bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–01–26
forty-six papers selected by
Viktor Korolchuk, Newcastle University
  1. Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.
  2. Caloric restriction exacerbates renal post-ischemic injury and fibrosis by modulating mTORC1 signaling and autophagy.
  3. mTor limits autophagy to facilitate cell volume expansion and rapid wound repair in Drosophila embryos.
  4. Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.
  5. How close is autophagy-targeting therapy for Alzheimer's disease to clinical use? A summary of autophagy modulators in clinical studies.
  6. mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
  7. Mammalian nucleophagy: process and function.
  8. Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS.
  9. Microlipophagy from Simple to Complex Eukaryotes.
  10. Autophagy in Plant Health and Disease.
  11. Protocol for the visualization of pRps6-positive cells in larval zebrafish brains using whole-mount immunofluorescence and light-sheet microscopy.
  12. Splice age: mTORC1-mediated RNA splicing in metabolism and ageing.
  13. Molecular mechanisms of mTOR-mediated cisplatin response in tumor cells.
  14. The PKA signaling pathway regulates the association of the autophagy initiation complex with the lipidation machinery.
  15. ADAR1 Promotes the Progression and Temozolomide Resistance of Glioma Through p62-Mediated Selective Autophagy.
  16. Metformin-induced mitophagy suppresses auditory hair cell apoptosis via AMPK pathway.
  17. Ponatinib alleviates non-alcoholic steatohepatitis through TFEB-mediated autophagy.
  18. Inhibiting Autophagy by Chemicals During SCAPs Osteodifferentiation Elicits Disorganized Mineralization, While the Knock-Out of Atg5/7 Genes Leads to Cell Adaptation.
  19. Autophagy activation alleviates annulus fibrosus degeneration via the miR-2355-5p/mTOR pathway.
  20. The role of autophagy in Graves disease: knowns and unknowns.
  21. Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance.
  22. Insight into interplay between PANoptosis and autophagy: novel therapeutics in ischemic stroke.
  23. Intestinal RICT-1 regulates the larval germline progenitor pool via the vitellogenin VIT-3 in C. elegans.
  24. Cholesterol deficiency directs autophagy-dependent secretion of extracellular vesicles.
  25. Acrylamide Induces Antiapoptotic Autophagy and Apoptosis by Activating PERK Pathway in SH-SY5Y Cells.
  26. mTORC1 regulates the proliferation of SOX9+ porcine skin-derived stem cells (pSDSCs) by promoting S6K phosphorylation.
  27. Application of a near-infrared viscosity-responsive fluorescent probe for lysosomal targeting in fatty liver mice.
  28. The Role of Autophagy in Copper-Induced Apoptosis and Developmental Neurotoxicity in SH-SY5Y Cells.
  29. Spermidine Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders.
  30. Targeting autophagy to enhance chemotherapy and immunotherapy in oral cancer.
  31. Discovery of Evolutionary Loss of the Ubiquitin-like Autophagy-Related ATG12 System in a Lineage of Apicomplexa.
  32. The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes.
  33. Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies.
  34. Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
  35. Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction.
  36. Scutellarin inhibits pyroptosis via selective autophagy degradation of p30/GSDMD and suppression of ASC oligomerization.
  37. Autophagic flux modulates tumor heterogeneity and lineage plasticity in SCLC.
  38. Molecular architecture of human LYCHOS involved in lysosomal cholesterol signaling.
  39. The Dual Function of Autophagy in Doxorubicin-induced Cardiotoxicity: Mechanism and Natural products.
  40. TDP43 augments astrocyte inflammatory activity through mtDNA-cGAS-STING axis in NMOSD.
  41. Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin.
  42. ZDHHC2 promoted antimycobacterial responses by selective autophagic degradation of B-RAF and C-RAF in macrophages.
  43. Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.
  44. The Epstein-Barr virus deubiquitinase BPLF1 regulates stress-induced ribosome UFMylation and reticulophagy.
  45. Muscular TOR knockdown and endurance exercise ameliorate high salt and age-related skeletal muscle degradation by activating the MTOR-mediated pathway.
  46. Decoding lysosome communication.
  1. Autophagy. 2025 Jan 21.
    Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.
    Yinfeng Xu, Wei Wan.
      Induction of macroautophagy/autophagy has been established as an important function elicited by the CGAS-STING1 pathway during pathogen infection. However, it remains unknown whether lysosomal activity within the cell in these settings is concurrently enhanced to cope with the increased autophagic flux. Recently, we discovered that the CGAS-STING1 pathway elevates the degradative capacity of the cell by activating lysosome biogenesis. Intriguingly, we found that STING1-induced GABARAP lipidation, rather than TBK1 activation, serves as the key mediator triggering the nuclear translocation of transcription factor TFEB and enhances the expression of lysosome-related genes. Mechanistically, we demonstrated that lipidated GABARAP on single membranes, regulated by the V-ATPase-ATG16L1 axis, sequesters the FLCN-FNIP complex to abolish its function toward RRAGC-RRAGD, leading to a specific impairment of MTORC1-dependent phosphorylation of TFEB and resulting in its subsequent nuclear translocation. Functionally, we showed that STING1-induced lysosome biogenesis is essential for the clearance of cytoplasmic DNA and the elimination of invading pathogens. Collectively, our findings underscore the induction of lysosome biogenesis as a novel function of the CGAS-STING1 pathway.China; Yinfeng Xu; Email: yinfengxu@hnfnu.edu.cn; Hunan First Normal University, 1015 Feng-Lin-San Road, Changsha, Hunan 410,205, China.
    Keywords:  Autophagy; CGAS; GABARAP; STING1; TFEB; lysosome
    DOI:  https://doi.org/10.1080/15548627.2025.2456064
  2. Redox Biol. 2025 Jan 16. pii: S2213-2317(25)00013-8. [Epub ahead of print]80 103500
    Caloric restriction exacerbates renal post-ischemic injury and fibrosis by modulating mTORC1 signaling and autophagy.
    Lang Shi, Hongchu Zha, Juan Zhao, Haiqian An, Hua Huang, Yao Xia, Ziyu Yan, Zhixia Song, Jiefu Zhu.
       OBJECTIVE: This study investigates the effects of caloric restriction (CR) on renal injury and fibrosis following ischemia-reperfusion injury (IRI), with a focus on the roles of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling and autophagy.
    METHODS: A mouse model of unilateral IRI with or without CR was used. Renal function was assessed through serum creatinine and blood urea nitrogen levels, while histological analysis and molecular assays evaluated tubular injury, fibrosis, mTORC1 signaling, and autophagy activation. Inducible renal tubule-specific Atg7 knockout mice and autophagy inhibitor 3-MA were used to elucidate autophagy's role in renal outcomes.
    RESULTS: CR exacerbated renal dysfunction, tubular injury, and fibrosis in IRI mice, associated with suppressed mTORC1 signaling and enhanced autophagy. Rapamycin, an mTORC1 inhibitor, mimicked the effects of CR, further supporting the involvement of mTORC1-autophagy pathway. Tubule-specific Atg7 knockout and autophagy inhibitor 3-MA mitigated these effects, indicating a central role for autophagy in CR-induced renal damage. Glucose supplementation, but not branched-chain amino acids (BCAAs), alleviated CR-induced renal fibrosis and dysfunction by restoring mTORC1 activation. Finally, we identified leucyl-tRNA synthetase 1 (LARS1) as a key mediator of nutrient sensing and mTORC1 activation, demonstrating its glucose dependency under CR conditions.
    CONCLUSION: Our study provides novel insights into the interplay between nutrient metabolism, mTORC1 signaling, and autophagy in IRI-induced renal damages, offering potential therapeutic targets for mitigating CR-associated complications after renal IRI.
    Keywords:  Acute kidney injury; Autophagy; Caloric restriction; Ischemia-reperfusion injury; mTORC1
    DOI:  https://doi.org/10.1016/j.redox.2025.103500
  3. Dev Cell. 2025 Jan 10. pii: S1534-5807(24)00778-0. [Epub ahead of print]
    mTor limits autophagy to facilitate cell volume expansion and rapid wound repair in Drosophila embryos.
    Gordana Scepanovic, Negar Balaghi, Katheryn E Rothenberg, Rodrigo Fernandez-Gonzalez.
      Embryonic wounds repair rapidly, with no inflammation or scarring. Embryonic wound healing is driven by collective cell movements facilitated by the increase in the volume of the cells adjacent to the wound. The mechanistic target of rapamycin (mTor) complex 1 (TORC1) is associated with cell growth. We found that disrupting TORC1 signaling in Drosophila embryos prevented cell volume increases and slowed down wound repair. Catabolic processes, such as autophagy, can inhibit cell growth. Five-dimensional microscopy demonstrated that the number of autophagosomes decreased during wound repair, suggesting that autophagy must be tightly regulated for rapid wound healing. mTor inhibition increased autophagy, and activating autophagy prevented cell volume expansion and slowed down wound closure. Finally, reducing autophagy in embryos with disrupted TORC1 signaling rescued cell volume changes and rapid wound repair. Together, our results show that TORC1 activation upon wounding negatively regulates autophagy, allowing cells to increase their volumes to facilitate rapid wound healing.
    Keywords:  Drosophila embryo; cell volume; collective cell movement; epithelial morphogenesis; image analysis; quantitative microscopy; wound healing
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.039
  4. Sci Adv. 2025 Jan 24. 11(4): eadu5787
    Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.
    Felix Kraus, Yuchen He, Sharan Swarup, Katherine A Overmyer, Yizhi Jiang, Johann Brenner, Cristina Capitanio, Anna Bieber, Annie Jen, Nicole M Nightingale, Benton J Anderson, Chan Lee, Joao A Paulo, Ian R Smith, Jürgen M Plitzko, Steven P Gygi, Brenda A Schulman, Florian Wilfling, Joshua J Coon, J Wade Harper.
      Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in NPC1-/- and NPC2-/- mutants, where lysosomes accumulate cholesterol. Autophagic and endocytic cargo delivery failures correlated with elevated lysophosphatidylcholine species and multilamellar structures visualized by cryo-electron tomography. Loss of mitochondrial cristae, MICOS complex components, and OXPHOS components rich in iron-sulfur cluster proteins in NPC2-/- cells was largely alleviated when iron was provided through the transferrin system. This study reveals how lysosomal dysfunction affects mitochondrial homeostasis and underscores nMOST as a valuable discovery tool for identifying molecular phenotypes across LSDs.
    DOI:  https://doi.org/10.1126/sciadv.adu5787
  5. Front Cell Dev Biol. 2024 ;12 1520949
    How close is autophagy-targeting therapy for Alzheimer's disease to clinical use? A summary of autophagy modulators in clinical studies.
    Sofia Miranda Fernandes, Johanna Mayer, Per Nilsson, Makoto Shimozawa.
      Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by progressive decline of memory and cognitive functions, and it is the leading cause of dementia accounting for 60%-80% of dementia patients. A pathological hallmark of AD is the accumulation of aberrant protein/peptide aggregates such as extracellular amyloid plaques containing amyloid-beta peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. These aggregates result from the failure of the proteostasis network, which encompasses protein synthesis, folding, and degradation processes. Autophagy is an intracellular self-digesting system responsible for the degradation of protein aggregates and damaged organelles. Impaired autophagy is observed in most neurodegenerative disorders, indicating the link between autophagy dysfunction and these diseases. A massive accumulation of autophagic vacuoles in neurons in Alzheimer's brains evidences autophagy impairment in AD. Modulating autophagy has been proposed as a therapeutic strategy for AD because of its potential to clear aggregated proteins. However, autophagy modulation therapy for AD is not yet clinically available. This mini-review aims to summarize clinical studies testing potential autophagy modulators for AD and to evaluate their proximity to clinical use. We accessed clinicaltrials.gov provided by the United States National Institutes of Health to identify completed and ongoing clinical trials. Additionally, we discuss the limitations and challenges of these therapies.
    Keywords:  Alzheimer’s disease; autophagy impairment; autophagy modulators; clinical studies; protein homeostasis
    DOI:  https://doi.org/10.3389/fcell.2024.1520949
  6. FASEB J. 2025 Jan 31. 39(2): e70277
    mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
    Jingwen Li, Agnete B Madsen, Jonas R Knudsen, Carlos Henriquez-Olguin, Kaspar W Persson, Zhencheng Li, Steffen H Raun, Tianjiao Li, Bente Kiens, Jørgen F P Wojtaszewski, Erik A Richter, Leonardo Nogara, Bert Blaauw, Riki Ogasawara, Thomas E Jensen.
      The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.
    Keywords:  AMPK; exercise; mTORC1; mTORC2; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202402064R
  7. Autophagy. 2025 Jan 19.
    Mammalian nucleophagy: process and function.
    Fujian Ji, Enyong Dai, Rui Kang, Daniel J Klionsky, Tong Liu, Yu Hu, Daolin Tang, Kun Zhu.
      The nucleus is a highly specialized organelle that houses the cell's genetic material and regulates key cellular activities, including growth, metabolism, protein synthesis, and cell division. Its structure and function are tightly regulated by multiple mechanisms to ensure cellular integrity and genomic stability. Increasing evidence suggests that nucleophagy, a selective form of autophagy that targets nuclear components, plays a critical role in preserving nuclear integrity by clearing dysfunctional nuclear materials such as nuclear proteins (lamins, SIRT1, and histones), DNA-protein crosslinks, micronuclei, and chromatin fragments. Impaired nucleophagy has been implicated in aging and various pathological conditions, including cancer, neurodegeneration, autoimmune disorders, and neurological injury. In this review, we focus on nucleophagy in mammalian cells, discussing its mechanisms, regulation, and cargo selection, as well as evaluating its therapeutic potential in promoting human health and mitigating disease.
    Keywords:  Autophagy; disease; micronucleus; nuclear quality control; nucleophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2455158
  8. Nat Struct Mol Biol. 2025 Jan 17.
    Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS.
    Jie Zhao, Qingya Shen, Xihao Yong, Xin Li, Xiaowen Tian, Suyue Sun, Zheng Xu, Xiaoyu Zhang, Lu Zhang, Hao Yang, Zhenhua Shao, Haoxing Xu, Yiyang Jiang, Yan Zhang, Wei Yan.
      Cholesterol plays a pivotal role in modulating the activity of mechanistic target of rapamycin complex 1 (mTOR1), thereby regulating cell growth and metabolic homeostasis. LYCHOS, a lysosome-localized G-protein-coupled receptor-like protein, emerges as a cholesterol sensor and is capable of transducing the cholesterol signal to affect the mTORC1 function. However, the precise mechanism by which LYCHOS recognizes cholesterol remains unknown. Here, using cryo-electron microscopy, we determined the three-dimensional structural architecture of LYCHOS in complex with cholesterol molecules, revealing a unique arrangement of two sequential structural domains. Through a comprehensive analysis of this structure, we elucidated the specific structural features of these two domains and their collaborative role in the process of cholesterol recognition by LYCHOS.
    DOI:  https://doi.org/10.1038/s41594-024-01470-9
  9. Cells. 2025 Jan 18. pii: 141. [Epub ahead of print]14(2):
    Microlipophagy from Simple to Complex Eukaryotes.
    Ravinder Kumar, Colin Arrowood, Micah B Schott, Taras Y Nazarko.
      Lipophagy is a selective degradation of lipid droplets in lysosomes or vacuoles. Apart from its role in generating energy and free fatty acids for membrane repair, growth, and the formation of new membranes, lipophagy emerges as a key player in other cellular processes and disease pathogenesis. While fungal, plant, and algal cells use microlipophagy, the most prominent form of lipophagy in animal cells is macrolipophagy. However, recent studies showed that animal cells can also use microlipophagy to metabolize their lipid droplets. Therefore, to no surprise, microlipophagy is conserved from simple unicellular to the most complex multicellular eukaryotes, and many eukaryotic cells can operate both forms of lipophagy. Macrolipophagy is the most studied and better understood at the molecular level, while our understanding of microlipophagy is very sparse. This review will discuss microlipophagy from the perspective of its conservation in eukaryotes and its importance in diseases. To better appreciate the conserved nature of microlipophagy, different organisms and types of cells in which microlipophagy has been reported are also shown in a tabular form. We also point toward the gaps in our understanding of microlipophagy, including the signaling behind microlipophagy, especially in the cells of complex multicellular organisms.
    Keywords:  autophagy; chaperon-mediated autophagy; lipid droplets; lipophagy; macroautophagy; macrolipophagy; microautophagy; microlipophagy; selective autophagy; vacuolar microdomains
    DOI:  https://doi.org/10.3390/cells14020141
  10. Annu Rev Plant Biol. 2025 Jan 22.
    Autophagy in Plant Health and Disease.
    Angelina S Gross, Margot Raffeiner, Yonglun Zeng, Suayib Üstün, Yasin Dagdas.
      Autophagy has emerged as an essential quality control pathway in plants that selectively and rapidly removes damaged or unwanted cellular components to maintain cellular homeostasis. It can recycle a broad range of cargoes, including entire organelles, protein aggregates, and even invading microbes. It involves the de novo biogenesis of a new cellular compartment, making it intimately linked to endomembrane trafficking pathways. Autophagy is induced by a wide range of biotic and abiotic stress factors, and autophagy mutant plants are highly sensitive to stress, making it an attractive target for improving plant stress resilience. Here, we critically discuss recent discoveries related to plant autophagy and highlight open questions and future research areas.
    DOI:  https://doi.org/10.1146/annurev-arplant-060324-094912
  11. STAR Protoc. 2025 Jan 18. pii: S2666-1667(24)00752-4. [Epub ahead of print]6(1): 103587
    Protocol for the visualization of pRps6-positive cells in larval zebrafish brains using whole-mount immunofluorescence and light-sheet microscopy.
    Olga Doszyn, Tomasz Dulski, Justyna Zmorzynska.
      Due to their small size and transparency, larval zebrafish are a useful model for whole-brain imaging. Here, we present a protocol for the visualization of phosphorylated Rps6, a marker of mechanistic target of rapamycin complex 1 (mTORC1) activity, in the zebrafish brains at 5 days post fertilization (dpf), using whole-mount immunofluorescence and light-sheet microscopy. We describe steps for sample preparation, storage, staining, and imaging. This protocol can also be modified for staining with antibodies against other proteins. For complete details on the use and execution of this protocol, please refer to Doszyn et al.1.
    Keywords:  developmental biology; microscopy; model organisms; neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2024.103587
  12. Trends Cell Biol. 2025 Jan 21. pii: S0962-8924(25)00001-7. [Epub ahead of print]
    Splice age: mTORC1-mediated RNA splicing in metabolism and ageing.
    Pablo Lanuza-Gracia, Jonas Juan-Mateu, Juan Valcárcel.
      The target of rapamycin complex mTORC1 has key roles in cell growth and metabolism and its inhibition delays ageing. Recent work by Ogawa et al. in Caenorhabditis elegans argues that modulation of pre-mRNA splicing factors and alternative splicing are key mediators of mTORC1 signalling and can enhance longevity.
    DOI:  https://doi.org/10.1016/j.tcb.2025.01.001
  13. Heliyon. 2025 Jan 15. 11(1): e41483
    Molecular mechanisms of mTOR-mediated cisplatin response in tumor cells.
    Amirhosein Maharati, Yasamin Rajabloo, Meysam Moghbeli.
      Cisplatin (CDDP) is one of the main chemotherapeutic drugs that is widely used in many cancers. However, CDDP resistance is a frequent therapeutic challenge that reduces prognosis in cancer patients. Since, CDDP has noticeable side effects in normal tissues and organs, it is necessary to assess the molecular mechanisms associated with CDDP resistance to improve the therapeutic methods in cancer patients. Drug efflux, detoxifying systems, DNA repair mechanisms, and drug-induced apoptosis are involved in multidrug resistance in CDDP-resistant tumor cells. Mammalian target of rapamycin (mTOR), as a serine/threonine kinase has a pivotal role in various cellular mechanisms such as autophagy, metabolism, drug efflux, and cell proliferation. Although, mTOR is mainly activated by PI3K/AKT pathway, it can also be regulated by many other signaling pathways. PI3K/Akt/mTOR axis functions as a key modulator of drug resistance and unfavorable prognosis in different cancers. Regarding, the pivotal role of mTOR in CDDP response, in the present review we discussed the molecular mechanisms that regulate mTOR mediated CDDP response in tumor cells.
    Keywords:  Chemoresistance; Cisplatin; Prognosis; Treatment; mTOR
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e41483
  14. J Mol Biol. 2025 Jan 16. pii: S0022-2836(25)00020-8. [Epub ahead of print] 168954
    The PKA signaling pathway regulates the association of the autophagy initiation complex with the lipidation machinery.
    Miranda Bueno-Arribas, Celia Cruz-Cuevas, Beatriz Monforte-Martinez, María-Angeles Navas, Ricardo Escalante, Olivier Vincent.
      A key step in autophagy is the conjugation by the E3-like Atg12-Atg5-Atg16 complex of the ubiquitin-like protein Atg8 to phosphatidylethanolamine on the autophagosomal membrane, a process known as lipidation. Previous work in yeast showed that recruitment of the E3-like complex to the preautophagosomal structure is mediated by the interaction of Atg16 with the phosphatidylinositol 3-phosphate-binding protein Atg21, and by the association of Atg12 with the scaffold protein of the Atg1 kinase complex, Atg17. Here, we conducted a reverse two-hybrid screen to identify residues in Atg17 and Atg12 critical for Atg17-Atg12 binding, and used these data to generate a docking model of Atg12-Atg5-Atg16 with the Atg17 complex. In this model, a conserved alpha-helix in the N-terminal region of Atg12 binds to the convex side of crescent-shaped Atg17 and appears to form a four-helix bundle with the three helices of Atg17, similar to that described for the binding of Atg31 to Atg17. We further showed that, in agreement with previous work, Atg17-Atg12 and Atg21-Atg16 binding act cooperatively to mediate the recruitment of the E3-like complex, although our results show that alternative mechanisms are involved in this process. Finally, we found that phosphorylation of Atg12 by PKA prevents its interaction with Atg17, thus adding a new regulatory layer in the control of autophagy by the PKA signaling pathway.
    Keywords:  ATG12; ATG17; PKA; autophagy; reverse two-hybrid
    DOI:  https://doi.org/10.1016/j.jmb.2025.168954
  15. CNS Neurosci Ther. 2025 Jan;31(1): e70168
    ADAR1 Promotes the Progression and Temozolomide Resistance of Glioma Through p62-Mediated Selective Autophagy.
    Yuyan Zhang, Huiling Guo, Jiahao Bu, Weiwei Wang, Li Wang, Zhibo Liu, Yuning Qiu, Qimeng Wang, Lijuan Zhou, Xianzhi Liu, Liwei Ma, Jianwei Wei.
       BACKGROUND: Resistance to temozolomide (TMZ) remains is an important cause of treatment failure in patients with glioblastoma multiforme (GBM). ADAR1, as a member of the ADAR family, plays an important role in cancer progression and chemotherapy resistance. However, the mechanism by which ADAR1 regulates GBM progression and TMZ resistance is still unclear.
    METHODS: We first constructed stable transfected strains in which ADAR1 was knocked down and overexpressed to investigate the effect of ADAR1 on the first-line glioma chemotherapy drug TMZ. Subsequently, we validated that ADAR1 induces autophagy activation and used autophagy inhibitors to suppress autophagy, demonstrating that ADAR1 enhances TMZ resistance through autophagy. We further knocked down p62 (SQSTM1) based on the overexpression of ADAR1, and the results showed that ADAR1 regulates selective autophagy through the p62 regulation. Finally, we demonstrated through mutations at both edited and nonedited sites that ADAR1 regulates selective autophagy in an edited dependent way.
    RESULTS: Further analysis showed that in the presence of TMZ, elevated ADAR1 promoted TMZ induced autophagy activation. Further research revealed that ADAR1 enhances TMZ resistance through p62-mediated selective autophagy. Further, ADAR1 regulates selective autophagy in an edited dependent way. Our results indicate a relationship between ADAR1 levels and the response of glioma patients to TMZ treatment.
    CONCLUSIONS: We found that the expression of ADAR1 is upregulated in GBM and is associated with tumor grade and TMZ resistance. Elevated expression of ADAR1 predicts poor prognosis in GBM patients and promotes tumor growth in vivo or in vitro.
    Keywords:  ADAR1; TMZ resistance; autophagy; glioma; p62
    DOI:  https://doi.org/10.1111/cns.70168
  16. Brain Res Bull. 2025 Jan 16. pii: S0361-9230(25)00026-7. [Epub ahead of print] 111214
    Metformin-induced mitophagy suppresses auditory hair cell apoptosis via AMPK pathway.
    Yifan Lai, Jiawei Qiu, Kuang Zheng, Xiang Li, Yinuo Lin, Zhengzheng Li, Haiqiu Sun.
      Hearing loss is a pervasive issue affecting numerous individuals, and its etiology and categorization are multifaceted. Among these, sensorineural hearing loss (SNHL) emerges as the most prevalent variant among these. The primary causative factor underlying SNHL resides in the depletion of auditory hair cells within the cochlea, yet the pursuit of efficacious therapeutic interventions remains an ongoing challenge. Previous investigations have illuminated the role of mitochondrial dysfunction in precipitating cellular apoptosis, and mitophagy has emerged as a promising mechanism to ameliorate such dysfunction. Additionally, it has been noted that metformin possesses the specific ability to induce mitophagy. Herein, our objective is to explore the protective effects of metformin-induced mitophagy against apoptosis in auditory hair cells (HEI-OC1 cells) and explore its potential mechanisms. Our results revealed that metformin effectively triggered mitophagy in HEI-OC1 cells. Moreover, metformin treatment showed the ability to prevent tert-butyl hydroperoxide (TBHP) induced mitochondrial dysfunction and intrinsic apoptotic pathways. Mechanistically, we discovered that metformin activates AMP-activated protein kinase (AMPK) signaling in HEI-OC1 cells stimulated by TBHP, thereby triggering mitophagy. Overall, our results suggest that metformin may represent a promising and innovative therapeutic strategy for mitigating the onset of hearing loss.
    Keywords:  Metformin; apoptosis; autophagy; hearing loss; mitophagy
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111214
  17. Front Pharmacol. 2024 ;15 1505768
    Ponatinib alleviates non-alcoholic steatohepatitis through TFEB-mediated autophagy.
    Zhuomiao Lin, Meiqing Yang, Xihui Yu, Guozhu Tan, Jiahong Zhong.
       Objective: Non-alcoholic steatohepatitis (NASH) is a progressive liver disease with lipid accumulation, inflammation, and liver fibrosis. Ponatinib, a third-generation tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia, was found to improve metabolic disorders in mice. However, the role of ponatinib in liver inflammation and fibrosis remains to be elucidated. Here we aimed to determine the effect of ponatinib in non-alcoholic steatohepatitis.
    Methods: We explored the function and mechanism of ponatinib using a mouse model of NASH induced by a methionine and choline deficient (MCD) diet and LO2 cells cultured in MCD mimic medium.
    Results: Here, we found that ponatinib reduced liver lipid deposition, fibrosis, and inflammation induced by MCD diet without affecting body weight and blood glucose. Meanwhile, we found that ponatinib attenuated steatohepatitis and inflammation in LO2 cells induced by MCD mimic medium. We further discovered that the expression levels of LC3II and lysosomal associated membrane protein 1 (LAMP1) were reduced and the expression level of p62 was upregulated in both mouse and cell models, suggesting that autophagy was inhibited, which was restored by ponatinib treatment. In addition, transcription factor EB (TFEB) is a major regulator of autophagy and lysosome biogenesis and the transcription and protein expression levels of TFEB were decreased in steatosis hepatocytes, which could be ameliorated by ponatinib treatment.
    Conclusion: These results revealed that the beneficial effects of ponatinib on NASH via TFEB-mediated autophagy.
    Keywords:  NASH; TFEB; autophagy; methionine and choline deficient diet; ponatinib
    DOI:  https://doi.org/10.3389/fphar.2024.1505768
  18. Cells. 2025 Jan 20. pii: 146. [Epub ahead of print]14(2):
    Inhibiting Autophagy by Chemicals During SCAPs Osteodifferentiation Elicits Disorganized Mineralization, While the Knock-Out of Atg5/7 Genes Leads to Cell Adaptation.
    Damien Le Nihouannen, Claudine Boiziau, Sylvie Rey, Nicole Agadzhanian, Nathalie Dusserre, Fabrice Cordelières, Muriel Priault, Helene Boeuf.
      SCAPs (Stem Cells from Apical Papilla), derived from the apex of forming wisdom teeth, extracted from teenagers for orthodontic reasons, belong to the MSCs (Mesenchymal Stromal Cells) family. They have multipotent differentiation capabilities and are a potentially powerful model for investigating strategies of clinical cell therapies. Since autophagy-a regulated self-eating process-was proposed to be essential in osteogenesis, we investigated its involvement in the SCAP model. By using a combination of chemical and genetic approaches to inhibit autophagy, we studied early and late events of osteoblastic differentiation. We showed that blocking the formation of autophagosomes with verteporfin did not induce a dramatic alteration in early osteoblastic differentiation monitored by ALP (alkaline phosphatase) activity. However, blocking the autophagy flux with bafilomycin A1 led to ALP repression. Strikingly, the mineralization process was observed with both compounds, with calcium phosphate (CaP) nodules that remained inside cells under bafilomycin A1 treatment and numerous but smaller CaP nodules after verteporfin treatment. In contrast, deletion of Atg5 or Atg7, two genes involved in the formation of autophagosomes and essential to trigger canonical autophagy, indicated that both genes could be involved differently in the mineralization process with a modification of the ALP activity while final mineralization was not altered.
    Keywords:  ALP activity; LC3; SCAPs; alternative autophagy; bafilomycin A1; canonical autophagy; mesenchymal stem cells; mineralization; osteoblasts; verteporfin
    DOI:  https://doi.org/10.3390/cells14020146
  19. J Orthop Surg Res. 2025 Jan 23. 20(1): 86
    Autophagy activation alleviates annulus fibrosus degeneration via the miR-2355-5p/mTOR pathway.
    Zilin Yu, Chunyang Fan, Yubo Mao, Xiexing Wu, Haiqing Mao.
       BACKGROUND: Intervertebral disc degeneration disease (IVDD) is a major cause of disability and reduced work productivity worldwide. Annulus fibrosus degeneration is a key contributor to IVDD, yet its mechanisms remain poorly understood. Autophagy, a vital process for cellular homeostasis, involves the lysosomal degradation of cytoplasmic proteins and organelles. This study aimed to investigate the role of autophagy in IVDD using a hydrogen peroxide (H2O2)-induced model of rat annulus fibrosus cells (AFCs).
    METHODS: AFCs were exposed to H2O2 to model oxidative stress-induced degeneration. Protein expression levels of collagen I, collagen II, MMP3, and MMP13 were quantified. GEO database analysis identified alterations in miR-2355-5p expression, and its regulatory role on the mTOR pathway and autophagy was assessed. Statistical tests were used to evaluate changes in protein expression and pathway activation.
    RESULTS: H2O2 exposure reduced collagen I and collagen II expression to approximately 50% of baseline levels, while MMP3 and MMP13 expression increased twofold. Activation of autophagy restored collagen I and II expression and decreased MMP3 and MMP13 levels. GEO analysis revealed significant alterations in miR-2355-5p expression, confirming its role in regulating the mTOR pathway and autophagy.
    CONCLUSIONS: Autophagy, mediated by the miR-2355-5p/mTOR pathway, plays a protective role in AFCs degeneration. These findings suggest a potential therapeutic target for mitigating IVDD progression.
    DOI:  https://doi.org/10.1186/s13018-025-05492-x
  20. Front Cell Dev Biol. 2024 ;12 1480950
    The role of autophagy in Graves disease: knowns and unknowns.
    Hayder M Al-Kuraishy, Ghassan M Sulaiman, Hamdoon A Mohammed, Mohammed H Abu-Alghayth, Salim Albukhaty, Majid S Jabir, Ali K Albuhadily, Ali I Al-Gareeb, Daniel J Klionsky, Mosleh M Abomughaid.
      Graves disease (GD), an autoimmune disease affects the thyroid gland, results in hyperthyroidisms and goiter. The main cause of GD is not clearly defined; however, stimulating autoantibodies for thyroid stimulating hormone receptor (TSHR) known as thyroid-stimulating immunoglobulins (TSIs) are the primary proposed mechanism. The TSI activation of TSHRs of thyroid gland results in excessive release of thyroid hormones with the subsequent development of hyperthyroidism and goiter. The cellular process of macroautophagy/autophagy is implicated in the pathogenesis of GD and other thyroid diseases. Autophagy plays a critical role in many thyroid diseases and in different stages of the same disease through modulation of immunity and the inflammatory response. In addition, autophagy is also implicated in the pathogenesis of thyroid-associated ophthalmopathy (TAO). However, the exact role of autophagy in GD is not well explained. Therefore, this review discusses how autophagy is intricately involved in the pathogenesis of GD regarding its protective and harmful effects.
    Keywords:  Graves disease; autoantibodies; autophagy; pathogenesis; thyroid-associated ophthalmopathy
    DOI:  https://doi.org/10.3389/fcell.2024.1480950
  21. Mol Cancer. 2025 Jan 17. 24(1): 23
    Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance.
    Peng Zhao, Shuangshuang Yin, Yuling Qiu, Changgang Sun, Haiyang Yu.
      Drug resistance is a common challenge in clinical tumor treatment. A reduction in drug sensitivity of tumor cells is often accompanied by an increase in autophagy levels, leading to autophagy-related resistance. The effectiveness of combining chemotherapy drugs with autophagy inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected by various types of autophagy. Therefore, ferroptosis and pyroptosis have crosstalk via autophagy, potentially leading to a switch in cell death types under certain conditions. As two forms of inflammatory programmed cell death, ferroptosis and pyroptosis have different effects on inflammation, and the cGAS-STING signaling pathway is also involved. Therefore, it also plays an important role in the progression of some chronic inflammatory diseases. This review discusses the relationship between autophagy, ferroptosis and pyroptosis, and attempts to uncover the reasons behind the evasion of tumor cell death and the nature of drug resistance.
    Keywords:  Autophagy; CMA; Drug resistance; Ferritinophagy; Ferroptosis; Inflammation; LMP; Mitophagy; Pyroptosis; cGAS-STING
    DOI:  https://doi.org/10.1186/s12943-024-02217-2
  22. Front Mol Neurosci. 2024 ;17 1482015
    Insight into interplay between PANoptosis and autophagy: novel therapeutics in ischemic stroke.
    He-Yan Tian, Yun-Xing Lei, Jing-Tao Zhou, Long-Jun Liu, Tong Yang, Yue Zhou, Jin-Wen Ge, Chen Xu, Zhi-Gang Mei.
      PANoptosis is a novelly defined mode of programmed cell death that involves the activation of multiple cellular death pathways, including pyroptosis, apoptosis, and necroptosis, triggering robust inflammatory reactions. Autophagy is a crucial cellular process that maintains cellular homeostasis and protects cells from various stresses. PANoptosis and autophagy, both vital players in the intricate pathological progression of ischemic stroke (IS), a brain ailment governed by intricate cell death cascades, have garnered attention in recent years for their potential interplay. While mounting evidence hints at a crosstalk between these two processes in IS, the underlying mechanisms remain elusive. Therefore, this review delves into and dissects the intricate mechanisms that underpin the intersection of PANoptosis and autophagy in this devastating condition. In conclusion, the crosstalk between PANoptosis and autophagy in IS presents a promising target for the development of novel stroke therapies. Understanding the interplay between these two pathways offers a much-needed insight into the underlying mechanisms of IS and opens the possibility for new therapeutic strategies.
    Keywords:  PANoptosis; apoptosis; autophagy; ischemic stroke; necroptosis; pyroptosis; therapeutics
    DOI:  https://doi.org/10.3389/fnmol.2024.1482015
  23. bioRxiv. 2025 Jan 09. pii: 2025.01.08.632040. [Epub ahead of print]
    Intestinal RICT-1 regulates the larval germline progenitor pool via the vitellogenin VIT-3 in C. elegans.
    Anke Kloock, E Jane Albert Hubbard.
      Populations of proliferating cells such as stem cells and tumors are often nutrient responsive. Highly conserved signaling pathways communicate information about the surrounding environmental, organismal, and cellular nutrient conditions. One such pathway is the Target of Rapamycin (TOR) pathway. The TOR kinase exists in two complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). TORC1 has been researched extensively and its regulation, particularly by amino acids, is well characterized. TORC1 activity promotes both stem cell fate and proliferation in the Caenorhabditis elegans hermaphrodite germline stem cell system to facilitate expansion of the larval germline Progenitor Zone (PZ) pool in response to nutrients. By contrast, a role for TORC2 in germline development has not been investigated. Here, we show that RICT-1, the sole ortholog of the TORC2-specific component RICTOR, also promotes expansion of the larval PZ, acting largely through SGK-1. Further, unlike the germline-autonomous role for TORC1 components, intestinal rict-1 is both necessary and sufficient for full germline PZ pool establishment. Furthermore, neither DAF-2/IIS nor DAF-7/TGF-ß pathways mediate the effects of RICT-1. Rather, intestinal RICT-1 likely acts via vitellogenins, intestinally produced yolk proteins previously characterized for provisioning the adult germ line, but not previously characterized for a role in larval germ line development. By comparative RNA-seq on staged L4 larvae, we found vitellogenin genes among highly differentially abundant mRNAs. Genetic analysis supports a role for vit-3 in germline development in a linear pathway with rict-1. Our results establish the C. elegans germ line as a fruitful model for investigating TORC2 and its connection to stem cells and lipid biology.
    Keywords:  Rictor; Stem Cells; TORC2; Vitellogenins
    DOI:  https://doi.org/10.1101/2025.01.08.632040
  24. bioRxiv. 2025 Jan 12. pii: 2025.01.11.632510. [Epub ahead of print]
    Cholesterol deficiency directs autophagy-dependent secretion of extracellular vesicles.
    Jazmine D W Yaeger, Sonali Sengupta, Austin L Walz, Mayu Morita, Terry K Morgan, Paola D Vermeer, Kevin R Francis.
      Extracellular vesicle (EV) secretion is an important, though not fully understood, intercellular communication process. Lipid metabolism has been shown to regulate EV activity, though the impact of specific lipid classes is unclear. Through analysis of small EVs (sEVs), we observe aberrant increases in sEV release within genetic models of cholesterol biosynthesis disorders, where cellular cholesterol is diminished. Inhibition of cholesterol synthesis at multiple synthetic steps mimics genetic models in terms of cholesterol reduction and sEVs secreted. Further analyses of sEVs from cholesterol-depleted cells revealed structural deficits and altered surface marker expression, though these sEVs were also more easily internalized by recipient cells. Transmission electron microscopy of cells with impaired cholesterol biosynthesis demonstrated multivesicular and multilamellar structures potentially associated with autophagic defects. We further found autophagic vesicles being redirected toward late endosomes at the expense of autophagolysosomes. Through CRISPR-mediated inhibition of autophagosome formation, we mechanistically determined that release of sEVs after cholesterol depletion is autophagy dependent. We conclude that cholesterol imbalance initiates autophagosome-dependent secretion of sEVs, which may have pathological relevance in diseases of cholesterol disequilibrium.
    DOI:  https://doi.org/10.1101/2025.01.11.632510
  25. Toxics. 2025 Jan 07. pii: 41. [Epub ahead of print]13(1):
    Acrylamide Induces Antiapoptotic Autophagy and Apoptosis by Activating PERK Pathway in SH-SY5Y Cells.
    Yiqi Wang, Ying Liu, Xing Zhang, Yang Jiao, Lian Duan, Ruijie Cheng, Ning Yang, Hong Yan.
      Acrylamide (ACR) is a commonly used organic compound that exhibits evident neurotoxicity in humans. Our previous studies showed that the mechanisms of ACR-caused neurotoxicity included apoptosis, PERK-mediated endoplasmic reticulum stress, and autophagy, but the relationships among them were still unclear. This paper investigated the relationships among apoptosis, autophagy, and the PERK pathway to demonstrate the mechanism of ACR neurotoxicity further. Different doses of ACR were set to value ACR toxicity. Then, a PERK inhibitor and autophagy inhibitor, GSK2606414 and 3-methyladenine (3-MA), were used separately to inhibit the PERK pathway and autophagy activation in SH-SY5Y cells under ACR treatment. With the increase of ACR dose, the apoptotic rate increased in a dose-dependent manner. After the inhibition of the PERK pathway, the activated apoptosis and autophagosome accumulation caused by ACR were alleviated. Under 3-MA and ACR treatment, the autophagy inhibition deteriorated apoptosis in SH-SY5Y cells but had no significant effect on ACR-induced PERK pathway activation; thus, PERK pathway-induced autophagy had an antiapoptotic role in this condition. This paper provides an experimental basis for exploring potential molecular targets to prevent and control ACR toxicity.
    Keywords:  PERK pathway; acrylamide; apoptosis; autophagy
    DOI:  https://doi.org/10.3390/toxics13010041
  26. Histochem Cell Biol. 2025 Jan 20. 163(1): 25
    mTORC1 regulates the proliferation of SOX9+ porcine skin-derived stem cells (pSDSCs) by promoting S6K phosphorylation.
    Ming-Xin Zang, Geng Zhang, Ying Zhang, Sha-Sha Wang, Xiang-Wei Zhai, Na Zhao, Wei Ge, Jin-Wen Xie, Wei Shen, Shun-Feng Cheng.
      Skin-derived stem cells (SDSCs) are a subtype of adult stem cells (ASCs) that are widely harvested and exempt from ethical restrictions in clinical applications. These cells possess capabilities for self-renewal, proliferation, and multi-lineage differentiation. Compared to model animals like rats and mice, pigs exhibit greater physiological similarity to humans. Porcine skin has very similar histological and physiological characteristics to human skin. Therefore, porcine skin is becoming increasingly significant as an in vitro model for research. In this study, porcine skin-derived stem cells (pSDSCs) were isolated and cultured in vitro for experiments. The expression of stemness-related gene SOX9 was detected. RNA sequencing (RNA-seq) results found that the mammalian target of rapamycin (mTOR) signaling pathway was significantly enriched in SOX9+ pSDSCs. To investigate the role of the mTOR signaling pathway, we added rapamycin (RAPA), an inhibitor of the mTOR complex 1 (mTORC1), and found that the proliferation rate of SOX9+ pSDSCs decreased significantly during culture. In addition, western blotting (WB) results demonstrated that mTORC1 promoted proliferation by phosphorylating S6 kinase (S6K) and then activating cyclin D1(CCND1) in SOX9+ pSDSCs. These findings provide insights into the mechanisms of adult stem cell proliferation.
    Keywords:  Proliferation; mTOR signaling pathway; mTORC1; pSDSCs
    DOI:  https://doi.org/10.1007/s00418-025-02354-9
  27. Bioorg Chem. 2025 Feb;pii: S0045-2068(25)00042-2. [Epub ahead of print]155 108162
    Application of a near-infrared viscosity-responsive fluorescent probe for lysosomal targeting in fatty liver mice.
    Junlei Hao, Xiao Li, Suntao Shi, Haijuan Zhang, Hailiang Zhu, Jiang Wu, Mingyong Gao, Baoxin Zhang.
      Viscosity is a fundamental property in biological systems, influencing organelle function and molecular diffusion. Abnormal viscosity is associated with diseases such as metabolic disorders, neurodegeneration, and cancer. Lysosomes, central to cellular degradation and recycling, are sensitive to viscosity changes, which can disrupt enzymatic activity and cellular homeostasis. Monitoring lysosomal viscosity provides essential information on lysosomal health, helping to uncover underlying mechanisms in various diseases. Recognizing the need for effective monitoring of lysosomal viscosity changes in living cells, we have developed a near-infrared (NIR) viscosity-responsive fluorescent probe, VFLyso, specifically designed for lysosomal targeting. Based on the twisted intramolecular charge transfer (TICT) mechanism, VFLyso exhibits strong NIR fluorescence, a fast response, and a notable fluorescence response to viscosity variations (F/F0 = 65.5-fold), along with excellent selectivity and stability under physiological conditions. Our studies demonstrated that VFLyso could accurately monitor lysosomal viscosity changes in both cell cultures and animal models, including zebrafish and mouse models of fatty liver. This work not only provides a powerful tool for real-time monitoring of lysosomal viscosity but also offers valuable insights into the role of viscosity in disease progression, paving the way for potential diagnostic applications in related disorders.
    Keywords:  Fatty liver; Fluorescence imaging; Lysosome; NIR fluorescence probe; Viscosity
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108162
  28. Toxics. 2025 Jan 17. pii: 63. [Epub ahead of print]13(1):
    The Role of Autophagy in Copper-Induced Apoptosis and Developmental Neurotoxicity in SH-SY5Y Cells.
    Lu Lu, Ying Zhang, Wei Shi, Qian Zhou, Zhuoqi Lai, Yuepu Pu, Lihong Yin.
      Copper (Cu) is a global environmental pollutant that poses a serious threat to humans and ecosystems. Copper induces developmental neurotoxicity, but the underlying molecular mechanisms are unknown. Neurons are nonrenewable, and they are unable to mitigate the excessive accumulation of pathological proteins and organelles in cells, which can be ameliorated by autophagic degradation. In this study, we established an in vitro model of Cu2+-exposed (0, 15, 30, 60 and 120 μM) SH-SY5Y cells to explore the role of autophagy in copper-induced developmental neurotoxicity. The results showed that copper resulted in the reduction and shortening of neural synapses in differentiated cultured SH-SY5Y cells, a downregulated Wnt signaling pathway, and nuclear translocation of β-catenin. Exposure to Cu2+ increased autophagosome accumulation and autophagic flux blockage in terms of increased sequestosome 1 (p62/SQSTM1) and microtubule-associated protein 1 light chain 3B (LC3B) II/LC3BI expressions and inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway. Furthermore, copper induced apoptosis, characterized by increased expressions of Bcl2 X protein (Bax), caspase 3, and Poly (ADP-ribose) polymerase (PARP) and decreased expression of B-cell lymphoma 2 (Bcl2). Compared with the 120 μM Cu2+ exposure group alone, autophagy activator rapamycin pretreatment increased expression of Wnt and β-catenin nuclear translocation, decreased expression of LC3BII/LC3BI and p62, as well as upregulated expression of Bcl2 and downregulated expressions of caspase 3 and PARP. In contrast, after autophagy inhibitor chloroquine pretreatment, expressions of Wnt and β-catenin nuclear translocation were decreased, expression levels of LC3BII/LC3BI and p62 were upregulated, expression of Bcl2 was decreased, while expression levels of caspase 3, Bax, and PARP were increased. In conclusion, the study demonstrated that autophagosome accumulation and autophagic flux blockage were associated with copper-induced developmental neurotoxicity via the Wnt signaling pathway, which might deepen the understanding of the developmental neurotoxicity mechanism of environmental copper exposure.
    Keywords:  Wnt signaling pathway; autophagy; copper; developmental neurotoxicity
    DOI:  https://doi.org/10.3390/toxics13010063
  29. J Inherit Metab Dis. 2025 Jan;48(1): e12841
    Spermidine Recovers the Autophagy Defects Underlying the Pathophysiology of Cell Trafficking Disorders.
    Yaiza Díaz-Osorio, Helena Gimeno-Agud, Rosanna Mari-Vico, Sofía Illescas, Jose Miguel Ramos, Alejandra Darling, Àngels García-Cazorla, Alfonso Oyarzábal.
      Cell trafficking alterations are a growing group of disorders and one of the largest categories of Inherited Metabolic Diseases. They have complex and variable clinical presentation. Regarding neurological manifestations they can present a wide repertoire of symptoms ranging from neurodevelopmental to neurodegnerative disorders. The study of monogenic cell trafficking diseases draws an scenario to understanding this complex group of disorders and to find new therapeutic avenues. Within their pathophysiology, alterations in autophagy outstand as a targetable mechanism of disease, ammended to be modulated through different strategies. In this work we have studied the pathophysiology of two cell trafficking disorders due to mutations in SYNJ1 and NBAS genes. Specifically, we have assesed the autophagic flux in primary fibroblast cultures of the patients and gender/age-matched controls and whether it could be address with a therapeutic purpose. The results have shaped autophagy as one of the hallmarks of the disease. Moreover, we tested in vitro the effect of spermidine, a natural polyamine that acts as an autopagy inductor. Due to the positive results, its efficacy was evaluated later on the patients as well, in a series of n-of-1 clinical trials, achieving improvement in some clinical aspects related to motricity and cognition. Defining autophagy alterations as a common feature in the pathophysiology of cell trafficking disorders is a great step towards their treatment, as it represents a potential actionable target for the personalized treatement of these disorders.
    Keywords:  NBAS; SYNJ1; autophagy; cell trafficking; neurodevelopmental diseases; spermidine
    DOI:  https://doi.org/10.1002/jimd.12841
  30. Front Immunol. 2024 ;15 1535649
    Targeting autophagy to enhance chemotherapy and immunotherapy in oral cancer.
    Xiaoli Zeng, Yue Chen, Jing Wang, Miao He, Junyao Qiu, Yun Huang.
      Oral cancer is a highly malignant disease characterized by recurrence, metastasis, and poor prognosis. Autophagy, a catabolic process induced under stress conditions, has been shown to play a dual role in oral cancer development and therapy. Recent studies have identified that autophagy activation in oral epithelial cells suppresses cancer cell survival by inhibiting key pathways such as the mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK), while activating the adenosine monophosphate-activated protein kinase (AMPK) pathway. Inducing autophagy promotes degradation of eukaryotic initiation factor 4E, thus reducing metastasis and enhancing the efficacy of chemotherapy, radiotherapy, and immunotherapy. Furthermore, autophagy induction can modulate the tumor immune microenvironment and enhance antitumor immunity. This review comprehensively summarizes the relationship between autophagy and oral cancer, focusing on its mechanisms and therapeutic potential when combined with conventional treatments. While promising, the precise mechanisms and clinical applications of autophagy inducers in oral cancer therapy remain to be elucidated, offering new directions for future research to improve treatment outcomes and reduce recurrence.
    Keywords:  apoptosis; autophagy; chemotherapy; immunotherapy; oral cancer; radiotherapy
    DOI:  https://doi.org/10.3389/fimmu.2024.1535649
  31. Cells. 2025 Jan 15. pii: 121. [Epub ahead of print]14(2):
    Discovery of Evolutionary Loss of the Ubiquitin-like Autophagy-Related ATG12 System in a Lineage of Apicomplexa.
    Xiaoxia X Lin, Yun D Bai, Sichang T Wang, Akira Nozawa, Tatsuya Sawasaki, Tatsunori Masatani, Kenji Hikosaka, Masahito Asada, Hirokazu Sakamoto.
      The autophagy-related ubiquitin-like conjugation systems, the ATG8 and ATG12 systems, are universally conserved in eukaryotes. However, the covalent bond in the ATG12 system has recently been shown to be evolutionarily lost in Apicomplexa. Here, we show that all genes associated with the ATG12 system are absent in piroplasmida, a lineage within Apicomplexa. Comparative genomics of ATGs further shows that piroplasm ATG3 has lost the region necessary for ATG12 binding. However, our in vitro functional analysis using recombinant proteins demonstrated that ATG3 retained the ability to interact with ATG8 in Babesia bovis, a model species in piroplasmida. These findings provide evidence that the ATG8 system is functional, while the ATG12 system is completely lost in the common ancestor of piroplasmida and highlight the evolutionary flexibility of the ATG12 system in Apicomplexa.
    Keywords:  ATG12 system; Apicomplexa; autophagy; piroplasmida
    DOI:  https://doi.org/10.3390/cells14020121
  32. Sci Adv. 2025 Jan 24. 11(4): eado3852
    The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes.
    Yvonne Eibach, Silke Kreher, Mareike S Poetsch, Ay Lin Kho, Ulrich Gaertner, Christoph S Clemen, Rolf Schröder, Kai Guo, Hendrik Milting, Benjamin Meder, Michael Potente, Manfred Richter, Andre Schneider, Silke Meiners, Mathias Gaute, Thomas Braun.
      Protein homeostasis is crucial for maintaining cardiomyocyte (CM) function. Disruption of proteostasis results in accumulation of protein aggregates causing cardiac pathologies such as hypertrophy, dilated cardiomyopathy (DCM), and heart failure. Here, we identify ubiquitin-specific peptidase 5 (USP5) as a critical determinant of protein quality control (PQC) in CM. CM-specific loss of mUsp5 leads to the accumulation of polyubiquitin chains and protein aggregates, cardiac remodeling, and eventually DCM. USP5 interacts with key components of the proteostasis machinery, including PSMD14, and the absence of USP5 increases activity of the ubiquitin-proteasome system and autophagic flux in CMs. Cardiac-specific hUSP5 overexpression reduces pathological remodeling in pressure-overloaded mouse hearts and attenuates protein aggregate formation in titinopathy and desminopathy models. Since CMs from humans with end-stage DCM show lower USP5 levels and display accumulation of ubiquitinated protein aggregates, we hypothesize that therapeutically increased USP5 activity may reduce protein aggregates during DCM. Our findings demonstrate that USP5 is essential for ubiquitin turnover and proteostasis in mature CMs.
    DOI:  https://doi.org/10.1126/sciadv.ado3852
  33. Neurotherapeutics. 2025 Jan 17. pii: S1878-7479(25)00003-0. [Epub ahead of print] e00525
    Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies.
    Kyle C McGill Percy, Zhunren Liu, Xin Qi.
      Alzheimer's disease (AD) is characterized by progressive neurodegeneration, marked by the accumulation of amyloid-β (Aβ) plaques and tau tangles. Emerging evidence suggests that mitochondrial dysfunction plays a pivotal role in AD pathogenesis, driven by impairments in mitochondrial quality control (MQC) mechanisms. MQC is crucial for maintaining mitochondrial integrity through processes such as proteostasis, mitochondrial dynamics, mitophagy, and precise communication with other subcellular organelles. In AD, disruptions in these processes lead to bioenergetic failure, gene dysregulation, the accumulation of damaged mitochondria, neuroinflammation, and lipid homeostasis impairment, further exacerbating neurodegeneration. This review elucidates the molecular pathways involved in MQC and their pathological relevance in AD, highlighting recent discoveries related to mitochondrial mechanisms underlying neurodegeneration. Furthermore, we explore potential therapeutic strategies targeting mitochondrial dysfunction, including gene therapy and pharmacological interventions, offering new avenues for slowing AD progression. The complex interplay between mitochondrial health and neurodegeneration underscores the need for innovative approaches to restore mitochondrial function and mitigate the onset and progression of AD.
    Keywords:  Alzheimer's disease; Amyloid beta; Gene therapy; Mitochondrial quality control; Pharmacotherapy; Tauopathy
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00525
  34. Front Pharmacol. 2024 ;15 1474310
    Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
    Mengjiao Xu, Peng Feng, Jun Yan, Lei Li.
      Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.
    Keywords:  chronic obstructive pulmonary disease; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; therapeutic strategies
    DOI:  https://doi.org/10.3389/fphar.2024.1474310
  35. Commun Biol. 2025 Jan 21. 8(1): 105
    Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction.
    Shih-Cheng Wu, Yan-Jhen Chen, Shih-Han Su, Pai-Hsiang Fang, Rei-Wen Liu, Hui-Ying Tsai, Yen-Jui Chang, Hsing-Han Li, Jian-Chiuan Li, Chun-Hong Chen.
      Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.
    DOI:  https://doi.org/10.1038/s42003-025-07457-6
  36. Pharmacol Res. 2025 Jan 15. pii: S1043-6618(25)00030-1. [Epub ahead of print]212 107605
    Scutellarin inhibits pyroptosis via selective autophagy degradation of p30/GSDMD and suppression of ASC oligomerization.
    Danyue Li, Weilv Xu, Suhui He, Xinyue Li, Yumeng Wang, Qian Lv, Nan Chen, Lu Dong, Feng Guo, Fushan Shi.
      Most of the pyroptosis inhibitors targeted Gasdermin D (GSDMD) are functioning by restraining GSDMD-N (p30) oligomerization. For the first time, this work discovered a pyroptosis inhibitor taking effect by degrading p30 and GSDMD. As the principal bioactive constituent in Erigeron breviscapus, scutellarin (SCU) assumes a pivotal role in the realm of anti-inflammatory processes. In this study, SCU demonstrated efficacy in hindering pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome, absent in melanoma 2 (AIM2) inflammasome, NLR-family CARD-containing protein 4 (NLRC4) inflammasome, and that activated through the non-canonical pathway. The inhibitory effect is achieved by thwarting apoptosis-associated speck-like protein containing CARD (ASC) oligomerization and inducing the ubiquitin-dependent selective autophagy of p30/GSDMD. Throughout the autophagic process, SCU facilitates selective autophagy of the pyroptosis executor p30/GSDMD through K33-linked polyubiquitination at Lys51 catalyzed by the E3 ligase tripartite motif-containing 21 (TRIM21). This process contributes to the recognition of p30/GSDMD by the cargo receptor sequestosome 1 (SQSTM1)/p62. The characteristic positions SCU as a prospective clinical intervention for a broader spectrum of inflammatory-related disorders.
    Keywords:  Autophagy; Gasgermin D; P30; Scutellarin; TRIM21; Ubiquitin-dependent
    DOI:  https://doi.org/10.1016/j.phrs.2025.107605
  37. Front Oncol. 2024 ;14 1509183
    Autophagic flux modulates tumor heterogeneity and lineage plasticity in SCLC.
    Yujie Hao, Mingchen Li, Wenxu Liu, Zhenyi Ma, Zhe Liu.
       Introduction: Small cell lung cancer (SCLC) is characterized by significant heterogeneity and plasticity, contributing to its aggressive progression and therapy resistance. Autophagy, a conserved cellular process, is implicated in many cancers, but its role in SCLC remains unclear.
    Methods: Using a genetically engineered mouse model (Rb1fl/fl ; Trp53fl/fl ; GFP-LC3-RFP-LC3△G), we tracked autophagic flux in vivo to investigate its effects on SCLC biology. Additional in vitro experiments were conducted to modulate autophagic flux in NE and non-NE SCLC cell lines.
    Results: Tumor subpopulations with high autophagic flux displayed increased proliferation, enhanced metastatic potential, and neuroendocrine (NE) characteristics. Conversely, low-autophagic flux subpopulations exhibited immune-related signals and non-NE traits. In vitro, increasing autophagy induced NE features in non-NE cell lines, while autophagy inhibition in NE cell lines promoted non-NE characteristics.
    Discussion: This study provides a novel model for investigating autophagy in vivo and underscores its critical role in driving SCLC heterogeneity and plasticity, offering potential therapeutic insights.
    Keywords:  SCLC; autophagic flux; genetically engineered mouse model; heterogeneity; lineage transition; plasticity; small cell lung cancer
    DOI:  https://doi.org/10.3389/fonc.2024.1509183
  38. Nat Struct Mol Biol. 2025 Jan 17.
    Molecular architecture of human LYCHOS involved in lysosomal cholesterol signaling.
    Qi Xiong, Zhini Zhu, Tingting Li, Xiaotian Li, Zixuan Zhou, Yulin Chao, Chuanhui Yang, Suihan Feng, Qianhui Qu, Dianfan Li.
      Lysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, revealing a unique fusion architecture comprising a G-protein-coupled receptor (GPCR)-like domain and a transporter domain that mediates homodimer assembly. The NhaA-fold transporter harbors a previously uncharacterized intramembrane Na+ pocket. The GPCR-like domain is stabilized, by analogy to canonical GPCRs, in an inactive state through 'tethered antagonism' by a lumenal loop and strong interactions at the cytosol side preventing the hallmark swing of the sixth transmembrane helix seen in active GPCRs. A cholesterol molecule and an associated docosahexaenoic acid (DHA)-phospholipid are entrapped between the transporter and GPCR-like domains, with the DHA-phospholipid occupying a pocket previously implicated in cholesterol sensing, indicating inter-domain coupling via dynamic lipid-protein interactions. Our work provides a high-resolution framework for functional investigations of the understudied LYCHOS protein.
    DOI:  https://doi.org/10.1038/s41594-024-01474-5
  39. Semin Cancer Biol. 2025 Jan 17. pii: S1044-579X(25)00010-0. [Epub ahead of print]
    The Dual Function of Autophagy in Doxorubicin-induced Cardiotoxicity: Mechanism and Natural products.
    Nannan Tan, Hanwen Luo, Weili Li, Guanjing Ling, Yan Wei, Wei Wang, Yong Wang.
      Doxorubicin (DOX) is an anthracycline antitumor drug discovered in 1969, which can care for leukemia, breast cancer, lymphoma, and sarcoma. However, cardiotoxicity induced by DOX seriously limits its clinical value. The etiopathogenesis and therapeutic strategies are not unified. Autophagy is a critical mechanism in the progression of DOX-induced cardiotoxicity (DIC), autophagy intervention is a potential therapeutic strategy for DIC. Natural product has been considered as a complementary and alternative approach to treat cardiovascular disease. In this review, we summarize the pathology of autophagy in DIC and the natural products for DIC therapy.
    Keywords:  Autophagy; Cardio-oncology; Doxorubicin-induced cardiotoxicity; Natural medicine
    DOI:  https://doi.org/10.1016/j.semcancer.2025.01.004
  40. J Neuroinflammation. 2025 Jan 22. 22(1): 14
    TDP43 augments astrocyte inflammatory activity through mtDNA-cGAS-STING axis in NMOSD.
    Zhuhe Liu, Yunmeng Bai, Bingtian Xu, Haixia Wen, Kechun Chen, Jingfang Lin, Yuanyuan Wang, Jiangping Xu, Haitao Wang, Fudong Shi, Jigang Wang, Honghao Wang.
      Abnormality in transactivating response region DNA binding protein 43 (TDP43) is well-recognized as the pathological hallmark of neurodegenerative diseases. However, the role of TDP43 in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. Here, our observations demonstrate an upregulation of TDP43 in both in vitro and in vivo models of NMOSD, as well as in biological samples from NMOSD patients. Single-nucleus RNA sequencing revealed that NMOSD induced A1-like reactive astrocytes and astrocyte mitochondrial dysfunction in mice. We further found that NMOSD provoked the translocation of TDP43 to mitochondria and the release of mitochondrial DNA (mtDNA) into the cytoplasm. NMOSD caused activation of mtDNA/cyclic GMP-AMP synthase (cGAS) / stimulator of interferon genes (STING) pathway and A1-type inflammatory activation in astrocytes. Crucially, the knockdown of TDP43 markedly ameliorated NMOSD-induced mitochondrial dysfunction and the activation of the cGAS/STING pathway in astrocytes. Conversely, overexpression of TDP43 exacerbated these pathological changes. Specific silencing astrocytic TDP43 ameliorated NMOSD-induced injury in mice, and conversely, TDP43 overexpression intensified the injury. Meanwhile, both cGAS and STING inhibitors attenuated NMOSD-induced injury in mice. In summary, our data suggest that TDP43 exacerbates inflammatory activation of astrocytes in NMOSD through upregulating the mtDNA/cGAS/STING signaling pathway. Therefore, targeting TDP43 represents a compelling therapeutic strategy for NMOSD.
    Keywords:  Inflammatory activation; Mitochondrial dysfunction; NMOSD; TDP43; cGAS/STING
    DOI:  https://doi.org/10.1186/s12974-025-03348-z
  41. Nat Commun. 2025 Jan 17. 16(1): 737
    Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin.
    Jeonghyun Oh, Christy Catherine, Eun Seon Kim, Kwang Wook Min, Hae Chan Jeong, Hyojin Kim, Mijin Kim, Seung Hae Ahn, Nataliia Lukianenko, Min Gu Jo, Hyeon Seok Bak, Sungsu Lim, Yun Kyung Kim, Ho Min Kim, Sung Bae Lee, Hyunju Cho.
      Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington's disease (HD). Since no current treatment delays the progression of HD, we develop a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. Here, we engineer the ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins to peroxisomes, to remove mHttex1 aggregates. Using yeast toxicity-based screening with a random mutant library, we identify two yeast PEX19 variants and engineer equivalent mutations into human PEX19 (hsPEX19). These variants effectively delay mHttex1 aggregation in vitro and in cellular HD models. The mutated hydrophobic residue in the α4 helix of hsPEX19 variants binds to the N17 domain of mHttex1, thereby inhibiting the initial aggregation process. Overexpression of the hsPEX19-FV variant rescues HD-associated phenotypes in primary striatal neurons and in Drosophila. Overall, our data reveal that engineering ATP-independent membrane protein chaperones is a promising therapeutic approach for rational targeting of mHttex1 aggregation in HD.
    DOI:  https://doi.org/10.1038/s41467-025-56030-6
  42. Sci Adv. 2025 Jan 24. 11(4): eadq7706
    ZDHHC2 promoted antimycobacterial responses by selective autophagic degradation of B-RAF and C-RAF in macrophages.
    Junli Sheng, Xiaolong You, Dingnai Nie, Yuling Fu, Qiao Ling, Xiaodan Yang, Yitian Chen, Li Ma, Shengfeng Hu.
      S-Palmitoylation is a reversible post-translational modification involving saturated fatty acid palmitate-to-cysteine linkage in the protein, which guides many aspects of macrophage physiology in health and disease. However, the precise role and underlying mechanisms of palmitoylation in Mycobacterium tuberculosis infection of macrophages remain elusive. Here, we found that M. tuberculosis infection induced the expression of zinc-finger DHHC domain-type palmitoyl-transferases (ZDHHCs), particularly ZDHHC2, in mouse macrophages. Furthermore, ZDHHC2 deficiency in mouse macrophages impaired the immunity against M. tuberculosis and reduced the production of various proinflammatory cytokines. Mechanistic studies revealed the involvement of ZDHHC2 in mediating the palmitoylation of B-RAF and C-RAF, affecting their autophagic degradation and stabilizing protein levels. The increased abundance of B-RAF and C-RAF subsequently increases the activity of the extracellular signal-regulated kinase (ERK) signaling pathway, affecting the survival of M. tuberculosis within macrophages. These findings suggest that ZDHHC2 is a potential target for treating tuberculosis.
    DOI:  https://doi.org/10.1126/sciadv.adq7706
  43. Am J Hum Genet. 2025 Jan 10. pii: S0002-9297(24)00461-0. [Epub ahead of print]
    Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.
    Rebecca Buchert, Martin D Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva, Ulviyya Guliyeva, Moath Hamdallah, Muriel Holder-Espinasse, Rauan Kaiyrzhanov, Doreen Klingler, Mahmoud Koko, Lars Matthies, Joohyun Park, Marc Sturm, Ana Velic, Stephanie Spranger, Tipu Sultan, Hartmut Engels, Holger Lerche, Henry Houlden, Alistair T Pagnamenta, Ingo Borggraefe, Yvonne Weber, Penelope E Bonnen, Reza Maroofian, Olaf Riess, Jonasz J Weber, Melanie Philipp, Tobias B Haack.
      Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and ciliogenesis. Depletion of Kics2 in zebrafish resulted in ciliary dysfunction consistent with a role of mTORC1 in cilia biology. These in vitro and in vivo functional studies confirmed the pathogenicity of identified KICS2 variants. Our genetic and experimental data provide evidence that variants in KICS2 are a factor involved in intellectual disability due to its dysfunction impacting mTORC1 regulation and cilia biology.
    Keywords:  C12orf66; KICS2; KICSTOR complex; MTOR regulation; ciliogenesis; intellectual disability
    DOI:  https://doi.org/10.1016/j.ajhg.2024.12.019
  44. Autophagy. 2025 Jan 22. 1-23
    The Epstein-Barr virus deubiquitinase BPLF1 regulates stress-induced ribosome UFMylation and reticulophagy.
    Jiangnan Liu, Noemi Nagy, Carlos Ayala-Torres, Solenne Bleuse, Francisco Aguilar-Alonso, Ola Larsson, Maria G Masucci.
      The synthesis of membrane and secreted proteins is safeguarded by an endoplasmic reticulum-associated ribosome quality control (ER-RQC) that promotes the disposal of defective translation products by the proteasome or via a lysosome-dependent pathway involving the degradation of portions of the ER by macroautophagy (reticulophagy). The UFMylation of RPL26 on ER-stalled ribosomes is essential for activating the ER-RQC and reticulophagy. Here, we report that the viral deubiquitinase (vDUB) encoded in the N-terminal domain of the Epstein-Barr virus (EBV) large tegument protein BPLF1 hinders the UFMylation of RPL26 on ribosomes that stall at the ER, promotes the stabilization of ER-RQC substrates, and inhibits reticulophagy. The vDUB did not act as a de-UFMylase or interfere with the UFMylation of the ER membrane protein CYB5R3 by the UFL1 ligase. Instead, it copurified with ribosomes in sucrose gradients and abrogated a ZNF598- and LTN1-independent ubiquitination event required for RPL26 UFMylation. Physiological levels of BPLF1 impaired the UFMylation of RPL26 in productively EBV-infected cells, pointing to an important role of the enzyme in regulating the translation quality control that allows the efficient synthesis of viral proteins and the production of infectious virus.Abbreviation: BPLF1, BamH1 P fragment left open readingframe-1; CDK5RAP3, CDK5regulatory subunit associated protein 3; ChFP, mCherry fluorescent protein; DDRGK1, DDRGKdomain containing 1; EBV, Epstein-Barr virus; eGFP, enhancedGFP; ER-RQC, endoplasmicreticulum-associated ribosome quality control; LCL, EBV-carryinglymphoblastoid cell line; GFP, green fluorescent protein; RQC, ribosome quality control; SRP, signal recognition particle; UFM1, ubiquitin fold modifier 1; UFL1, UFM1 specific ligase 1.
    Keywords:  EBV; Macroautophagy; Ribosome; UFM1; viral DUB
    DOI:  https://doi.org/10.1080/15548627.2024.2440846
  45. PLoS One. 2025 ;20(1): e0311159
    Muscular TOR knockdown and endurance exercise ameliorate high salt and age-related skeletal muscle degradation by activating the MTOR-mediated pathway.
    Shi-Jie Wang, Deng-Tai Wen, Ying-Hui Gao, Jing-Feng Wang, Xing-Feng Ma.
      The target of rapamycin(TOR)gene is closely related to metabolism and cellular aging, but it is unclear whether the TOR pathways mediate endurance exercise against the accelerated aging of skeletal muscle induced by high salt intake. In this study, muscular TOR gene overexpression and RNAi were constructed by constructing MhcGAL4/TOR-overexpression and MhcGAL4/TORUAS-RNAi systems in Drosophila. The results showed that muscle TOR knockdown and endurance exercise significantly increased the climbing speed, climbing endurance, the expression of autophagy related gene 2(ATG2), silent information regulator 2(SIR2), and pparγ coactivator 1(PGC-1α) genes, and superoxide dismutases(SOD) activity, but it decreased the expression of the TOR gene and reactive oxygen species(ROS) level, and it protected the myofibrillar fibers and mitochondria of skeletal muscle in Drosophila on a high-salt diet. TOR overexpression yielded similar results to the high salt diet(HSD) alone, with the opposite effect of TOR knockout found in regard to endurance exercise and HSD-induced age-related skeletal muscle degradation. Therefore, the current findings confirm that the muscle TOR gene plays an important role in endurance exercise against HSD-induced age-related skeletal muscle degeneration, as it determines the activity of the mammalian target of rapamycin(MTOR)/SIR2/PGC-1α and MTOR/ATG2/PGC-1α pathways in skeletal muscle.
    DOI:  https://doi.org/10.1371/journal.pone.0311159
  46. Science. 2025 Jan 24. 387(6732): 359-361
    Decoding lysosome communication.
    Soni Savai Pullamsetti, Rajkumar Savai.
      Lysosome interaction with other organelles may be linked to pulmonary hypertension.
    DOI:  https://doi.org/10.1126/science.adv1201
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