a proxisome screen identifies several proteins involved in autophagic and lysosomal pathways in the RAF1 molecular space. Two of these, SPG11 and the lipid phosphatase MTMR4, are RAF1 substrates. RAF1 ablation causes the appearance of enlarged autolysosomes and alters the phosphoinositide composition of autolysosomes. RAF1 and MTMR4 colocalize on autolysosomes, and overexpression of a MTMR4 mutant mimicking phosphorylation of the RAF1-dependent site rescues the lysosomal phenotypes induced by RAF1 ablation. Our data identify an RAF1 function in lysosomal homeostasis and a substrate through which the kinase regulates phospholipid metabolism at the lysosome, ALR, and autophagy.
    Keywords:  CP: Cell biology; RAF1 interactome; RAF1 substrates; autophagic lysosome reformation; autophagy; lysosomal homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115490
  3. Elife. 2025 Apr 04. pii: RP103137. [Epub ahead of print]13
    Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis.
    Kaili Du, Hongyu Chen, Zhaonan Pan, Mengli Zhao, Shixue Cheng, Yu Luo, Wenhe Zhang, Dan Li.
      Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
    Keywords:  NPC1; TFEB agonists; cell biology; cholesterol accumulation; human; lysosome; mouse
    DOI:  https://doi.org/10.7554/eLife.103137
  4. Sci Adv. 2025 Apr 04. 11(14): eadr6415
    Retromer promotes the lysosomal turnover of mtDNA.
    Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.
      Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.
    DOI:  https://doi.org/10.1126/sciadv.adr6415
  5. Circ Heart Fail. 2025 Mar 31. e012632
    Mucopolysaccharidosis Type IIIA Presenting as Hypertrophic Cardiomyopathy.
    Filippo Pinto E Vairo, Jeffrey B Geske, Ravinder J Singh, Roy B Dyer, Konstantinos C Siontis, Maria O'Connell, Christopher Schmitz, Laura Lambert, Karl J Clark, Kimiyo M Raymond, Joseph J Maleszewski, Tim Wood, Pavel N Pichurin, Eric W Klee, Naveen L Pereira.
      
    Keywords:  cardiomyopathies; heart failure; inborn genetic diseases; lysosomal storage diseases
    DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.012632
  6. Cell Rep. 2025 Mar 28. pii: S2211-1247(25)00254-2. [Epub ahead of print]44(4): 115483
    PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth.
    Rajan S Thakur, Kate M O'Connor-Giles.
      Building synaptic connections requires coordinating a host of cellular activities from cell signaling to protein turnover, placing a high demand on intracellular communication. Membrane contact sites (MCSs) formed between organelles have emerged as key signaling hubs for coordinating diverse cellular activities, yet their roles in the developing nervous system remain obscure. We investigate the in vivo function of the endoplasmic reticulum (ER) MCS tethering and lipid-transfer protein PDZD8, which was recently linked to intellectual disability, in the nervous system. We find that PDZD8 is required for activity-dependent synaptic bouton formation in multiple paradigms. PDZD8 is sufficient to drive excess synaptic bouton formation through an autophagy-dependent mechanism and required for synapse development when autophagy is limited. PDZD8 accelerates autophagic flux by promoting lysosome maturation at ER-late endosome/lysosome MCSs. We propose that PDZD8 functions in the nervous system to increase autophagy during periods of high demand, including activity-dependent synaptic growth.
    Keywords:  CP: Cell biology; CP: Neuroscience; Drosophila; autophagy; lipid transfer protein; lysosomes; membrane contact sites; neurodevelopment; synapse
    DOI:  https://doi.org/10.1016/j.celrep.2025.115483
  7. J Cell Sci. 2025 Mar 31. pii: jcs.263788. [Epub ahead of print]
    Vps41 functions as a molecular ruler for HOPS tethering complex function.
    Caroline König, Dmitry Shvarev, Jieqiong Gao, Eduard Haar, Nicole Susan, Kathrin Auffarth, Lars Langemeyer, Arne Moeller, Christian Ungermann.
      Fusion at the lysosome (or the yeast vacuole) requires the conserved hexameric HOPS tethering complex. HOPS binds to the vacuolar Rab7-like GTPase Ypt7 via its subunits Vps41 and Vps39 and supports fusion by promoting SNARE assembly. In contrast to its sister complex CORVET, the Ypt7-interacting domain of Vps41 in the HOPS complex is connected to the core by a long, extended α-solenoid domain. Here, we show that this solenoid acts as a molecular ruler to position the Ypt7-interaction part of Vps41 relative to the core of HOPS to support function. Mutant complexes with a shortened or extended α-solenoid part in Vps41 still tether membranes, but fail to efficiently support their fusion. In vivo, Vps41 mutants grow poorly, show defects in vacuolar morphology, endolysosomal sorting and autophagy. Importantly, if a length-compensating linker is inserted instead of the shortened α-solenoid, these defects are rescued. This suggests that the Rab-specific Vps41 subunit requires the exact length, but not the α-solenoid domain for functionality, implying a revised model how HOPS supports fusion.
    Keywords:  HOPS; Rab GTPase; Vacuole; Vps41; Ypt7; α-solenoid
    DOI:  https://doi.org/10.1242/jcs.263788
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