bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–04–06
43 papers selected by
Viktor Korolchuk, Newcastle University
  1. Conserved components of the macroautophagy machinery in Caenorhabditis elegans.
  2. RAF1 kinase contributes to autophagic lysosome reformation.
  3. APOE4 impairs autophagy and Aβ clearance by microglial cells.
  4. HEATR3 recognizes membrane rupture and facilitates xenophagy in response to Salmonella invasion.
  5. A non-fluorescent immunohistochemistry method for measuring autophagy flux using MAP1LC3/LC3 and SQSTM1 as core markers.
  6. Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem cells.
  7. Multi-omics study reveals differential expression and phosphorylation of autophagy-related proteins in autism spectrum disorder.
  8. The life and times of brain autophagic vesicles.
  9. A depression-associated protein FKBP5 functions in autophagy initiation through scaffolding the VPS34 complex.
  10. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis.
  11. PDZD8 promotes autophagy at ER-lysosome membrane contact sites to regulate activity-dependent synaptic growth.
  12. Covalent inhibitors possessing autophagy-modulating capabilities: charting novel avenues in drug design and discovery.
  13. TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus.
  14. First responder to starvation: microreticulophagy clears aberrant membrane proteins in quick bites.
  15. Neuronal antenna senses signals from the Bone to Sustain Cognition by boosting autophagy.
  16. The role of the mTOR pathway in breast cancer stem cells (BCSCs): mechanisms and therapeutic potentials.
  17. HTLV-1 Tax induces PINK1-Parkin-dependent mitophagy to mitigate activation of the cGAS-STING pathway.
  18. Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.
  19. Research progress on the regulation mechanism of DEPTOR expression and its role in tumorigenesis.
  20. Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells.
  21. TNFAIP8L2 maintains Hair cell function and Regulates Age-related hearing loss via mTORC1 Signaling.
  22. Retromer promotes the lysosomal turnover of mtDNA.
  23. Roles of Autophagy, Mitophagy, and Mitochondria in Left Ventricular Remodeling after Myocardial Infarction.
  24. Redox regulation of autophagy in Arabidopsis: The different ROS effects.
  25. α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.
  26. 3,4-Dimethoxychalcone alleviates limb ischemia/reperfusion injury by TFEB-mediated autophagy enhancement and antioxidative response.
  27. Targeting of Lysosomes as a Therapeutic Target in Cancer.
  28. Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin.
  29. Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.
  30. RAB18 deficiency disrupts lipid metabolism and autophagy in mice.
  31. p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.
  32. A dual reporter system for intracellular and extracellular amino acid sensing in budding yeast.
  33. Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.
  34. RNA N6-methyladenosine demethylase FTO promotes diabetic wound healing through TRIB3-mediated autophagy in an m6A-YTHDF2-dependent manner.
  35. DEPTOR suppresses lymphomagenesis by promoting EGFR degradation via HUWE1 E3 ligase.
  36. Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission.
  37. DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
  38. Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation.
  39. TM9SF1 inhibits colorectal cancer metastasis by targeting Vimentin for Tollip-mediated selective autophagic degradation.
  40. TPCs: From plant to human.
  41. Phosphoinositide signalling in cell motility and adhesion.
  42. Mpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes.
  43. Vorinostat attenuates UVB-induced skin senescence by modulating NF-κB and mTOR signaling pathways.
  1. Genetics. 2025 Apr 04. pii: iyaf007. [Epub ahead of print]
    Conserved components of the macroautophagy machinery in Caenorhabditis elegans.
    Hong Zhang, Alicia Meléndez.
      Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation and recycling. In Caenorhabditis elegans, autophagy participates in diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, and adaptive immunity. Genetic screens in C. elegans have identified a set of metazoan-specific autophagy genes that form the basis for our molecular understanding of steps unique to the autophagy pathway in multicellular organisms. Suppressor screens have uncovered multiple mechanisms that modulate autophagy activity under physiological conditions. C. elegans also provides a model to investigate how autophagy activity is coordinately controlled at an organismal level. In this chapter, we will discuss the molecular machinery, regulation, and physiological functions of autophagy, and also methods utilized for monitoring autophagy during C. elegans development.
    Keywords:   C. elegans ; P granules; WormBook; aggrephagy; autophagy; development; dietary restriction; hormesis; lipophagy; longevity; lysophagy; lysosome; mitophagy; xenophagy
    DOI:  https://doi.org/10.1093/genetics/iyaf007
  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. Inflamm Res. 2025 Apr 01. 74(1): 61
    APOE4 impairs autophagy and Aβ clearance by microglial cells.
    Rawan Bassal, Maria Rivkin-Natan, Alon Rabinovich, Daniel Moris Michaelson, Dan Frenkel, Ronit Pinkas-Kramarski.
      Alzheimer's disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.
    Keywords:  Alzheimer's disease (AD); Amyloid β; Apolipoprotein E4 (apoE4); Autophagy
    DOI:  https://doi.org/10.1007/s00011-025-02016-5
  4. 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
  5. FEBS Open Bio. 2025 Apr 03.
    A non-fluorescent immunohistochemistry method for measuring autophagy flux using MAP1LC3/LC3 and SQSTM1 as core markers.
    Shahla Shojaei, Amir Barzegar Behrooz, Marco Cordani, Mahmoud Aghaei, Negar Azarpira, Daniel J Klionsky, Saeid Ghavami.
      Macroautophagy/autophagy is a crucial cellular process for degrading and recycling damaged proteins and organelles, playing a significant role in diseases such as cancer and neurodegeneration. Evaluating autophagy flux, which tracks autophagosome formation, maturation, and degradation, is essential for understanding disease mechanisms. Current fluorescence-based methods are resource-intensive, requiring advanced equipment and expertise, limiting their use in clinical laboratories. Here, we introduce a non-fluorescent immunohistochemistry (IHC) method using MAP1LC3/LC3 and SQSTM1 as core markers for autophagy flux assessment. LC3 levels reflect autophagosome formation, whereas SQSTM1 degradation and a decrease in the number of its puncta indicate active flux (i.e., lysosomal turnover). We optimized chromogenic detection using diaminobenzidine (DAB) staining and developed a scoring system based on puncta number and the percentage of stained cells. This accessible, cost-effective method enables reliable autophagy quantification using a standard light microscope, bridging the gap between experimental research and clinical diagnostics. Our protocol allows accurate autophagy evaluation in fixed tissues, offering practical applications in biomedical research and clinical pathology assessment.
    Keywords:  autophagometer; autophagy flux measurement; cellular homeostasis analysis; chromogenic detection; cost‐effective autophagy assay; non‐fluorescent immunohistochemistry
    DOI:  https://doi.org/10.1002/2211-5463.70014
  6. bioRxiv. 2025 Mar 13. pii: 2025.03.10.642434. [Epub ahead of print]
    Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem cells.
    Luana Chiquetto, Meg Schuetz, Qian Dong, Mia Warmka, Liana Valin, Ashley Jones, Patrick Hunt, Copper Petermeier, Jie Wang, Nate Roundy, Zev J Greenberg, Wei Yang, Christine R Zhang, Grant A Challen, Cliff J Luke, Robert A J Signer, Wandy L Beatty, Stephen Sykes, Weikai Li, David J Kast, Laura G Schuettpelz.
      Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics via promotion of microtubule catastrophe and sequestration of free tubulin heterodimers. Stathmin 1 is highly expressed in hematopoietic stem cells (HSCs), and overexpressed in leukemic cells, however its role in HSCs is not known. Herein, we found that loss of Stathmin 1 is associated with altered microtubule architecture in HSCs, and markedly impaired HSC function. Transcriptomic studies suggested alterations in oxidative phosphorylation in Stmn1 -/- HSCs, and further mechanistic studies revealed defective mitochondrial structure and function in the absence of Stathmin 1 with increased ROS production. Microtubules associate with mitochondria and lysosomes to facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stathmin 1-deficient HSCs. Finally, stimulation of autophagy improved the colony forming ability of Stmn1 -/- hematopoietic stem and progenitor cells. Together, our data identify Stathmin 1 as a novel regulator of mitophagy and mitochondrial health in HSCs.
    Key Points: The microtubule regulating protein Stathmin 1 is highly expressed in HSPCs and promotes normal microtubule architecture.Loss of Stathmin 1 in HSPCs leads to impaired autophagy with abnormal mitochondrial morphology, decreased respiratory capacity, and impaired cellular function.
    DOI:  https://doi.org/10.1101/2025.03.10.642434
  7. Sci Rep. 2025 Mar 29. 15(1): 10878
    Multi-omics study reveals differential expression and phosphorylation of autophagy-related proteins in autism spectrum disorder.
    Eden Deri, Shashank Kumar Ojha, Maryam Kartawy, Igor Khaliulin, Haitham Amal.
      Our multi-omics study investigated the molecular mechanisms underlying autism spectrum disorder (ASD) using Shank3Δ4-22 and Cntnap2-/- mouse models. Through global- and phospho- proteomics of the mouse cortex, we focused on shared molecular changes and found that autophagy was particularly affected in both models. Global proteomics identified a small number of differentially expressed proteins that significantly impact postsynaptic components and synaptic function, including key pathways such as mTOR signaling. Phosphoproteomics revealed unique phosphorylation sites in autophagy-related proteins such as ULK2, RB1CC1, ATG16L1, and ATG9, suggesting that altered phosphorylation patterns contribute to impaired autophagic flux in ASD. SH-SY5Y cells with SHANK3 gene deletion showed elevated LC3-II and p62 levels, indicating autophagosome accumulation and autophagy initiation, while the reduced level of the lysosomal activity marker LAMP1 suggested impaired autophagosome-lysosome fusion. The study highlights the involvement of reactive nitrogen species and nitric oxide (NO) on autophagy disruption. Importantly, inhibition of neuronal NO synthase (nNOS) by 7-NI normalized autophagy markers levels in the SH-SY5Y cells and primary cultured neurons. We have previously shown that nNOS inhibition improved synaptic and behavioral phenotypes in Shank3Δ4-22 and Cntnap2-/- mouse models. Our multi-omics study reveals differential expression and phosphorylation of autophagy-related proteins in ASD but further investigation is needed to prove the full involvement of autophagy in ASD. Our study underscores the need for further examination into the functional consequences of the identified phosphorylation sites, which may offer potential novel therapeutic autophagy-related targets for ASD treatment.
    DOI:  https://doi.org/10.1038/s41598-025-95860-8
  8. J Mol Biol. 2025 Mar 26. pii: S0022-2836(25)00171-8. [Epub ahead of print] 169105
    The life and times of brain autophagic vesicles.
    Lisa Gambarotto, Erin Wosnitzka, Vassiliki Nikoletopoulou.
      Most of the knowledge on the mechanisms and functions of autophagy originates from studies in yeast and other cellular models. How this valuable information is translated to the brain, one of the most complex and evolving organs, has been intensely investigated. Fueled by the tight dependence of the mammalian brain on autophagy, and the strong links of human brain diseases with autophagy impairment, the field has revealed adaptations of the autophagic machinery to the physiology of neurons and glia, the highly specialized cell types of the brain. Here, we first provide a detailed account of the tools available for studying brain autophagy; we then focus on the recent advancements in understanding how autophagy is regulated in brain cells, and how it contributes to their homeostasis and integrated functions. Finally, we discuss novel insights and open questions that the new knowledge has raised in the field.
    Keywords:  autophagic vesicles; brain; glia; homeostasis; neurons; selective autophagy; synapse
    DOI:  https://doi.org/10.1016/j.jmb.2025.169105
  9. Mol Neurobiol. 2025 Apr 02.
    A depression-associated protein FKBP5 functions in autophagy initiation through scaffolding the VPS34 complex.
    Hyungsun Park, Jisoo Park, Taewan Kim, Hansol Heo, Jaerak Chang, Craig Blackstone, Seongju Lee.
      Common variants in the FKBP5 gene have been implicated in recurrence of major depressive disorder (MDD) and response to antidepressant treatment. Although the relationship between FKBP5 and MDD has been revealed through several studies, the detailed molecular mechanisms by which FKBP5 regulates responsiveness to antidepressants have not been fully understood. Here, we aimed to elucidate the molecular mechanisms of FKBP5 in autophagy initiation and its potential role in the antidepressant response. We found that FKBP5 deficiency impaired the initiation of basal and stress-induced autophagy, accompanied by reduced protein levels of the PIK3C3/VPS34 complex, which is essential for autophagy initiation. Mechanistically, we demonstrated that FKBP5 physically binds to the VPS34 complex components, facilitating their assembly and subsequent autophagy initiation. Particularly, our study revealed that FKBP5 mediates antidepressant-induced autophagy by promoting the VPS34 complex assembly. These findings were consistent in neuronal cells, where FKBP5 depletion resulted in decreased autophagy and impaired the VPS34 complex assembly. Understanding the interplay between FKBP5, autophagy, and MDD may provide new insights into more effective treatments for MDD and related disorders.
    Keywords:  Antidepressant; Autophagy; Depressive disorder; FKBP5; VPS34 complex
    DOI:  https://doi.org/10.1007/s12035-025-04897-3
  10. 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
  11. 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
  12. Drug Discov Today. 2025 Apr 01. pii: S1359-6446(25)00060-1. [Epub ahead of print] 104347
    Covalent inhibitors possessing autophagy-modulating capabilities: charting novel avenues in drug design and discovery.
    Yutong Wang, Shiyu Luo, Hongbao Sun, Shuai Huang, Lianhai Shan, Jifa Zhang.
      Autophagy is a crucial cellular process in degrading damaged organelles and maintaining cellular homeostasis. By forming irreversible bonds with specific proteins, covalent inhibitors present a distinct advantage in regulating autophagy and its related pathways. These inhibitors can provide sustained modulation of autophagy at lower doses, improving therapeutic efficacy while minimizing adverse effects. We discuss their mechanisms, including how they affect autophagy-related enzymes and pathways, and their potential applications in the treatment of cancers and other autophagy-related disorders. Studying autophagy-related pathway targets will provide new insights for the development of covalent inhibitors and enhance therapeutic strategies for complex conditions.
    Keywords:  AMPK; Covalent inhibitors; PI3K/Akt/mTOR; autophagy; cancer
    DOI:  https://doi.org/10.1016/j.drudis.2025.104347
  13. Acta Biochim Biophys Sin (Shanghai). 2025 Mar 31.
    TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus.
    Chen Li, Ang Ma, Yu Bai, Zitao Liu, Linghan Tian, Ziyuan Wang, Huaishun Ma, Zhengpu Chen, Zhengheng Gao, Shijie Feng, Ping Fu.
      The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial for host defense, sustained activation of this pathway contributes to autoimmune pathologies, including systemic lupus erythematosus (SLE). Maintaining immune homeostasis requires precise regulation of STING activity to prevent hyperactivation. Our study identifies TRIM21 as a novel positive regulator of cGAS-STING signaling in SLE pathogenesis. Our results demonstrate that TRIM21 overexpression stabilizes STING by suppressing autophagic degradation, whereas TRIM21 depletion accelerates this clearance process. Mechanistically, TRIM21 catalyzes the K63-linked polyubiquitylation of the selective autophagy receptor p62/SQSTM1, disrupting its interaction with STING. This post-translational modification prevents the sequestration of STING into autophagosomes, thereby stabilizing the adaptor protein and amplifying downstream type I interferon responses. Our findings reveal a previously unrecognized regulatory circuit in which TRIM21 orchestrates cross-talk between ubiquitin signaling and autophagy to control STING turnover. The TRIM21-p62 axis represents a potential therapeutic target for attenuating pathological interferon production in STING-dependent autoimmune disorders. This work advances our understanding of immune regulation by demonstrating how E3 ligase-mediated ubiquitin modifications modulate cargo recognition in selective autophagy pathways. The identified mechanism provides new insights into the molecular interplay between protein ubiquitylation and autophagic degradation in maintaining the innate immune balance, offering novel perspectives for developing targeted therapies against interferonopathies associated with cGAS-STING hyperactivity.
    Keywords:  TRIM21; autophagy; cGAS-STING signaling; p62/SQSTM1; systemic lupus erythematosus; ubiquitylation
    DOI:  https://doi.org/10.3724/abbs.2025046
  14. Autophagy. 2025 Apr 02.
    First responder to starvation: microreticulophagy clears aberrant membrane proteins in quick bites.
    Yaneris Alvarado Cartagena, Valeriya Gyurkovska, Nava Segev.
      Cells can use two different pathways for recycling their non-essential components in the lysosome during nutritional stress: macroautophagy and microautophagy. While the well-established macroautophagy pathway requires de novo formation of the double-membrane autophagosome, microautophagy involves direct engulfment of cargo by the lysosomal membrane. Recently, using a yeast model, we identified a novel microreticulophagy pathway induced by nutritional stress that selectively clears aberrant membrane proteins that accumulate during normal growth. This effective clearance occurs rapidly and precedes the degradation of normal ER- or mitochondrial-membrane proteins by macroautophagy. We showed that the nutritional-stress induced selective microreticulophagy pathway requires the ubiquitin-ligase Rsp5, its adaptor Ssh4, and the ESCRT complex. Moreover, live-cell fluorescence microscopy with high temporal and special resolution demonstrated that individual microautophagy events occur within seconds. Thus, cells use the effective microreticulophagy pathway to dispose of misfolded or excess membrane proteins as a first response to starvation. If the stress persists, the more costly macroautophagy pathway is activated for degrading normal cellular components. These findings point to an intricate interplay between microautophagy and macroautophagy during nutritional stress, which optimizes stress responses and could have significant implications for understanding how cells maintain homeostasis or progress to disease states.
    Keywords:  Aberrant membrane proteins; ER-phagy; ERAD; macroautophagy; microautophagy; nutritional stress
    DOI:  https://doi.org/10.1080/15548627.2025.2487675
  15. Autophagy. 2025 Mar 31.
    Neuronal antenna senses signals from the Bone to Sustain Cognition by boosting autophagy.
    Victoria Blanchet, Franck Oury, David Romeo-Guitart.
      The common occurrence of cognitive decline is one of the most significant manifestations of aging in the brain, with the hippocampus - critical for learning and memory - being one of the first regions to exhibit functional deterioration. BGLAP/OCN/osteocalcin (bone gamma-carboxyglutamate protein), a pro-youth systemic factor produced by the bone, improves age-related cognitive decline by boosting hippocampal neuronal autophagy. However, the mechanism by which hippocampal neurons detect BGLAP/OCN in the systemic milieu and adapt their downstream response was previously unknown. We determined that BGLAP/OCN modulates core primary cilia (PC) proteins, suggesting that this "extracellular antenna" may play a role in mediating BGLAP/OCN's anti-aging effects. Furthermore, selective downregulation of core PC proteins in the hippocampus impairs learning and memory by reducing neuronal macroautophagy/autophagy. In contrast, restoring core PC protein levels in the hippocampus of aged mice improved this phenotype and was necessary for the induction of autophagy machinery by BGLAP/OCN. Together, these findings reveal a novel mechanism through which pro-youth systemic factors, like BGLAP/OCN, can regulate neuronal autophagy and foster cognitive resilience during aging.
    Keywords:  Aging; Autophagy; Cognition; Pro-youth factors; primary cilia
    DOI:  https://doi.org/10.1080/15548627.2025.2487038
  16. Stem Cell Res Ther. 2025 Mar 29. 16(1): 156
    The role of the mTOR pathway in breast cancer stem cells (BCSCs): mechanisms and therapeutic potentials.
    Chen Zhang, Xu Shu, Chuanzheng Yin, Shaobo Hu, Pian Liu.
      Breast cancer remains the most frequently diagnosed cancer globally, exerting a profound impact on women's health and healthcare systems. Central to its pathogenesis and therapeutic resistance are breast cancer stem cells (BCSCs), which possess unique properties such as self-renewal, differentiation, and resistance to conventional therapies, contributing to tumor initiation, metastasis, and recurrence. This comprehensive review elucidates the pivotal role of the mechanistic target of rapamycin (mTOR) pathway in regulating BCSCs and its implications for breast cancer progression and treatment resistance. We explore the cellular mechanisms by which mTOR influences metastasis, metabolism, autophagy, and ferroptosis in BCSCs, highlighting its contribution to epithelial-to-mesenchymal transition (EMT), metabolic reprogramming, and survival under therapeutic stress. On a molecular level, mTOR interacts with key signaling pathways including PI3K/Akt, Notch, IGF-1R, AMPK, and TGF-β, as well as regulatory proteins and non-coding RNAs, orchestrating a complex network that sustains BCSC properties and mediates chemoresistance and radioresistance. The review further examines various therapeutic strategies targeting the mTOR pathway in BCSCs, encompassing selective PI3K/Akt/mTOR inhibitors, monoclonal antibodies, natural products, and innovative approaches such as nanoparticle-mediated drug delivery. Clinical trials investigating mTOR inhibitors like sirolimus and combination therapies with agents such as everolimus and trastuzumab are discussed, underscoring their potential in eradicating BCSCs and improving patient outcomes. Additionally, natural compounds and repurposed drugs offer promising adjunctive therapies by modulating mTOR activity and targeting BCSC-specific vulnerabilities. In conclusion, targeting the mTOR pathway presents a viable and promising avenue for enhancing breast cancer treatment efficacy by effectively eliminating BCSCs, reducing tumor recurrence, and improving overall patient survival. Continued research and clinical validation of mTOR-targeted therapies are essential to translate these insights into effective clinical interventions, ultimately advancing personalized cancer management and therapeutic outcomes for breast cancer patients.
    Keywords:  Autophagy; Breast cancer; Cancer stem cells; Chemoresistance; Clinical trials; Ferroptosis; Metastasis; PI3K/Akt; Targeted therapy; mTOR pathway
    DOI:  https://doi.org/10.1186/s13287-025-04218-4
  17. bioRxiv. 2025 Mar 15. pii: 2025.03.15.643451. [Epub ahead of print]
    HTLV-1 Tax induces PINK1-Parkin-dependent mitophagy to mitigate activation of the cGAS-STING pathway.
    Suchitra Mohanty, Sujit Suklabaidya, Nelli Mnatsakanyan, Steven Jacobson, Edward W Harhaj.
      Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax regulatory protein plays a critical role in HTLV-1 persistence and pathogenesis; however, the underlying mechanisms are poorly understood. Here we show that Tax dynamically regulates mitochondrial reactive oxygen species (ROS) and membrane potential to trigger mitochondrial dysfunction. Tax is recruited to damaged mitochondria through its interaction with the IKK regulatory subunit NEMO and directly engages the ubiquitin-dependent PINK1-Parkin pathway to induce mitophagy. Tax also recruits autophagy receptors NDP52 and p62/SQSTM1 to damaged mitochondria to induce mitophagy. Furthermore, Tax requires Parkin to limit the extent of cGAS-STING activation and suppress type I interferon (IFN). HTLV-1-transformed T cell lines and PBMCs from HAM/TSP patients exhibit hallmarks of chronic mitophagy which may contribute to immune evasion and pathogenesis. Collectively, our findings suggest that Tax manipulation of the PINK1-Parkin mitophagy pathway represents a new HTLV-1 immune evasion strategy.
    Keywords:  HTLV-1; NDP52; NEMO; Parkin; STING; Tax; cGAS; mitochondria; mitophagy
    DOI:  https://doi.org/10.1101/2025.03.15.643451
  18. Sci Adv. 2025 Apr 04. 11(14): eadt4955
    Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.
    Ana G Dumitras, Giorgia Piccoli, Frederik Tellkamp, Lena Keufgens, Martina Baraldo, Sabrina Zorzato, Laura Cussonneau, Leonardo Nogara, Marcus Krüger, Bert Blaauw.
      Skeletal muscle fibers are classified as glycolytic or oxidative, with differing susceptibilities to muscle wasting. However, the intracellular signaling pathways regulating fiber-specific muscle trophism remain unclear because of a lack of experimental models measuring protein synthesis. We developed a mouse model overexpressing a mutated transfer RNA synthetase in muscle fibers, enabling specific protein labeling using an artificial methionine substitute, which can be revealed through click chemistry. This model revealed that denervation increases protein labeling in oxidative muscle fibers through mammalian target of rapamycin complex 1 (mTORC1) activation, while deleting the mTORC1 scaffold protein Raptor reduces labeling in glycolytic fibers. On the other hand, increased muscle activity acutely decreases protein synthesis, accompanied by reduced mTORC1 signaling, glycogen depletion, and adenosine 5'-monophosphate kinase activation. Our findings identify nerve activity as an inhibitory signal for mTORC1-dependent protein synthesis in skeletal muscle, enhancing the understanding of fiber-specific responses to exercise and pathological conditions.
    DOI:  https://doi.org/10.1126/sciadv.adt4955
  19. Neoplasma. 2025 Mar 28. pii: 241203N504. [Epub ahead of print]
    Research progress on the regulation mechanism of DEPTOR expression and its role in tumorigenesis.
    Jinni Jiang, Chengyu Zhao, Minglei Yang, Guofang Zhao, Jianfeng Shu.
      The mammalian target of rapamycin (mTOR) is a critical sensor and integrator of extracellular stimuli and intracellular signaling pathways, forming structurally and functionally distinct protein complexes (mTORC1, mTORC2, and mTORC3) with various proteins. It serves as a central regulator of vital biological processes like cell proliferation, survival, and autophagy. Numerous studies have linked mTOR pathway activation to tumor progression. DEPTOR, a common negative regulator of mTORC1 and mTORC2, exhibits complex loop regulatory mechanisms beyond simple mTOR pathway modulation. Depending on the cell type or tissue environment, DEPTOR can act as either an oncogene or a tumor suppressor gene. Given its complex role in tumorigenesis, precise regulation of DEPTOR expression across different tumor types is imperative. DEPTOR has emerged as a key focus in research on human malignant tumors. While recent years have seen through investigations into DEPTOR expression regulation in tumors, a systematic literature review is lacking. This review provides a detailed summary of the mechanisms regulating DEPTOR expression, an mTOR inhibitor in tumors, covering DNA induction, transcription, translation, and post-translational modification. Additionally, it explores the potential applications of DEPTOR/mTOR signaling axis-related compounds in tumor therapy.
    DOI:  https://doi.org/10.4149/neo_2025_241203N504
  20. Biochem Biophys Res Commun. 2025 Mar 24. pii: S0006-291X(25)00412-7. [Epub ahead of print]759 151698
    Ormeloxifene induces mitochondrial fission-mediated pro-death autophagy in colon cancer cells.
    Rakesh Kumar Sharma, Rohit Sahai, Nishakumari Chentunarayan Singh, Mayank Maheshwari, Nisha Yadav, Jayanta Sarkar, Kalyan Mitra.
      Ormeloxifene (ORM) is a nonsteroidal selective estrogen receptor modulator (SERM), developed by the CSIR-Central Drug Research Institute that is approved as an oral contraceptive. However, it has also shown promising anti-cancer activity, especially in breast cancer. Here, we have investigated the anti-cancer effect of ORM on colon cancer cells and show that its antiproliferative activity is mediated through mitochondrial fission and autophagy-associated cell death. We observed that ORM treatment led to an elevation in autophagy markers like LC3II, Beclin1, and Atg7. Autophagy induction and LC3II turnover were monitored by immunofluorescence staining and confocal microscopy. Transmission electron microscopy results confirmed the formation of autophagosomes and autophagolysosomes. Autophagic flux was confirmed by the increased expression of LC3II in cells co-treated with BafilomycinA1(autophagy inhibitor) and ORM. This was further corroborated using tandem mRFP-GFP-LC3 (tfLC3) transfection in DLD-1 cells. Interestingly, we observed that inhibition of autophagy reduced the apoptotic cell population, suggesting pro-death autophagy. ORM treatment caused notable ultrastructural alterations indicative of cellular stress. Notably, ORM triggered the generation of mitochondrial ROS, associated with increased levels of mitochondrial fission and a decrease in mitochondrial fusion proteins. Changes in mitochondrial dynamics were observed under the TEM, which included reduced mitochondrial size and increased mitochondrial number. Inhibition of mitochondrial fission resulted in enhanced cell survival and a concomitant decrease in the autophagic markers, implying that ORM-induced autophagy depends on mitochondrial fission. Taken together, our findings bring to light a novel mechanism where Ormeloxifene targets mitochondrial dynamics to promote autophagy-associated cell death in colon cancer cells.
    Keywords:  Autophagy; Cancer; Cell death; Mitochondrial fission; Ormeloxifene
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151698
  21. Mol Ther. 2025 Mar 30. pii: S1525-0016(25)00218-7. [Epub ahead of print]
    TNFAIP8L2 maintains Hair cell function and Regulates Age-related hearing loss via mTORC1 Signaling.
    Wen Li, Yu Li, Min Wang, Hao Liu, Guodong Hong, Luhan Jiang, Ziyi Liu, Yunhao Wu, Liangjie Yuan, Xiaoxu Zhao, Zuhong He, Siwei Guo, Yu Xiao, Xiuli Bi, Ming Xia, Guichang Zou, Lining Zhang, Jiangang Gao, Xiaolong Fu.
      Age-related hearing loss (ARHL) is one of the most prevalent and complex disorders. Our previous study demonstrated that abnormal activation of mTORC1 signaling in the cochlear neurosensory epithelium (NSE) causes auditory hair cell damage and contributes to ARHL. However, the underlying mechanism of mTORC1 activation remains unclear. In this study, we identified TNF-alpha-induced protein 8-like 2 (TNFAIP8L2), an immune regulatory gene, as a potential candidate. To elucidate the effect of TNFAIP8L2 on mTORC1 signaling in the NSE and on hearing function, we generated a Tnfaip8l2-deficient (Tnfaip8l2-/-) mouse model. We discovered that Tnfaip8l2-deficiency led to features of oxidative stress in cochlear hair cells and age-related hearing degeneration, exhibiting a similar phenotype to the mTORC1-overactivated Tsc1-cKO mice described previously. Furthermore, rapamycin, a well-known mTORC1 inhibitor, significantly mitigated the hearing dysfunction caused by Tnfaip8l2-deficiency. Mechanistically, we found that TNFAIP8L2 regulates mTORC1 signaling by simultaneously inhibiting the GTPase activity of RHEB and RAC1. Notably, both RHEB and RAC1 inhibitors alleviated the hearing phenotype observed in Tnfaip8l2-/- mice by inhibiting mTORC1 signaling. Collectively, our results provide insights into the activation of the mTORC1 pathway in aged mouse cochleae and positions TNFAIP8L2 as a valuable theoretical strategy.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.046
  22. 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
  23. Rev Cardiovasc Med. 2025 Mar;26(3): 28195
    Roles of Autophagy, Mitophagy, and Mitochondria in Left Ventricular Remodeling after Myocardial Infarction.
    Xin Zhang, Shuai Shao, Qiuting Li, Yi Wang, Mowei Kong, Chunxiang Zhang.
      This review examines the mechanisms of left ventricular dysfunction, focusing on the interplay between ventricular remodeling, autophagy, and mitochondrial dysfunction following myocardial infarction. Left ventricular dysfunction directly affects the heart's pumping efficiency and can lead to severe clinical outcomes, including heart failure. After myocardial infarction, the left ventricle may suffer from weakened contractility, diastolic dysfunction, and cardiac remodeling, progressing to heart failure. Thus, this article discusses the pathophysiological processes involved in ventricular remodeling, including the injury and repair of infarcted and non-infarcted myocardia, adaptive changes, and specific changes in left ventricular systolic and diastolic functions. Furthermore, the role of autophagy in maintaining cellular energy homeostasis, clearing dysfunctional mitochondria, and the key role of mitochondrial dysfunction in heart failure is addressed. Finally, this article discusses therapeutic strategies targeting mitochondrial dysfunction and enhancing mitophagy, providing clinicians and researchers with the latest insights and future research directions.
    Keywords:  autophagy; heart failure; left ventricular dysfunction; myocardial infarction; therapeutic strategies; ventricular remodeling
    DOI:  https://doi.org/10.31083/RCM28195
  24. Plant Physiol Biochem. 2025 Mar 18. pii: S0981-9428(25)00328-6. [Epub ahead of print]223 109800
    Redox regulation of autophagy in Arabidopsis: The different ROS effects.
    Germán Robert, Alejandro Enet, Laura Saavedra, Ramiro Lascano.
      Autophagy plays a key role in the responses to different stress condition in plants. Reactive oxygen species (ROS) are common modulators of stress responses, having both toxic and signaling functions. In this context, the relationship between ROS and autophagy regulation remains unclear, and in some aspects, contradictory. In this study, we employed pharmacological and genetic approaches to investigate the effects of different ROS on the cytoplastic redox state and autophagic flux in Arabidopsis thaliana. Our results demonstrated that oxidative treatments with H2O2 and MV, which drastically increased the oxidized state of the cytoplasm, reduced the autophagic flux. Conversely, singlet oxygen, which did not have significant effects on the cytoplasmic redox state, increased the autophagic flux. Additionally, our findings indicated that after H2O2 and high light treatments and during the recovery period, the cytoplasm returned to its reduced state, while autophagy was markedly induced. In summary, our study unveils the differential effects of ROS on the autophagic flux, establishing a correlation with the redox state of the cytoplasm. Moreover, it emphasizes the dynamic nature of autophagy in response to oxidative stress and the subsequent recovery period.
    Keywords:  Arabidopsis thaliana; Autophagy; Hydrogen peroxide; Reactive oxygen species; Redox state; Singlet oxygen; Stress; Superoxide radical
    DOI:  https://doi.org/10.1016/j.plaphy.2025.109800
  25. Neurobiol Dis. 2025 Mar 27. pii: S0969-9961(25)00105-6. [Epub ahead of print]209 106889
    α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease.
    Yakum B Mingo, Martha L Escobar Galvis, Michael X Henderson.
      Two major neuropathological features of Parkinson's disease (PD) are α-synuclein Lewy pathology and mitochondrial dysfunction. Although both α-synuclein pathology and mitochondrial dysfunction may independently contribute to PD pathogenesis, the interaction between these two factors is not yet fully understood. In this review, we discuss the physiological functions of α-synuclein and mitochondrial homeostasis in neurons as well as the pathological defects that ensue when these functions are disturbed in PD. Recent studies have highlighted that dysfunctional mitochondria can become sequestered within Lewy bodies, and cell biology studies have suggested that α-synuclein can directly impair mitochondrial function. There are also PD cases caused by genetic or environmental perturbation of mitochondrial homeostasis. Together, these studies suggest that mitochondrial dysfunction may be a common pathway to neurodegeneration in PD, triggered by multiple insults. We review the literature surrounding the interaction between α-synuclein and mitochondria and highlight open questions in the field that may be explored to advance our understanding of PD and develop novel, disease-modifying therapies.
    Keywords:  Cell death; Mitochondrial complex I; PINK1; Parkin; mtDNA; α-Synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2025.106889
  26. FASEB J. 2025 Apr 15. 39(7): e70496
    3,4-Dimethoxychalcone alleviates limb ischemia/reperfusion injury by TFEB-mediated autophagy enhancement and antioxidative response.
    Yi-Hui Qiu, Yin-He Zhang, Zi-Chang Wu, Jing-Yong Huang, Bi-Cheng Chen, Jian Xiao, Fan-Feng Chen.
      Caloric restriction mimetics (CRMs) replicate the positive effects of caloric restriction (CR) and have demonstrated therapeutic benefits in neuroinflammatory and cardiovascular diseases. However, it remains uncertain whether CRMs enhance functional recovery following ischemia/reperfusion (I/R) injury, as well as the specific mechanisms involved in this process. This study examines the therapeutic potential of the CRM 3,4-dimethoxychalcone (3,4-DC) in limb I/R injury. Histology, tissue swelling analysis, and laser doppler imaging (LDI) were used to assess the viability of the limbs. Western blotting and immunofluorescence were utilized to examine apoptosis levels, oxidative stress (OS), autophagy, transcription factor EB (TFEB) activity, and mucolipin 1 (MCOLN1)-calcineurin signaling pathway. The administration of 3,4-DC notably alleviated hypoperfusion, tissue swelling, skeletal muscle fiber damage, and cellular injury in the limb caused by I/R. The pharmacological blockade of autophagy negated the antioxidant and antiapoptotic effects of 3,4-DC. Moreover, RNA interference-mediated TFEB silencing eliminated the 3,4-DC-induced restoration of autophagy, antioxidant response, and antiapoptotic effects. Additionally, our findings revealed that 3,4-DC modulates TFEB activity via the MCOLN1-calcineurin signaling pathway. 3,4-DC facilitates functional recovery by enhancing TFEB-driven autophagy, while simultaneously suppressing oxidative stress and apoptosis following I/R injury, suggesting its potential value in clinical applications.
    Keywords:  3,4‐dimethoxychalcone; apoptosis; autophagy; limb ischemia–reperfusion; oxidative stress
    DOI:  https://doi.org/10.1096/fj.202402609RR
  27. Curr Mol Pharmacol. 2025 Apr 03.
    Targeting of Lysosomes as a Therapeutic Target in Cancer.
    Biyu Liu, Chengsheng Yang, Jiayi Liu, Minzhi Peng, Junquan Mao, Sanyuan Tang, Weiguo Huang.
      Lysosomes are important intracellular organelles involved in degradation metabolism, maintenance of homeostasis, cell survival and programmed death regulation, and play an important role in immunity. Some studies have shown that lysosomes are closely linked to tumor development. Lysosomes in tumor cells increase in size and activity to adapt to rapid proliferation. Cancer cells provide strong support for their unrestricted growth and proliferation by precisely regulating the number, composition and functional activities of lysosomes and also create favorable conditions for malignant behaviors such as survival, migration, invasion, and metastatic spread of cancer cells. Lysosomes play a central role in tumor progression, and in recent years, lysosomes have become an important target for anticancer strategies aimed at interfering with their function or modulating related signaling pathways to inhibit tumors. Current anti-cancer strategies include the following five aspects: (1) targeting tumor cell energy metabolism and lysosomes to inhibit growth; (2) inhibiting lysosomal histone proteases to block degradation metabolism; (3) destabilizing lysosomal membranes to trigger tumor cell death; (4) modulating lysosomal calcium signaling to affect tumor cell function; and (5) interfering with the mTOR signaling pathway to inhibit tumor growth and proliferation. These lysosome-targeted anticancer strategies offer broad prospects and potential for the development of novel anticancer drugs and therapies and are expected to bring more effective and safer therapeutic options for cancer patients.
    Keywords:  Antitumor therapy; Autophagy.; Biological functions; Lysosome
    DOI:  https://doi.org/10.2174/0118761429354659250320051057
  28. bioRxiv. 2025 Mar 13. pii: 2025.03.10.642477. [Epub ahead of print]
    Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin.
    Christian J Elliehausen, Szczepan S Olszewski, Carolyn G Shult, Aditya R Ailiani, Michaela E Trautman, Reji Babygirija, Dudley W Lamming, Troy A Hornberger, Dennis M Minton, Adam R Konopka.
      An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2mg/kg; 1x/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2mg/kg; 3x/week). Frequent but not intermittent rapamycin suppressed skeletal muscle mTORC1 signaling in PoWeR trained mice. PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin treated mice. Conversely, frequent and intermittent rapamycin treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that 1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and 2) the detrimental effects of rapamycin on body composition and glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.
    DOI:  https://doi.org/10.1101/2025.03.10.642477
  29. Autophagy. 2025 Mar 31.
    Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.
    Yuyuan Zhu, Min Cao, Yancheng Tang, Yifan Liu, Haiji Wang, Jiaqi Qi, Cainian Huang, Chenghao Yan, Xu Liu, Sijia Jiang, Yufei Luo, Shaogui Wang, Bo Zhou, Haodong Xu, Ying-Ying Lu, Liming Wang.
      Mitochondria serve as the primary source of intracellular reactive oxygen species (ROS), which play a critical role in orchestrating cell death pathways such as pyroptosis in various types of cancers. PINK1-mediated mitophagy effectively removes damaged mitochondria and reduces detrimental ROS levels, thereby promoting cell survival. However, the regulation of pyroptosis by PINK1 and ROS in neuroblastoma remains unclear. In this study, we demonstrate that inhibition or deficiency of PINK1 sensitizes ROS signaling and promotes pyroptosis in neuroblastoma cells via the BAX-caspase-GSDME signaling pathway. Specifically, inhibition of PINK1 by AC220 or knockout of PINK1 impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Activated BAX facilitates the release of CYCS (cytochrome c, somatic) from the mitochondria into the cytosol, activating CASP3 (caspase 3). Subsequently, activated CASP3 cleaves and activates GSDME, inducing pyroptosis. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression in vivo. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.
    Keywords:  Cell death; GSDME; PINK1; mitochondrial ROS; mitophagy; neuroblastoma
    DOI:  https://doi.org/10.1080/15548627.2025.2487037
  30. Biochem Biophys Res Commun. 2025 Mar 20. pii: S0006-291X(25)00387-0. [Epub ahead of print]760 151673
    RAB18 deficiency disrupts lipid metabolism and autophagy in mice.
    Li-Wei Zhang, Ya-Qi Han, Yan Yang, Yun-Jie Li, Ying-Xian Ma, Sheng-Li Ming.
      Mutation of the small G protein member RAB18 can lead to Warburg Micro Syndrome, characterized clinically by visual impairment and hind limb weakness. However, the cellular and molecular functions of RAB18 in mice are not fully understood. We obtained 3 Rab18+/+ and 3 Rab18-/- mice by using CRISPR/Cas9 technology. Rab18-/- mice exhibit symptoms of ocular shrinkage and hind limb weakness, along with griping/curling when tail suspended. Through metabolomics analysis, we found that Rab18 knockout affects lipid, vitamin, and amino acid metabolism while also impacting the autophagy signaling pathway. Lipid analysis of the mouse liver revealed that Rab18 knockout led to an increase in hepatic lipid droplets, promoted elevated TC and TG levels, and impaired fatty acid release. Interestingly, Rab18 knockout promoted the expression of lipogenic genes and proteins but did not affect the expression of lipolytic genes and proteins. Since lipophagy, involved in lipid droplet breakdown, plays a key role, we found that Rab18 knockout inhibited the expression of liver autophagy-related genes and proteins. In summary, our results suggest that Rab18 plays a role in autophagy in mice, likely contributing to mechanisms of lipid accumulation.
    Keywords:  Autophagy; Lipid metabolism; Rab18
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151673
  31. bioRxiv. 2025 Mar 20. pii: 2025.03.20.644464. [Epub ahead of print]
    p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.
    Jordan Matthew Ngo, Justin Krish Williams, Morayma Mercedes Temoche-Diaz, Abinayaa Murugupandiyan, Randy Schekman.
      Exosomes are multivesicular body-derived extracellular vesicles that are secreted by metazoan cells. Exosomes have utility as disease biomarkers, and exosome-mediated miRNA secretion has been proposed to facilitate tumor growth and metastasis. Previously, we demonstrated that the Lupus La protein (La) mediates the selective incorporation of miR-122 into metastatic breast cancer-derived exosomes; however, the mechanism by which La itself is sorted into exosomes remains unknown. Using unbiased proximity labeling proteomics, biochemical fractionation, superresolution microscopy and genetic tools, we establish that the selective autophagy receptor p62 sorts La and miR-122 into exosomes. We then performed small RNA sequencing and found that p62 depletion reduces the exosomal secretion of tumor suppressor miRNAs and results in their accumulation within cells. Our data indicate that p62 is a quality control factor that modulates the miRNA composition of exosomes. Cancer cells may exploit p62-dependent exosome cargo sorting to eliminate tumor suppressor miRNAs and thus to promote cell proliferation.
    DOI:  https://doi.org/10.1101/2025.03.20.644464
  32. Mol Biol Cell. 2025 Apr 02. mbcE24040162
    A dual reporter system for intracellular and extracellular amino acid sensing in budding yeast.
    Jurgita Paukštytė, Emma Cervera Tena, Juha Saarikangas.
      Amino acid homeostasis is essential for cellular functions such as growth, metabolism, and signaling. In budding yeast Saccharomyces cerevisiae, the General Amino Acid Control (GAAC) and Target of Rapamycin Complex 1 (TORC1) pathways are utilized for intracellular amino acid sensing, while the Ssy1-Ptr3-Ssy5 (SPS) pathway is used for extracellular sensing. These pathways maintain homeostasis by responding to variations in amino acid levels to regulate amino acid biosynthesis and uptake. However, their interactions under various conditions and behavior at single-cell resolution remain insufficiently understood. We developed fluorescent transcriptional reporters to monitor amino acid biosynthesis and uptake pathways in single cells, revealing pathway engagement in response to different amino acid levels and types. Inhibition experiments demonstrated that the SPS pathway influences TORC1 and GAAC activities differently. Additionally, pathway engagement varied between liquid culture and colony environments. In colonies, some cells specialized in either amino acid synthesis or uptake. Disruption of the SPS pathway hindered this specialization and increased cell death rates in aging colonies, indicating a role for metabolic differentiation in maintaining colony viability. Collectively, this study introduces a new tool for exploring cellular amino acid homeostasis and highlights the importance of cellular differentiation in amino acid control for colony survival.
    DOI:  https://doi.org/10.1091/mbc.E24-04-0162
  33. Autophagy. 2025 Apr 03.
    Mitophagy-mediated S1P facilitates muscle adaptive responses to endurance exercise through SPHK1-S1PR1/S1PR2 in slow-twitch myofibers.
    Minghong Leng, Fenghe Yang, Junhui Zhao, Yufei Xiong, Yiqing Zhou, Mingyang Zhao, Shi Jia, Limei Liu, Qiaoxia Zheng, Lebin Gan, Jingjing Ye, Ming Zheng.
      Endurance exercise triggers adaptive responses especially in slow-twitch myofibers of skeletal muscles, leading to the remodeling of myofiber structure and the mitochondrial network. However, molecular mechanisms underlying these adaptive responses, with a focus on the fiber type-specific perspective, remains largely unknown. In this study we analyzed the alterations of transcriptomics and metabolomics in distinct skeletal myofibers in response to endurance exercise. We determined that genes associated with sphingolipid metabolism, namely those encoding SPHK1, S1PR1, and S1PR2, are enriched in slow-twitch but not fast-twitch myofibers from both mouse and human skeletal muscles, and found that the SPHK1-S1PR pathway is essential for adaptive responses of slow-twitch to endurance exercise. Importantly, we demonstrate that endurance exercise causes the accumulation of ceramides on stressed mitochondria, and the mitophagic degradation of ceramides results in an increase of the sphingosine-1-phosphate (S1P) level. The elevated S1P thereby facilitates mitochondrial adaptation and enhances endurance capacity via the SPHK1-S1PR1/S1PR2 axis in slow-twitch muscles. Moreover, administration of S1P improves endurance performance in muscle atrophy mice by emulating these adaptive responses. Our findings reveal that the SPHK1-S1P-S1PR1/S1PR2 axis through mitophagic degradation of ceramides in slow-twitch myofibers is the central mediator to endurance exercise and highlight a potential therapeutic target for ameliorating muscle atrophy diseases.
    Keywords:  Endurance exercise; mitochondrial biogenesis; mitophagy; skeletal muscle; sphingosine-1-phosphate
    DOI:  https://doi.org/10.1080/15548627.2025.2488563
  34. Cell Death Dis. 2025 Mar 29. 16(1): 222
    RNA N6-methyladenosine demethylase FTO promotes diabetic wound healing through TRIB3-mediated autophagy in an m6A-YTHDF2-dependent manner.
    Zheng Dong, Shiyan Li, Yumeng Huang, Tianzhe Chen, Youjun Ding, Qian Tan.
      N6-methyladenosine (m6A) RNA modification impaired autophagy results in delayed diabetic wound healing. In this study, it was found that fat mass and obesity-associated protein (FTO) was significantly downregulated in the epidermis of diabetic patients, STZ-induced mice and db/db mice (type I and II diabetic mice) with prolonged hyperglycemia, as well as in different types of keratinocyte cell lines treated with short-term high glucose medium. The knockout of FTO affected the biological functions of keratinocytes, including enhanced apoptosis, inhibited autophagy, and delayed wound healing, producing consistent results with high-glucose medium treatment. High-throughput analysis revealed that tribbles pseudokinase 3 (TRIB3) served as the downstream target gene of FTO. In addition, both in vitro and in vivo experiments, TRIB3 overexpression partially rescued biological functions caused by FTO-depletion, promoting keratinocyte migration and proliferation via autophagy. Epigenetically, FTO modulated m6A modification in the 3'UTR of TRIB3 mRNA and enhanced TRIB3 stability in a YTHDF2-dependent manner. Collectively, this study identifies FTO as an accelerator of diabetic wound healing and modulates autophagy via regulating TRIB3 in keratinocytes, thereby benefiting the development of a m6A-targeted therapy for refractory diabetic wounds.
    DOI:  https://doi.org/10.1038/s41419-025-07494-3
  35. Cell Death Differ. 2025 Apr 01.
    DEPTOR suppresses lymphomagenesis by promoting EGFR degradation via HUWE1 E3 ligase.
    Xiufang Xiong, Xiaoyu Chen, Shengpeng Shao, Danrui Cui, Ruirui Qu, Baohui Wang, Ying Ma, Hui Pan, Yi Sun, Yongchao Zhao.
      DEPTOR, a naturally occurring inhibitor of mTOR, plays crucial roles in tumorigenesis and is frequently dysregulated in a variety of human cancers. Interestingly, DEPTOR could act either as a tumor suppressor or as an oncogene in a manner dependent of cellular context or tissue environment. Whether and how DEPTOR regulates lymphomagenesis remains elusive. In this study, we report that in a mouse lymphoma model induced by heterozygous Pten loss, Deptor knockout (KO) markedly accelerates lymphomagenesis, whereas degradation-resistant DeptorS275A knock-in (KI) variant significantly inhibits it. Furthermore, Deptor KO mice spontaneously developed lymphomas in the later stages of their lifespan, and Deptor KO further shortened overall lifespan in Ptenfl/fl;MMTV-Cre mice. Consistently, DEPTOR protein levels are significantly lower in human lymphoma tissues, as compared to normal lymph nodes. Mechanistically, DEPTOR, on one hand, enhances the interaction of EGFR to HUWE1 E3 ubiquitin ligase for targeted ubiquitination and proteasomal degradation, and subsequent inactivation of the MAPK signal. On the other hand, DEPTOR inactivates both mTORC1 and mTORC2 signals. Collectively, our study demonstrated that DEPTOR is a tumor suppressor that inhibits lymphomagenesis upon Pten-loss. The strategy that reactivates DEPTOR could be a promising approach for the treatment of lymphoma.
    DOI:  https://doi.org/10.1038/s41418-025-01497-5
  36. Res Sq. 2025 Mar 13. pii: rs.3.rs-6043477. [Epub ahead of print]
    Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission.
    You-Kyung Lee, Cong Xiao, Xiaoting Zhou, Le Wang, Meghan G McReynolds, Zhiping Wu, Eric Purisic, Henry Kim, Xianting Li, Zhiping Pang, Jinye Dai, Junmin Peng, Nan Yang, Zhenyu Yue.
      Human genomic studies have identified protein-truncating variants in AKAP11 associated with both bipolar disorder (BD) and schizophrenia (SCZ), implicating a shared disease mechanism driven by loss-of-function. AKAP11, a protein kinase A (PKA) adaptor, plays a key role in degrading the PKA-RI complex through selective autophagy. However, the neuronal functions of AKAP11 and the impact of its loss-of-function remains largely uncharacterized. Through multi-omics approaches, cell biology, and electrophysiology analysis in mouse models and human induced neurons, we delineated a central role of AKAP11 in coupling PKA kinase network regulation to synaptic transmission. Loss of AKAP11 distorted compartment-specific PKA and GSK3α/β activities and impaired cellular functions that significantly overlap with pathways associated with BD and SCZ. Moreover, we identified interactions between AKAP11, the PKA-RI adaptor SPHKAP, and the ER-resident autophagy-related proteins VAPA/B, which co-adapt and mediate PKA-RI complex degradation in neurons. Notably, AKAP11 deficiency impaired neurotransmission, providing key insights into the mechanism underlying AKAP11-associated psychiatric diseases.
    DOI:  https://doi.org/10.21203/rs.3.rs-6043477/v1
  37. Cell Commun Signal. 2025 Apr 01. 23(1): 158
    DNM1L-mediated fission governs mitophagy & mitochondrial biogenesis during myogenic differentiation.
    Fasih A Rahman, Jasmine M Friedrich Yap, Tyler M Joseph, Amanda M Adam, Sarah M Chapman, Joe Quadrilatero.
       BACKGROUND: Remodeling of the mitochondrial network is implicated in myogenesis. Remodeling processes including mitochondrial fission, mitophagy, and biogenesis are important as they finetune the mitochondrial network to meet the increased energetic demand of myotubes. Evidence suggests that mitochondrial fission governs other mitochondrial remodeling processes; however, this relationship is unclear in the context of myogenesis.
    METHODS: We used C2C12 myoblasts to study changes in mitochondrial remodeling processes and their role in regulating myogenesis. To investigate this, we employed genetic manipulation with adenoviruses to modify the levels of key molecules involved in mitochondrial remodeling, including DNM1L, BNIP3, and PPARGC1A.
    RESULTS: We demonstrate that overexpression of fission protein DNM1L accelerated mitophagic flux, but reduced myotube size without affecting mitochondrial biogenesis. Conversely, DNM1L knockdown reduced mitophagic flux, impaired myoblast differentiation, and suppressed mitochondrial biogenesis signaling. Additionally, DNM1L knockdown increased mitochondrial apoptotic signaling through CASP9 and CASP3 activation. Attempts to rescue myogenesis through overexpression of the mitophagy receptor BNIP3 or the biogenesis regulator PPARGC1A were unsuccessful in the absence of proper mitochondrial fission. Furthermore, DNM1L overexpression in BNIP3-deficient cells enhanced mitophagic flux, but did not promote myogenesis.
    CONCLUSION: These results underscore the complex interdependencies among mitochondrial remodeling processes and highlight the necessity for sequential activation of mitochondrial fission, mitophagy, and biogenesis.
    Keywords:  Apoptosis; Mitochondrial biogenesis; Mitochondrial fission; Mitophagy; Myogenesis; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12964-025-02142-x
  38. Aging (Albany NY). 2025 Apr 02. null
    Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation.
    Sofie Lautrup, Shi-Qi Zhang, Shinichiro Funayama, Lisa Lirussi, Tina Visnovska, Hoi-Hung Cheung, Marc Niere, Yuyao Tian, Hilde Loge Nilsen, Geir Selbæk, Janna Saarela, Yoshiro Maezawa, Koutaro Yokote, Per Nilsson, Wai-Yee Chan, Hisaya Kato, Mathias Ziegler, Vilhelm A Bohr, Evandro F Fang.
      Werner syndrome (WS), caused by mutations in the RecQ helicase WERNER (WRN) gene, is a classical accelerated aging disease with patients suffering from several metabolic dysfunctions without a cure. While, as we previously reported, depleted NAD+ causes accumulation of damaged mitochondria, leading to compromised metabolism, how mitochondrial NAD+ changes in WS and the impact on WS pathologies were unknown. We show that loss of WRN increases senescence in mesenchymal stem cells (MSCs) likely related to dysregulation of metabolic and aging pathways. In line with this, NAD+ augmentation, via supplementation with nicotinamide riboside, reduces senescence and improves mitochondrial metabolic profiles in MSCs with WRN knockout (WRN-/-) and in primary fibroblasts derived from WS patients compared to controls. Moreover, WRN deficiency results in decreased mitochondrial NAD+ (measured indirectly via mitochondrially-expressed PARP activity), and altered expression of key salvage pathway enzymes, including NMNAT1 and NAMPT; ChIP-seq data analysis unveils a potential co-regulatory axis between WRN and the NMNATs, likely important for chromatin stability and DNA metabolism. However, restoration of mitochondrial or cellular NAD+ is not sufficient to reinstall cellular proliferation in immortalized cells with siRNA-mediated knockdown of WRN, highlighting an indispensable role of WRN in proliferation even in an NAD+ affluent environment. Further cell and animal studies are needed to deepen our understanding of the underlying mechanisms, facilitating related drug development.
    Keywords:  NAD+; Werner syndrome; mitochondria; premature aging; proliferation
    DOI:  https://doi.org/10.18632/aging.206236
  39. Cell Death Differ. 2025 Apr 02.
    TM9SF1 inhibits colorectal cancer metastasis by targeting Vimentin for Tollip-mediated selective autophagic degradation.
    Huifen Wang, Jia Hu, Di Wang, Yudie Cai, Weiwei Zhu, Rui Deng, Yize Zhang, Zihui Dong, Zhe Yang, Juan Xiao, Ang Li, Zhibo Liu.
      Selective autophagy is a finely regulated degradation pathway that can either promote or suppress cancer progression depending on its specific target cargoes. In this study, we report that transmembrane 9 superfamily member 1 (TM9SF1) suppresses colorectal cancer metastasis via selective autophagic degradation of Vimentin. Tm9sf1 knockout significantly increases tumor numbers and size, as well as enhances tumor invasion in colorectal cancer model. In vitro and in vivo phenotypical analyses reveal that TM9SF1 functions as a metastasis suppressor in colorectal cancer. Mechanistically, TM9SF1 facilitates the K63-linked ubiquitination of Vimentin by the E3 ligase TRIM21. The K63-linked ubiquitination of Vimentin serves as a recognition signal for autophagic degradation mediated by autophagic cargo receptor Tollip. Consequently, the downregulation of Vimentin results in a decreased number of F-actin-rich stress fibers and filopodium-like protrusions, ultimately inhibiting colorectal cancer metastasis. Moreover, TM9SF1 is downregulated in colorectal cancer patients with advanced stage compared to those with early stage and associated with favorable prognosis. Overall, our findings identify a novel TM9SF1-TRIM21-Vimentin-Tollip pathway involved in colorectal cancer metastasis, which may provide promising therapeutic targets for the treatment of metastatic colorectal cancer.
    DOI:  https://doi.org/10.1038/s41418-025-01498-4
  40. Physiol Rev. 2025 Apr 03.
    TPCs: From plant to human.
    Yvonne Eileen Klingl, Arnas Petrauskas, Dawid Jaślan, Christian Grimm.
      In 2005, the Arabidopsis thaliana two-pore channel TPC1 channel was identified as a vacuolar Ca²⁺-release channel. In 2009 three independent groups published studies on mammalian TPCs as NAADP-activated endolysosomal Ca2+ release channels, results that were eventually challenged by two other groups, claiming mammalian TPCs to be PI(3,5)P2 activated Na+ channels. By now this dispute seems to have been largely reconciled. Lipophilic small molecule agonists of TPC2, mimicking either the NAADP or the PI(3,5)P2 mode of channel activation, revealed, together with structural evidence, that TPC2 can change its selectivity for Ca2+ versus Na+ in a ligand-dependent fashion (N- versus P-type activation). Furthermore, NAADP-binding proteins, JPT2 and Lsm12 were discovered, corroborating the hypothesis that NAADP activation of TPCs only works in the presence of these auxiliary NAADP-binding proteins. Pathophysiologically, loss or gain of function of TPCs has effects on autophagy, exocytosis, endocytosis, and intracellular trafficking, e.g., LDL cholesterol trafficking leading to fatty liver disease or viral and bacterial toxin trafficking, corroborating roles of TPCs in infectious diseases such as Ebola or Covid19. Defects in trafficking of EGFR and 1-integrin suggested roles in cancer. In neurodegenerative lysosomal storage disease models, P-type activation of TPC2 was found to have beneficial effects on both in vitro and in vivo hallmarks of Niemann- Pick disease type C1, Batten disease, and Mucolipidosis type IV. Here, we cover the latest on structure, function, physiology, and pathophysiology of these channels with a focus initially on plant followed by mammalian TPCs, and we discuss their potential as drug targets, including currently available pharmacology.
    Keywords:  TPC; TPCN1; TPCN2; lysosomal
    DOI:  https://doi.org/10.1152/physrev.00044.2024
  41. Nat Cell Biol. 2025 Apr 01.
    Phosphoinositide signalling in cell motility and adhesion.
    Xiaoting Hou, Chang Ren, Jing Jin, Yu Chen, Xinyu Lyu, Kangle Bi, Noah D Carrillo, Vincent L Cryns, Richard A Anderson, Jichao Sun, Mo Chen.
      Cell motility and adhesion are fundamental components for diverse physiological functions, including embryonic development, immune responses and tissue repair. Dysregulation of these processes can lead to a range of diseases, including cancer. Cell motility and adhesion are complex and often require regulation by an intricate network of signalling pathways, with phosphatidylinositol phosphates (PIPs) having a central role. PIPs are derived from phosphatidylinositol phosphorylation and are instrumental in mediating membrane dynamics, intracellular trafficking, cytoskeletal organization and signal transduction, all of which are crucial for cellular responses to environmental stimuli. Here we discuss the mechanisms through which PIPs modulate cell motility and adhesion by examining their roles at focal adhesions, within the cytoskeleton, at protein scaffolds and in the nucleus. By providing a comprehensive overview of PIP signalling, this Review underscores their significance in maintaining cellular homeostasis and highlights their potential as therapeutic targets in diseases characterized by aberrant cell motility and adhesion.
    DOI:  https://doi.org/10.1038/s41556-025-01647-4
  42. EMBO Rep. 2025 Apr 02.
    Mpf1 affects the dual distribution of tail-anchored proteins between mitochondria and peroxisomes.
    Nitya Aravindan, Daniela G Vitali, Julia Breuer, Jessica Oberst, Einat Zalckvar, Maya Schuldiner, Doron Rapaport.
      Most cellular proteins require targeting to a distinct cellular compartment to function properly. A subset of proteins is distributed to two or more destinations in the cell and little is known about the mechanisms controlling the process of dual/multiple targeting. Here, we provide insight into the mechanism of dual targeting of proteins between mitochondria and peroxisomes. We perform a high throughput microscopy screen in which we visualize the location of the model tail-anchored proteins Fis1 and Gem1 in the background of mutants in virtually all yeast genes. This screen identifies three proteins, whose absence results in a higher portion of the tail-anchored proteins in peroxisomes: the two paralogues Tom70, Tom71, and the uncharacterized gene YNL144C that we rename mitochondria and peroxisomes factor 1 (Mpf1). We characterize Mpf1 to be an unstable protein that associates with the cytosolic face of the mitochondrial outer membrane. Furthermore, our study uncovers a unique contribution of Tom71 to the regulation of dual targeting. Collectively, our study reveals, for the first time, factors that influence the dual targeting of proteins between mitochondria and peroxisomes.
    Keywords:  Dual Targeting; Fis1; Mitochondria; Peroxisomes; Tail-anchored Proteins
    DOI:  https://doi.org/10.1038/s44319-025-00440-6
  43. Sci Rep. 2025 Mar 29. 15(1): 10905
    Vorinostat attenuates UVB-induced skin senescence by modulating NF-κB and mTOR signaling pathways.
    Qianlong Dai, Zhiwei Wang, Xue Wang, Wei Lian, Yuchen Ge, Shujia Song, Fuxing Li, Bingxiang Zhao, Lihua Li, Xiaobo Wang, Min Zhou, Jianjie Cheng.
      Excessive exposure to ultraviolet B (UVB) radiation induces oxidative stress and inflammatory responses, accelerating the senescence process of skin cells. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is typically administered to patients with peripheral T-cell lymphoma, cutaneous T-cell lymphoma, or multiple myeloma. However, its effect on UVB-induced skin photoaging remains unclear. In this study, we used UVB to induce senescence in human immortalized keratinocyte cell line (HaCaT cells) and skin photoaging in Balb/c mice to investigate the potential of SAHA in mitigating photoaging. First, we established a UVB-induced photoaging model in HaCaT cells. We observed that UVB exposure significantly upregulated the activity of senescence-associated β-galactosidase, p16, p21, IL-1β, IL-6, and matrix metalloproteinases [collagenase (MMP-1), matrix metalloproteinase-3 (MMP-3), and gelatinase (MMP-9)]. Supplementation with SAHA effectively alleviated cellular senescence in HaCaT cells. Next, we used UVB to induce photoaging in Balb/c mouse skin. The study demonstrated that UVB markedly caused skin senescence in Balb/c mice, while SAHA effectively mitigated the changes induced by UVB irradiation. Mechanistically, we found that UVB activated the mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB) signaling pathways, whereas SAHA inhibited the upregulation of both mTOR and NF-κB. In summary, these findings suggest that SAHA may protect against UVB-induced cellular senescence and skin photoaging by inhibiting the mTOR and NF-κB signaling pathways. Therefore, SAHA could be a potential anti-senescence agent for mitigating skin photoaging.
    Keywords:  Anti-photoaging; NF-κB; UVB-induced; Vorinostat; mTOR
    DOI:  https://doi.org/10.1038/s41598-025-95624-4
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