bims-auttor 2025-11-09 papers

bims-auttor

Biomed News

on Autophagy and mTOR

Issue of 2025–11–09
38 papers selected by
Viktor Korolchuk, Newcastle University

The role of autophagy in synucleinopathy: clearance versus spread of α-synuclein.
Golgiphagy mediated by TM9SF3 acts as quality control for stressed Golgi.
Lysosomal and mTORC1 signaling dysregulation underpin the pathology of spastic paraplegia type 80.
The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.
Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.
Devil or angel: A review of autophagy in ischemia-reperfusion injury.
Crosstalk between lipid droplets and autophagy in cancer: A nexus for therapeutic targeting.
Insights into the Procedures and Interpretation of Autophagy in Trypanosoma cruzi.
The role of thrombospondin-1 in trehalose-induced autophagy and ocular hypertension in mice.
Architecture of the human KICSTOR and GATOR1-KICSTOR complexes.
The Japan autophagy consortium.
Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in C. elegans.
Drosophila as a Model to Monitor Multi-organ Autophagy.
Aβ and tau clearance through aerobic exercise: unveiling the β2-adrenergic receptor's role in regulating autophagy-lysosomal pathways.
The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.
Regulation of macroautophagy and microautophagic lipophagy by phosphatidylserine synthase Cho1 and external ethanolamine.
Cepharanthine-induced mitophagy through regulation of FBXL4-BNIP3 drives ferroptosis leading to robust anti-lung cancer efficacy.
Mitoxantrone elicits ROS-dependent elimination of dysfunctional mitochondria through mitophagy to control viability of intracellular mycobacteria in human macrophages.
DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy.
Monitoring phospholipid dynamics in vivo with a fluorescent dye octadecyl rhodamine B.
Mitophagy suppression via lncRNA H19 silencing: a novel strategy to overcome cisplatin resistance in lung adenocarcinoma.
Cell Surface LAMP-2C Is Internalized in a Clathrin-Dependent Manner and Transported to the Recycling and Lysosomal Pathways.
Identification of ATG7 as a protein ATG8ylation substrate.
TORC1-dependent sorting of PI(3,5)P2 is required for vacuole membrane remodeling and signaling endosome formation.
IST1 alleviated acrylamide-induced apoptosis and cognitive impairment through regulating autophagy flux blockage in SH-SY5Y cells and C57BL/6J mice.
Sestrin2 is Induced Upon Cellular Stress but Has No Effect on Myotube Size or Amino Acid Sensing in C2C12 Myotubes.
LncRNA NEAT1 modulates myeloma cell autophagy and apoptosis by competitively binding miR-195-5p to regulate CEBPA.
Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling.
Loss of Fanconi anemia proteins causes a reliance on lysosomal exocytosis.
The m6A demethylase FTO links TLR7 to mitochondrial oxidation driving age-associated B cell formation in systemic lupus erythematosus.
Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).
Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease therapy.
Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.
Secretome translation shaped by lysosomes and lunapark-marked ER junctions.
Transaldolase 1 impacts Parkinson's disease pathogenesis via metabolic reprogramming and autophagy-lysosomal pathway.
PIKfyve inhibition in myeloma disrupts autophagy and the lysosome, increasing MHC expression and cholesterol metabolism.
CNX:FAM134B-driven ERLAD of ATZ polymers proceeds via enhanced formation of VAPA:ORP1L:RAB7 contact sites between ER and endolysosomes.
Caught in the act: how a brake on cell growth is anchored to lysosomes.

Autophagy Rep. 2025 ;4(1): 2577406

The role of autophagy in synucleinopathy: clearance versus spread of α-synuclein.

Emily Birnbaum, Zhenyu Yue.

  Emerging evidence suggests that the propagation of α-synuclein pathology underlies the progression of Parkinson's disease and supports the hypothesis that transmission of α-synuclein aggregates contributes to dopaminergic degeneration. Autophagy, a cellular degradation process, removes protein aggregates and damaged organelles and aids in α-synuclein clearance. However, fibrillar α-synuclein aggregates may evade and even disrupt autophagy, causing toxic spread. The role of autophagy may be multifaceted in the propagation of α-synuclein: clearing α-synuclein aggregates and damaged organelles (protective) versus the release of α-synuclein aggregates (harmful). Here we review how neuronal and glial autophagy regulate α-synuclein clearance and spreading. We also discuss the need for future research to address the interplay of autophagy and α-synuclein aggregates toward therapeutic development.

Keywords:  Parkinson’s disease; autophagy; fibrils; synucleinopathy; α-synuclein

DOI:  https://doi.org/10.1080/27694127.2025.2577406
Dev Cell. 2025 Nov 03. pii: S1534-5807(25)00604-5. [Epub ahead of print]60(21): 2841-2843

Golgiphagy mediated by TM9SF3 acts as quality control for stressed Golgi.

Hallvard L Olsvik, Terje Johansen.

Selective autophagy is important for organelle quality control. In this issue of Developmental Cell, Yang et al. identify the Golgi resident transmembrane protein TM9SF3 as a selective autophagy receptor required for lysosomal degradation of Golgi fragments (Golgiphagy) following nutrient stress, pH disruption, blockade of ER-to-Golgi trafficking, and defects in Golgi-mediated glycosylation functions.

DOI: https://doi.org/10.1016/j.devcel.2025.09.019
Nat Commun. 2025 Nov 07. 16(1): 9833

Lysosomal and mTORC1 signaling dysregulation underpin the pathology of spastic paraplegia type 80.

Yiqiang Zhi, Tongtong Zhang, Danping Lu, Shuhuai Lin, Huizhen Su, Yupei Wu, Qiyuan Chang, Shuyuan Wang, Chenning Lv, Honggao Fu, Li-Yu Chen, Wan-Jin Chen, Ning Wang, Zhifei Fu, Xiang Lin, Dan Xu.

Endosomal sorting complex required for transport (ESCRT) is the major membrane remodeling complex, closely associated with endolysosomal repair and hereditary spastic paraplegias (HSP) diseases. Loss of function mutations in the ESCRT-I component UBAP1 causes a rare type of HSP (spastic paraplegia 80, SPG80), while the underlying pathological mechanism is unclear. Here, we found that UBAP1 but not SPG80 causing mutant was efficiently recruited to damaged lysosomes and mediated lysosome recovery. Loss of UBAP1 results in dysfunction of lysosomes, disconnecting mTOR localization on lysosomes, leading to cytoplasmic mTORC1 activation and TFEB dephosphorylation, as confirmed in vitro and in vivo models. Administration of rapamycin, a specific inhibitor of mTORC1, enhances mTOR lysosomal localization and TFEB phosphorylation. This pharmacological intervention effectively attenuated disease progression and restored lysosomal homeostasis in Ubap1 deficiency mice. Our findings reveal UBAP1's role in lysosome regulation and suggest rapamycin may benefit patients with HSP and other motor neuron disorders.

DOI: https://doi.org/10.1038/s41467-025-64800-5
Sci Rep. 2025 Nov 07. 15(1): 39117

The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.

Stefan Redl, Felix Von Zweydorf, Christian J Gloeckner, Inmaculada Posadas, Valentín Ceña, Michael W Hess, Giovanni Piccoli, María Dolores Pérez-Carrión.

  Parkinson's disease (PD) is a neurodegenerative pathology characterized by movement-associated symptoms due to the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Autophagy is an essential mechanism that restores homeostasis and promotes cell survival. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are among the most common in the familial cases. The LRRK2 E193K mutation falls in the Armadillo (ARM) domain and modifies LRRK2 interactome. The role of LRRK2 in autophagy has been widely explored, but the impact of E193K mutation on autophagy remains unknown. We found that the E193K variant increases autophagy in primary fibroblasts obtained from an E193K carrier. By cryo-based electron microscopy we observed that E193K fibroblasts present a higher amount of phagophores/autophagosomes. We showed that LRRK2 binds to the Dynein-1 complex, an essential regulator of retrograde transport of autophagosomes. Noteworthy, the E193K mutation jeopardizes this interaction and increases the cellular sensitivity to 1-methyl-4-phenylpyridinium (MPP+) toxin in fibroblasts as well as in a heterologous cell model. Our study reveals that the LRRK2 E193K variant influences the autophagic regulation and suggests that the dysregulation of the LRRK2-Dynein-1 complex causes autophagic defects and, eventually, cell death.

Keywords:  Autophagy; Dynein-1 complex; LRRK2 protein; Organelle morphometry; Parkinson´s disease; Ultrastructure

DOI:  https://doi.org/10.1038/s41598-025-26716-4
Acta Neuropathol Commun. 2025 Nov 07. 13(1): 228

Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.

Martin J Berg, Veeranna, Corrinne M Rosa, Asok Kumar, Panaiyur S Mohan, Philip Stavrides, Sandipkumar Darji, Deanna M Marchionini, Dun-Sheng Yang, Ralph A Nixon.

   BACKGROUND: Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington's disease (HD). Stimulating autophagy may enhance clearance of mHTT and its aggregates which has been considered as a possible therapeutic strategy. However, the role and competence of the autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown.
METHODS: Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex or cerebellum of HD brains staged from Grade HD2 to HD4 by Vonsattel neuropathological criteria compared to controls.
RESULTS: Immunolabeling revealed the localization of HTT/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins sequestosome 1 (p62/SQSTM1) and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes/lysosomes and, ultrastructurally, autophagic vacuole/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT/mHTT and p62/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. In addition, cargo-loaded autophagosomes and cathepsin-positive autolysosomes were readily observed, implying a lack of significant blockage in autophagosome formation and autophagosome-lysosome fusion.
CONCLUSIONS: The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but the observed progressive HTT build-up and AL accumulation at advanced disease stages may signify a failure in autophagy substrate clearance. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, could lead to therapeutic benefits in HD patients.

Keywords:  Autophagy; Human brain; Huntington’s disease; Lysosome; Pathobiology

DOI:  https://doi.org/10.1186/s40478-025-02131-8
Medicine (Baltimore). 2025 Oct 17. 104(42): e45330

Devil or angel: A review of autophagy in ischemia-reperfusion injury.

Guilin Zhou, Lanlan Zhang, Wenya Bai, Jia Liu, Junjie Li, Huan Jiang, Xin Li, Jianlin Shao.

  Ischemia-reperfusion injury (IRI) is a secondary injury that occurs after recanalization of the blood flow in ischemic tissues or organs. Autophagy is a lysosome-dependent cellular process that eliminates misfolded proteins and functionally impaired organelles to maintain intracellular homeostasis. Autophagy plays a pivotal role in IRI occurrence and development. Autophagy acts as a "double-edged sword" in this context, and its role (positive or negative) in IRI remains controversial, complicating efforts to target autophagy to alleviate IRI. In this review, we explore the role of autophagy in various IRI diseases with the aim of providing insights for research focused on mitigating IRI through autophagy regulation.

Keywords:  autophagy; cell death; ischemia–reperfusion injury; lysosome; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1097/MD.0000000000045330
Pharmacol Res. 2025 Nov 04. pii: S1043-6618(25)00448-7. [Epub ahead of print]222 108023

Crosstalk between lipid droplets and autophagy in cancer: A nexus for therapeutic targeting.

Xiaofen Li, Jiwen Zhang, Shiping Luo, Xiaoqin Yu, Chuangui Song.

  Metabolic reprogramming is a cornerstone of cancer cell adaptation to the demanding tumor microenvironment, requiring fine-tuned control over energy, lipid metabolism, and stress responses. Central to this adaptation is the profound and bidirectional interplay between two key cellular processes: lipid storage in lipid droplets (LDs) and cellular recycling via autophagy. LDs are dynamic organelles that have emerged as critical metabolic and signaling hubs, extending far beyond their role as simple lipid depots. Autophagy, a fundamental degradation system, supplies essential metabolites during stress by engulfing cellular material in autophagosomes. These pathways are deeply intertwined: LDs not only provide lipids and proteins for autophagosome formation but are also selectively targeted for degradation by autophagy in a process known as lipophagy. This degradation releases free fatty acids that fuel mitochondrial β-oxidation, enabling cancer cells to withstand hypoxic and nutrient-poor conditions. Moreover, lipophagy prevents lipotoxicity by eliminating excess lipids, thus maintaining cellular homeostasis. Here, we review the molecular mechanisms governing the LD-autophagy axis in cancer, discuss its pivotal roles in tumor progression, metastasis, and therapeutic resistance, and explore the promise of targeting this nexus for future cancer therapies. Unraveling this complex network provides not only a new paradigm for understanding cancer metabolism but also offers a compelling rationale for developing novel pharmacological agents to combat tumor metabolic plasticity and therapeutic resistance.

Keywords:  Autophagy; Cancer Therapy; Lipid Droplets; Lipophagy; Metabolic Reprogramming; Tumor Microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2025.108023
Methods Mol Biol. 2026 ;2982 409-425

Insights into the Procedures and Interpretation of Autophagy in Trypanosoma cruzi.

Gabriel Ferri, María Belén López, Juan Agustín Cueto, María Cristina Vanrell, Patricia Silvia Romano.

  Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a life-threatening neglected illness endemic to Latin America. Despite efforts, it has recently become a global concern due to human migration from endemic to non-endemic areas. Exploring parasite pathways to interrupt the T. cruzi life cycle may lead to new treatments. In particular, autophagy plays a relevant role throughout its life cycle. In this context, the modulation of autophagy could provide multiple targets for new trypanocidal drugs. In this chapter, we describe various techniques developed to study autophagy in T. cruzi, such as fluorescence and electron microscopy to visualize autophagic structures in living or fixed parasites, and Western blotting to analyze autophagosome formation by tagging the LC3-like protein TcAtg8.1. The interpretation of these techniques allows for the distinction between changes in autophagic flux and specific differences in the steps of this pathway. Understanding the dynamics of autophagy in T. cruzi could assist researchers in exploring its potential role as a therapeutic target for Chagas disease.

Keywords:  Atg8.1; Autophagy; Immunofluorescence; Transmission electron microscopy; Trypanosoma cruzi; Western blot

DOI:  https://doi.org/10.1007/978-1-0716-4848-3_27
Sci Rep. 2025 Nov 06. 15(1): 38930

The role of thrombospondin-1 in trehalose-induced autophagy and ocular hypertension in mice.

Choi-Ying Ling, Kit-Ying Choy, Hoi-Lam Li, Choi-Yee Tse, Wei-Ying Yang, Nga-Wai Wong, W Daniel Stamer, Chi-Wai Do, Dennis Yan-Yin Tse, Samantha Sze-Wan Shan.

  Prolonged use of dexamethasone (DEX) increases intraocular pressure (IOP) and the risk of glaucoma. Recent studies have shown that DEX upregulates thrombospondin-1 (THBS1) gene expression and induces dysregulation of macroautophagy/autophagy in primary human trabecular meshwork (hTM) cells. Trehalose, a natural disaccharide, activates autophagy and protects cells against environmental stresses. Here, we report that trehalose-induced autophagy enhanced outflow facility, reduced IOP, and protected against ocular hypertension in mice. We analyzed autophagy induction by trehalose in hTM cells. Our data demonstrated that trehalose transcriptionally upregulated prototypical autophagy related genes and activated autophagy through the downregulation of THBS1. Consistent with prior findings, the results indicated that THBS1 silencing or inhibition is a key cellular event for the regulation of aqueous humor outflow and IOP homeostasis. In conclusion, this study identified trehalose-induced autophagy as a protective mechanism against ocular hypertension which may have therapeutic potential.

Keywords:  Autophagy; Intraocular pressure; Ocular hypertension; Outflow facility; Thrombospondin-1; Trehalose

DOI:  https://doi.org/10.1038/s41598-025-22873-8
Nat Struct Mol Biol. 2025 Nov 06.

Architecture of the human KICSTOR and GATOR1-KICSTOR complexes.

Fei Teng, Huan Zeng, Xinyi Mai, Shujun Chen, Lulu Wang, Zeming Feng, Shuyun Tian, Shan Wang, Goran Stjepanovic, Chun-Yan Lim, Ming-Yuan Su.

The human KICSTOR complex, comprising KPTN, ITFG2, C12orf66 and the scaffolding protein SZT2, anchors the mTORC1 inhibitor GATOR1 to lysosomes. Mutations affecting KICSTOR subunits are associated with severe neurodevelopmental and epileptic disorders. Loss of KICSTOR mimics GATOR1 inactivation, resulting in constitutive mTORC1 activation, highlighting its critical role in nutrient sensing. Here, we used cryo-electron microscopy and computational modeling to determine the architectures of KICSTOR and the GATOR1-KICSTOR supercomplex. We show that SZT2 forms a crescent-shaped scaffold with repetitive tandem units, binding the ITFG2-KPTN heterodimer and C12orf66 at its C terminus. Structural and biochemical analyses revealed that GATOR1 binds the SZT2 N-terminal domain through NPRL3; disruption of this interaction hyperactivates mTORC1 and mislocalizes TFE3 independently of nutrient status. We further demonstrate the membrane-binding ability of KICSTOR, with SZT2 and C12orf66 preferentially interacting with negatively charged lipids-a requirement for lysosomal localization. These findings identify how KICSTOR positions GATOR1 on lysosomes to regulate nutrient-dependent mTORC1 signaling.

DOI: https://doi.org/10.1038/s41594-025-01693-4
Nat Struct Mol Biol. 2025 Nov 03.

The Japan autophagy consortium.

Miwako Ishido, Yoshiari Shimmyo, Etsuko Tsutsumi, Masaaki Komatsu.

DOI: https://doi.org/10.1038/s41594-025-01683-6
Mol Biol Cell. 2025 Nov 05. mbcE25040182

Sphingosine kinase SPHK-1 maintains sphingolipid metabolism to protect lysosome membrane integrity in C. elegans.

Yuan Li, Jie Zhang, Meijiao Li, Lujia Yang, Xiaochen Wang.

The maintenance of lysosome membrane integrity is vital for cell homeostasis and viability, but the underlying mechanisms are not well understood. In this study, we identified a novel role of SPHK-1, the sole C. elegans sphingosine kinase, in protecting lysosome membrane integrity. Loss of SPHK-1 affects lysosomal integrity and degradative function, causing cargo accumulation and lysosome membrane rupture. sphk-1(lf) mutants show severe defects in embryonic and larval development and have significantly shortened lifespan. We found that sphk-1(lf) mutants accumulate high levels of sphingosine, predominantly in lysosomes. Accordingly, sphingosine supplementation leads to appearance of damaged lysosomes in wild-type worms. We identified sptl-1 and sptl-3 mutations that fully suppress the lysosomal integrity defects in sphk-1(lf) mutants. sptl-1 and sptl-3 encode serine palmitoyltransferases that catalyze the first and rate-limiting step of de novo sphingolipid synthesis. Loss of sptl-1 alleviates sphingosine accumulation, reverses lysosomal integrity and degradation defects, and restores normal development and longevity in sphk-1(lf) mutants. Our study indicates that sphingolipid metabolism via sphingosine kinase is important for maintaining lysosome membrane integrity and function, and is essential for animal development and longevity.

DOI: https://doi.org/10.1091/mbc.E25-04-0182
Methods Mol Biol. 2025 Nov 07.

Drosophila as a Model to Monitor Multi-organ Autophagy.

Karan Selarka, Mrunmayee Kulkarni, Bhupendra V Shravage.

  Autophagy is a conserved lysosome-mediated pathway essential for cellular homeostasis, development, and stress responses. The fruit fly Drosophila melanogaster serves as a powerful model for autophagy research due to its genetic tractability and conservation of human disease genes. This chapter details fluorescence microscopy-based methods to monitor autophagy in multiple tissues, including the brain, midgut, Malpighian tubules, and ovary, under nutrient-replete and starvation conditions. Autophagosome dynamics are visualized using mCherry-Atg8a, while lysosomes are detected with CathepsinL immunostaining; colocalization of these markers in presence and absence of autophagy inhibitors can be used to measure autophagic flux. Clearance of Ref(2)P/p62 is additionally used as a readout for cargo degradation. Stepwise protocols are provided for tissue dissection, fixation, staining, and imaging, with guidance on data analysis and image processing. These approaches enable reproducible assessment of tissue-specific autophagy in vivo, offering valuable tools to investigate its roles in development, stress adaptation, and aging in Drosophila.

Keywords:  Atg8a; Autophagy; Brain; Drosophila; Malpighian tubules; Midgut; Ovary; Ref(2)P

DOI:  https://doi.org/10.1007/7651_2025_682
Autophagy Rep. 2025 ;4(1): 2572512

Aβ and tau clearance through aerobic exercise: unveiling the β2-adrenergic receptor's role in regulating autophagy-lysosomal pathways.

Liu Yang, Haitao Yu, Gao-Shang Chai.

  The systematic dissection of molecular mechanisms through which aerobic exercise (AE) mitigates neurodegenerative pathologies remains a significant challenge. Alzheimer's disease (AD) is characterized by impaired autophagy-lysosomal flux and the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. We recently identified the β2-adrenergic receptor (β2-AR) as a key mediator of exercise-induced bene = d sought to dissect its role in regulating distinct proteostatic pathways. We revealed that AE activates β2-AR signaling to promote lysosomal acidification via upregulation of VMA21, an essential assembly factor for the vacuolar ATPase (V-ATPase) proton pump, thereby facilitating Aβ clearance. Concurrently, AE enhanced autophagosome-lysosome fusion through the β2-AR - retinoid X receptor alpha (RXRα) - charged multivesicular body protein 4B (CHMP4B) axis, promoting tau degradation. Critically, pharmacological inhibition of β2-AR fully abolished these effects. Here, we propose an integrated mechanism through which β2-AR activation by AE could coordinate dual autophagy-lysosomal recovery processes and suggest that targeting this pathway offers a promising therapeutic strategy for AD and related proteostatic disorders.

Keywords:  Alzheimer’s disease; aerobic exercise; amyloid-β; autophagy; tau; β2-adrenergic receptor

DOI:  https://doi.org/10.1080/27694127.2025.2572512
Front Pharmacol. 2025 ;16 1693805

The dual role of glycogen synthase kinase-3 beta (GSK3β) in neurodegenerative pathologies: interplay between autophagy and disease progression.

Hassan H Alhassan, Komal Janiyani, Malvi Surti, Mohd Adnan, Mitesh Patel.

  Glycogen Synthase Kinase-3 Beta (GSK3β), a multifunctional serine/threonine kinase, plays a central role in cellular signaling pathways and autophagy regulation, processes critical to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS). Dysregulation of autophagy leads to the toxic accumulation of misfolded proteins and damaged organelles, contributing to neuronal loss in these disorders. This review explores the mechanistic interplay between GSK3β and autophagy, highlighting its modulation through key pathways, including mTOR, AMPK and Bcl-2 and its direct impact on autophagy-related proteins such as Beclin-1 and LC3. This review systematically discusses the disease-specific roles of GSK3β in autophagy dysregulation and protein aggregation, providing evidence from recent studies on neurodegenerative models. Additionally, therapeutic approaches targeting GSK3β are evaluated, including preclinical and clinical trials of GSK3β inhibitors and combination therapies with autophagy modulators, emphasizing their potential for improving neuroprotection and cellular homeostasis. Despite its promise, challenges such as off-target effects and pathway complexity remain significant. This review highlights the importance of GSK3β as both a therapeutic target and a biomarker, offering avenues for future research into selective GSK3β modulators that enhance autophagy and mitigate ND progression.

Keywords:  autophagy; cellular homeostasis; glycogen synthase kinase-3 beta; neurodegenerative diseases; protein aggregation

DOI:  https://doi.org/10.3389/fphar.2025.1693805
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Oct 30. pii: S1388-1981(25)00110-6. [Epub ahead of print] 159702

Regulation of macroautophagy and microautophagic lipophagy by phosphatidylserine synthase Cho1 and external ethanolamine.

Nanaru Mineoka, Rikako Konishi, Yuri Nakashima, Moe Muramoto, Kayoko Fukuda, Sayuri Kuriyama, Tatsunori Masatani, Akikazu Fujita.

  Phospholipids play crucial roles in autophagy; however, the underlying mechanisms remain elusive. We previously found that the phosphatidylserine (PtdSer) transporter Osh5 is critical for autophagosome formation. Therefore, in this study, we aimed to investigate the impact of the knockout of cho1, which encodes PtdSer synthase, on autophagy. Green fluorescent protein-autophagy-related gene 8 (GFP-Atg8) processing assay revealed a significant defect in the macroautophagic activity of the cho1∆ mutant, regardless of the presence or absence of ethanolamine (Etn). Notably, autophagosomes were absent in the cytosol, and macroautophagic bodies were not observed in the vacuoles of the starved cho1∆ mutant, underscoring the essential role of PtdSer synthesized using Cho1 in autophagosome biogenesis. In contrast, numerous microautophagic vesicles containing lipid droplets were observed in the vacuoles of cho1∆ mutants starved in the presence of Etn, suggesting the crucial role of phosphatidylethanolamine (PtdEtn) synthesized via the Kennedy pathway in microautophagic lipophagy when PtdSer synthesis using Cho1 is disrupted. Given recent evidence pointing to the involvement of the ubiquitination system in various autophagy-related processes, we also examined the role of ubiquitin-conjugating enzyme E2 gene ubc4. In addition, deletion of ubc4 gene led to a pronounced reduction in microautophagic lipophagy in starved cho1∆ cells, but not in wild-type cells. Together, these observations highlight an essential role for Ubc4-mediated ubiquitination in driving vacuolar microautophagic lipophagy specifically under Cho1-deficient conditions.

Keywords:  Electron microscopy; Freeze-fracture; Phospholipid; Rapid freezing; Ubiquitination

DOI:  https://doi.org/10.1016/j.bbalip.2025.159702
Free Radic Biol Med. 2025 Oct 31. pii: S0891-5849(25)01334-6. [Epub ahead of print]242 345-363

Cepharanthine-induced mitophagy through regulation of FBXL4-BNIP3 drives ferroptosis leading to robust anti-lung cancer efficacy.

Liu-Gen Li, Yong-Hong Xu, Ning Han, Fan Leng, Jun Hu, Hua-Zhen Xu, Hongyao Huang, Tong-Fei Li, Xiao Chen.

  Cepharanthine (Cep), a natural alkaloid from Stephania (Menispermaceae), exhibits broad-spectrum anti-cancer activity. In the present study, Cep was found to induce ferroptosis and mitophagy, for which the relationship and upstream targets remain unelucidated. Herein, the role of Cep in the induction of mitophagy was deeply investigated. Cep showed robust anti-lung cancer effects, as confirmed by decreased cell viability, elevated apoptosis, suppressed colony formation and inhibited growth of tumor grafts in Lewis cell-bearing mice. RNA-sequencing analysis revealed that Cep treatment significantly enriched differentially expressed genes (DEGs) in mitophagy and ferroptosis pathways, which were demonstrated in in vitro and in vivo experiments as well. In-depth investigations showed that inhibition of autophagy abolished Cep-mediated ferroptosis, but not vice versa. Moreover, genetic knockdown of BNIP3 dampened the mitophagy and ferroptosis of lung cancer cells induced by Cep. Additional data confirmed that Cep could bind to and thereby inhibit FBXL4, which attenuated the ubiquitination of BNIP3. FBXL4-mediated BNIP3 activation promoted the recruitment of LC3 to mitochondria and autophagic flux in the presence of Cep. Collectively, Our study elucidates a complete mechanistic pathway wherein Cep activates BNIP3-mediated mitophagy by inhibiting FBXL4, ultimately driving ferroptosis and offering a new therapeutic avenue for lung cancer.

Keywords:  Cepharanthine (Cep); FBXL4-BNIP3 axis; Ferroptosis; Lung cancer; Mitophagy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.302
Biochem Pharmacol. 2025 Nov 02. pii: S0006-2952(25)00777-4. [Epub ahead of print]243(Pt 1): 117512

Mitoxantrone elicits ROS-dependent elimination of dysfunctional mitochondria through mitophagy to control viability of intracellular mycobacteria in human macrophages.

Mousumi Das, Dev Kiran Nayak, Salina Patel, Ashish Kumar, Mustafeez Ali Quaderi, Pramathesh Kumar Dandsena, Lincoln Naik, Abtar Mishra, Amit Mishra, Ramandeep Singh, Sujit Kumar Bhutia, Assirbad Behura, Rohan Dhiman.

  Autophagy plays a critical role in clearance of Mycobacterium tuberculosis. It has emerged as a promising target for host-directed therapies against drug-resistant tuberculosis (TB). This insight opens up promising therapeutic avenues, suggesting that pharmacological activation of autophagy could effectively combat this highly persistent and harmful bacterium. The current study investigates the anti-mycobacterial properties of the anthracene-dione compound Mitoxantrone (MTX) through the activation of autophagy in differentiated THP-1 cells. The non-cytotoxic dose of MTX reduced the intracellular viability of mycobacteria compared to the control cells, and inhibition of autophagy reversed the effect of MTX on intracellular bacterial burden. Through multiparametric approaches, our investigation established the effect of MTX on mitochondria, the principal source of endogenous reactive oxygen species (ROS), acting as essential signal transducers that promote autophagy. Further, we have demonstrated that MTX decreased ATP production, which caused disruption of mitochondrial membrane proteins and increased mitochondrial ROS generation, resulting in mitochondrial fission and accelerating the initiation of mitophagy, leading to the elimination of intracellular mycobacteria. Our findings collectively demonstrated that MTX-induced mitochondrial dysfunction triggered interplay between two selective autophagic responses, diminishing mycobacterial infection and promoting its clearance. This study highlights MTX as a potential host-directed therapeutic candidate against TB through modulation of mitochondrial signaling pathways and autophagic responses.

Keywords:  Autophagy; Mitochondria; Mitophagy; Mitoxantrone; Mycobacteria

DOI:  https://doi.org/10.1016/j.bcp.2025.117512
Nat Commun. 2025 Nov 07. 16(1): 9841

DISC1 Protects Against Zika Virus Infection and Long-Term Neurological Damage Through AMPK-mTOR-Mediated Autophagy.

Shengze Zhang, Haolu Zha, Qiqi Chen, Nina Li, Chengying Zheng, Ting Xie, Pengjie Ma, Weijian Tian, Shaohui Bai, Chuming Luo, Ning Wang, Xuan Zou, Shisong Fang, Ying Jiang, Jianhui Yuan, Nan Wu, Caijun Sun, Yuelong Shu, Huanle Luo.

Disrupted in Schizophrenia 1 (DISC1) is essential for neuronal development and has been implicated in various psychiatric disorders. Our transcriptomic and proteomic analyses identified Zika virus (ZIKV) infection enhanced DISC1 expression, however, its functional role in ZIKV infection and caused congenital Zika syndrome (CZS) and ZIKV-induced long-term neurodevelopmental defects remain unexplored. In this study, we demonstrate that DISC1 attenuates ZIKV infection in human placental and neuroglia cells, as well as in murine macrophages and primary cortical cells. DISC1 also decreases ZIKV dissemination from peripheral tissues to key organs of mice, including the uterus, testis, and brain, thereby reducing fetal abortion rates and intrauterine growth restriction. Notably, DISC1 is associated with brain damage and long-term ZIKV effects, including memory loss, reduced anxiety and depression, declines in sociability and social novelty. Mechanistically, DISC1 activates autophagy by enhancing AMPKα phosphorylation and reducing mTOR phosphorylation, protecting against ZIKV infection. Additionally, DISC1 interacts with LC3 to further activate autophagy, partially contributing to reduce ZIKV infection. In conclusion, DISC1 plays a critical factor in controlling ZIKV infection and mitigating CZS and ZIKV-induced neurocognitive decline.

DOI: https://doi.org/10.1038/s41467-025-64809-w
Cell Struct Funct. 2025 Oct 31.

Monitoring phospholipid dynamics in vivo with a fluorescent dye octadecyl rhodamine B.

Li Hao, Caiyi Zhao, Kuninori Suzuki.

  Phospholipids are major components of biological membranes. They play an essential role in intracellular signaling and organelle dynamics; however, the availability of suitable lipid-specific probes is limited, which has hindered studies on their spatial distribution and functional dynamics in living cells. Previously, we demonstrated that octadecyl rhodamine B chloride (R18) is transported to the endoplasmic reticulum via nonvesicular membrane transport. In this study, we showed that R18 is internalized in a phosphatidylethanolamine (PE)-dependent manner in vivo. The internalization of R18 in Saccharomyces cerevisiae is blocked in PE-deficient mutants, but restored by ethanolamine supplementation, which suggests strict PE dependence. Moreover, R18 delivered to vacuoles through autophagy was not terminally retained, but underwent Pep4- and Atg15-dependent export from the vacuoles. The exported R18 was then redirected to endosomes following prolonged autophagy. These results suggest that R18 may serve as an indicator of PE dynamics and vacuole-endosome lipid transport, which contributes to lipid homeostasis inside vacuoles.Key words: autophagy, in vivo lipid dynamics, octadecyl rhodamine B (R18), phospholipase, phospholipid, vacuole, yeast.

Keywords:  autophagy; in vivo lipid dynamics; octadecyl rhodamine B (R18); phospholipase; phospholipid; vacuole; yeast

DOI:  https://doi.org/10.1247/csf.25126
Cell Cycle. 2025 Nov 05. 1-17

Mitophagy suppression via lncRNA H19 silencing: a novel strategy to overcome cisplatin resistance in lung adenocarcinoma.

Meng-Zhen Liu, Xiao-Yan Shao, Si-Han Wu, Qi-Qi Ning, Can Zhang, Wei-Wei Du, Rong-Rong Sun, San-Yuan Sun, You-Wei Zhang.

  Cisplatin (DDP) resistance substantially compromises treatment efficacy in lung adenocarcinoma (LUAD). This study investigates the role of mitochondrial long non-coding RNA (lncRNA) H19 in mediating DDP resistance. High-throughput sequencing and RT-qPCR analyses revealed pronounced H19 upregulation in DDP-resistant A549 (A549/DDP) cells relative to parental A549 cells. Subcellular localization studies indicated that H19 is primarily nuclear in A549 cells but translocates to mitochondria in A549/DDP cells. Functional assays demonstrated that H19 silencing in resistant cells attenuated chemoresistance, suppressed proliferation, migration, invasion, and colony formation in vitro, and delayed tumor growth in vivo. H19 knockdown impaired mitophagy and promoted apoptosis, mirroring autophagy inhibition and restoring DDP sensitivity. In contrast, H19 overexpression in A549 cells did not significantly alter mitophagy or cellular behavior. Furthermore, H19 silencing induced its relocalization from mitochondria back to the nucleus in resistant cells, while overexpression did not affect its nuclear localization. These findings establish that H19 translocation to mitochondria promotes DDP resistance, and its downregulation reverses this process by inhibiting mitophagy and resensitizing cells to DDP. As a nucleus-encoded mitochondria-associated lncRNA (ntmtlncRNA), H19 mediates intercompartmental communication, highlighting its potential as a therapeutic target for overcoming DDP resistance in LUAD.

Keywords:  LUAD; cisplatin resistance; lncRNA H19; mitophagy

DOI:  https://doi.org/10.1080/15384101.2025.2581634
Genes Cells. 2025 Nov;30(6): e70063

Cell Surface LAMP-2C Is Internalized in a Clathrin-Dependent Manner and Transported to the Recycling and Lysosomal Pathways.

Hiroshi Sakane, Yuna Takeda, Ikuto Okuda, Kanae Michihara, Kenji Akasaki.

  Lysosomes are acidic organelles that degrade a diverse range of substrates, and lysosome-associated membrane protein (LAMP)-1 and LAMP-2 are the major lysosomal membrane components. Three LAMP-2 splice variants have been identified, namely, LAMP-2A, LAMP-2B, and LAMP-2C. We previously demonstrated that when mouse LAMP-2C was stably expressed in HEK293 cells, a portion of it was present on the plasma membrane. LAMP-2C possesses a tyrosine-based motif that functions as a signal for lysosomal targeting and clathrin-mediated endocytosis (CME). However, whether cell surface LAMP-2C is indeed internalized via CME has not been clearly defined. If this occurs, it is unknown whether internalized LAMP-2C returns to the cell surface and/or moves to lysosomes from early endosomes. In this study, we found that cell surface LAMP-2C was internalized, and its internalization was impaired by knockdown of the clathrin heavy chain or the medium subunit of adaptor protein complex 2. Internalized LAMP-2C was transported to early endosomes, and a portion of the internalized LAMP-2C was recycled back to the plasma membrane. Furthermore, immunofluorescence and subcellular fractionation showed that the internalized LAMP-2C was transported to lysosomes. These results suggest that cell surface LAMP-2C is internalized by CME and that internalized LAMP-2C enters the recycling and lysosomal pathways.

Keywords:  LAMP‐2; clathrin; lysosome; recycling

DOI:  https://doi.org/10.1111/gtc.70063
Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01256-2. [Epub ahead of print]44(11): 116485

Identification of ATG7 as a protein ATG8ylation substrate.

Huazhong Xie, Jiahui Long, Yijun Huang, Yao Wang, Peiqing Liu, Min Li.

  Protein ATG8ylation is a post-translational modification where ubiquitin-like protein LC3/ATG8 forms covalent conjugation with cellular proteins, a process reversed by ATG4. In contrast to the well-characterized ATG8 lipidation/membrane ATG8ylation, research on protein ATG8ylation remains limited. In this study, we identify deconjugation-resistant LC3B Q116A and F80A/L82A mutants as tools for protein ATG8ylation. We demonstrate that protein ATG8ylation depends exclusively on ATG4, ATG3, and ATG7. Tandem affinity purification-mass spectrometry reveals ATG7 as a substrate of protein ATG8ylation with K140 as its modification site. We show that protein ATG8ylation of ATG7 forms a mono-LC3B conjugate, while ATG3 undergoes lysine-dependent, mixed-linkage poly-LC3B chains. ATG7 and ATG3 function as E1 and E2 enzymes in protein ATG8ylation, potentially cooperating with E3 ligases. Notably, endogenous ATG7 ATG8ylation attenuates autophagy by disrupting its interaction with ATG3. These findings highlight ATG7 as both a central catalytic enzyme and key substrate in autophagy regulation through protein ATG8ylation.

Keywords:  ATG3; ATG4; ATG7; CP: molecular biology; LC3 lipidation; autophagy; deconjugation-resistant; modification site; post-translational modification; protein ATG8ylation

DOI:  https://doi.org/10.1016/j.celrep.2025.116485
Mol Biol Cell. 2025 Nov 05. mbcE25100498

TORC1-dependent sorting of PI(3,5)P2 is required for vacuole membrane remodeling and signaling endosome formation.

Frederik Brinks, Annabel Arens, Rainer Kurre, Jacob Piehler, Lars Langemeyer, Christian Ungermann.

Lysosomes, as central organelles of the endolysosomal system, support cell growth by releasing nutrients derived from hydrolytic digestion of macromolecules. Additionally, they serve as storage organelles for ions and amino acids and must respond to changes in osmolarity by adjusting their membrane to maintain membrane integrity. The nutrient-sensing target of rapamycin complex 1 (TORC1) and the lipid kinase Fab1 (PIKfyve in mammals) are key regulators of these processes on yeast vacuoles. TORC1 phosphorylates Fab1, yet how their activities are functionally coupled is unknown. Here, we show that yeast TORC1 is essential for the sorting of Fab1-derived phosphatidylinositol-3,5-bisphosphate (PI(3,5)P₂) from vacuoles to signaling endosomes (SEs), whose formation depends on the CROP membrane remodeling complex. TORC1 phosphorylation activates Fab1, presumably to maintain elevated PI(3,5)P₂ levels on SEs toward cell growth. In mutants defective in endosome-vacuole fusion, PI(3,5)P₂ accumulates on endosomes adjacent to the vacuole, indicating that its hydrolysis primarily occurs on the vacuolar membrane. Our findings reveal that synthesis and spatial distribution of the vacuolar signaling lipid PI(3,5)P₂ are directly coordinated by TORC1, coupling nutrient sensing to membrane remodeling and endosomal signaling.

DOI: https://doi.org/10.1091/mbc.E25-10-0498
Ecotoxicol Environ Saf. 2025 Nov 03. pii: S0147-6513(25)01687-2. [Epub ahead of print]306 119342

IST1 alleviated acrylamide-induced apoptosis and cognitive impairment through regulating autophagy flux blockage in SH-SY5Y cells and C57BL/6J mice.

Yiqi Wang, Lian Duan, Ying Liu, Xing Zhang, Yang Jiao, Ruijie Cheng, Ning Yang, Hong Yan.

  Acrylamide (ACR) is a widely used environmental chemical with neurotoxicity. However, the molecular mechanism and intervention targets of ACR have not been fully elucidated. IST1 factor associated with ESCRT-III (IST1) is an important regulatory subunit of endosomal sorting and transport complex III (ESCRT-III). It can promote autophagy flux and accelerate the autophagic clearance of the phosphorylated Tau protein (p-Tau). This study aimed to explore the role of IST1 in ACR-caused apoptosis, autophagy flux blockage, and p-Tau accumulation. SH-SY5Y cells were exposed to ACR for 72 h at 0.5 and 0.75 mmol/L doses. IST1 overexpression (IST1oe) of SH-SY5Y cells and hippocampal IST1oe C57BL/6 J mice was conducted to evaluate the role of IST1 in ACR-caused neurotoxicity. Results showed that ACR treatment could cause apoptosis, autophagy flux blockage, decreased IST1 level, and abnormal expressions of learning and memory-related proteins, including p-CREB, BDNF, and p-Tau. The effect of ACR on IST1 protein was earlier than that of apoptosis- and autophagy-related proteins such as Bax, Bcl-2, LC3-II, and p62. IST1oe alleviated ACR-induced autophagy flux blockage by promoting autophagosome-lysosome fusion, thereby alleviating the changes in p-CREB, BDNF, p-Tau proteins, and cell apoptosis. IST1oe could alleviate ACR-led learning and memory dysfunction, alleviate the reduction of dendritic spines in C57BL/6 J mice. This study helped elucidate the neurotoxic mechanism of ACR and provide potential molecular targets for prevention and treatment.

Keywords:  Acrylamide; Apoptosis; Autophagy flux; IST1; Neurotoxicity

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119342
Biol Cell. 2025 Nov;117(11): e70040

Sestrin2 is Induced Upon Cellular Stress but Has No Effect on Myotube Size or Amino Acid Sensing in C2C12 Myotubes.

Jiani Qian, Stephanie D Gagnon, Vladimir Belhac, Carl J Hulston, Neil R W Martin.

  Sestrins are a stress-inducible family of proteins that function in cell survival and nutrient sensing through their regulation of mTORC1. Muscle wasting is associated with cellular stress, but to date, there is limited in vitro research investigating sestrins in skeletal muscle cells. Here we use C2C12 myotubes to understand how sestrin proteins (sestrin 1-3) are regulated by different forms of cellular stress linked to muscle wasting conditions. Furthermore, since sestrin2 is a well-characterised protein but is lowly expressed in muscle tissue in the absence of stress, we also aimed to determine if silencing this protein impacted parameters of muscle growth or nutrient sensing by mTORC1 under basal conditions. Incubating C2C12 myotubes with the endoplasmic reticulum (ER) stress-inducing agent tunicamycin, or a high concentration (1000 µM) of hydrogen peroxide (H2O2), increased sestrin2 protein levels with no change in sestrins 1 or 3. This increase was temporally associated with increased ER stress markers Ddit3 mRNA and ATF4 protein levels, and could be blocked by approximately half when myotubes were co-incubated with H2O2 and the ER-stress inhibitor 4-Phenylbutyrate. siRNA silencing of sestrin2 blunted the phosphorylation of the mTORC1 effector S6K1, but did not acutely influence protein synthesis or myotube size. Similarly, silencing sestrin2 did not affect mTORC1 signalling in response to nutrient deprivation. These data indicate that sestrin2 is stress-inducible and may play a role in protecting skeletal muscle from ER stress, but is less important in regulating mTORC1 and nutrient sensing in unstressed/basal conditions.

Keywords:  ER stress; mTORC1; myotubes; nutrient sensing; skeletal muscle

DOI:  https://doi.org/10.1111/boc.70040
Discov Oncol. 2025 Nov 03. 16(1): 2012

LncRNA NEAT1 modulates myeloma cell autophagy and apoptosis by competitively binding miR-195-5p to regulate CEBPA.

Ting Wang, Hongyue Xu, Wei Tao, Bin Bai, Xiuhui Chen, Bingyun Zhang, Yingchao Liu, Xueyong Zhang.



Keywords:  Apoptosis; Autophagy; CEBPA; LncRNA NEAT1; Modulates myeloma; miR-195-5p

DOI:  https://doi.org/10.1007/s12672-025-03869-2
EMBO Rep. 2025 Nov 06.

Loss of the lysosomal protein CLN3 triggers c-Abl-dependent YAP1 pro-apoptotic signaling.

Neuza Domingues, Alessia Calcagni', Sofia Freire, Joana Pires, Ricardo Casqueiro, Ivan L Salazar, Niculin Joachim Herz, Tuong Huynh, Katarzyna Wieciorek, Tiago Fleming Outeiro, Henrique Girão, Ira Milosevic, Andrea Ballabio, Nuno Raimundo.

  Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of Cln3Δ7/8 mice, an established model of Batten disease. Loss of CLN3 leads to DNA damage, activating the kinase c-Abl which phosphorylates YAP1, stimulating its pro-apoptotic signaling. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may pave a way for novel c-Abl-centric therapeutic strategies to target Batten disease.

Keywords:  Batten Disease; DNA Damage; Lysosome-Nucleus Communication; Lysosomes; YAP1

DOI:  https://doi.org/10.1038/s44319-025-00613-3
Cell Death Dis. 2025 Nov 04. 16(1): 791

Loss of Fanconi anemia proteins causes a reliance on lysosomal exocytosis.

Becky Xu Hua Fu, Albert Xu, Hua Li, Daniel E Johnson, Jennifer R Grandis, Luke A Gilbert.

Mutations in the Fanconi Anemia (FA) pathway lead to a rare genetic disease that increases risk of bone marrow failure, acute myeloid leukemia, and solid tumors. FA patients have a 500 to 800-fold increase in head and neck squamous cell carcinoma compared to the general population and the treatments for these malignancies are ineffective and limited due to the deficiency in DNA damage repair. Using unbiased CRISPR-interference screening, we found the loss of FA pathway function renders cells dependent on key exocytosis genes such as SNAP23. Further investigation revealed that loss of FA pathway function induced deficiencies in lysosomal health, dysregulation of autophagy and increased lysosomal exocytosis. The compromised cellular state caused by the loss of FA genes is accompanied by decreased lysosome abundance and increased lysosomal membrane permeabilization in cells. We found these signatures in vitro across multiple cell types and cell lines and in clinically relevant FA patient cancers. Our findings are the first to connect the FA pathway to lysosomal exocytosis and thus expands our understanding of FA as a disease and of induced dependencies in FA mutant cancers.

DOI: https://doi.org/10.1038/s41419-025-08164-0
Sci Transl Med. 2025 Nov 05. 17(823): eadu6015

The m6A demethylase FTO links TLR7 to mitochondrial oxidation driving age-associated B cell formation in systemic lupus erythematosus.

Qin Zeng, Lin Li, Xue Li, Linmang Qin, Tianxiao Feng, Yunfeng Zhu, Jieying Wang, Yaoyao Zou, Jianling Su, Guangfu Dong, Wuzheng Xia, Ting Xu, Guangfeng Zhang, Yang Cui, Haobo Lin, Xin Li, Yang Li.

Extrafollicular age-associated B cells (ABCs) excessively expand and produce autoantibodies in systemic lupus erythematosus (SLE), and the regulatory mechanism remains elusive. We found that the m6A demethylase fat mass and obesity-associated protein (FTO) was highly expressed in ABCs from patients with SLE, which was positively associated with renal immune damage. FTO overexpression in murine and human B cells facilitated ABC expansion and exacerbated SLE in lupus-prone mice, whereas FTO ablation ameliorated ABC-driven autoimmunity. FTO expression was up-regulated upon activation of the toll-like receptor 7-myeloid differentiation primary response protein 88 (TLR7-MyD88) signaling pathway. FTO, in turn, promoted TLR7-driven ABC differentiation by targeting ATPase H+ transporting V1 subunit G1 (ATP6V1G1), a subunit of the vacuolar H+-ATPase (V-ATPase), in an m6A-dependent manner. Mechanistically, FTO deficiency impaired lysosomal autophagy by reducing ATP6V1G1-mediated V-ATPase activity. The accumulation of damaged mitochondria led to mitochondrial dysfunction in human and murine B cells, characterized by reduced oxidative phosphorylation and elevated reactive oxygen species. This dysfunction limited cell proliferation and blocked ABC differentiation by dampening cellular responsiveness to interleukin-12. Thus, TLR7-FTO-ATP6V1G1 signaling metabolically shapes extrafollicular ABCs in SLE, providing a potential therapeutic target.

DOI: https://doi.org/10.1126/scitranslmed.adu6015
Int J Mol Med. 2026 Jan;pii: 13. [Epub ahead of print]57(1):

Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).

Chaowei Zhang, Yuxuan Han, Weiyi Yao, Qing Hong, Na Chen.

  Amino acid (AA) sensing plays an important role in maintaining cellular metabolic homeostasis as well as tumorigenesis and progression. Studies on classic AA sensing pathways such as rapamycin complex 1 (mTORC1) and general control nonderepressible 2 (GCN2) have revealed their central position in cancer metabolic reprogramming. AA sensing pathways are often hijacked in tumors to adapt to the nutrient‑deprived microenvironment, promoting cell proliferation, anti‑apoptosis and treatment tolerance. In addition, the regulation of AA sensing and transport plays a crucial role in maintaining the metabolic flexibility of tumor cells. By targeting the AA sensing mechanism, it is expected to disrupt the metabolic homeostasis of cancer cells, providing new strategies for precision therapy. The present review summarized the latest advances in the research on the role of the mTORC1 and GCN2 AA sensing pathways in tumor metabolism, emphasizing their potential and the challenges faced in cancer diagnosis and treatment. Additionally, it provided novel insights into the therapeutic targeting of AA sensing pathways and proposes future research directions aimed at overcoming current limitations in cancer metabolism therapy.

Keywords:  amino acid sensing; metabolic reprogramming; targeted cancer therapy; tumor microenvironment

DOI:  https://doi.org/10.3892/ijmm.2025.5684
Signal Transduct Target Ther. 2025 Nov 03. 10(1): 360

Microglia-derived nanovesicles synchronize macroautophagy and chaperone-mediated autophagy for Alzheimer's disease therapy.

Min Li, Shuang Chen, Rong Guo, Yang Wang, Mingrui Yang, Yingke Liu, Qiang Zhang, Shiyu Zhu, Jiaxin Li, Fang Chen, Bo Wang, Man Li, Qin He.

Dysregulated autophagy is a hallmark of Alzheimer's disease (AD), yet the extent of impairment in macroautophagy and chaperone-mediated autophagy (CMA) remains unclear. Here, we show that both pathways are disrupted in AD model mice, preceding β-amyloid accumulation and driving disease progression. However, therapeutic autophagy modulation is severely restricted by the blood-brain barrier (BBB). To overcome this, we developed Microglia-Liposome Fusion Extrusion (MiLi-FE), a method to engineer microglia-derived nanovesicles (AR@ENV) for the codelivery of AR7 (a CMA inducer) and rapamycin (a macroautophagy inducer). Leveraging its microglial membrane origin, AR@ENV effectively crosses the BBB and targets inflammatory sites in the AD brain, where it is internalized by neurons. Once inside, they synchronously activate both autophagy pathways: AR7 antagonizes retinoic acid receptor alpha (RARα) to enhance CMA, while rapamycin inhibits mTOR to promote macroautophagy. This coordinated activation enhances clearance of β-amyloid and other toxic aggregates, restores proteostasis, and provides robust neuroprotection. Furthermore, the strategy ameliorates neuroinflammation and significantly rescues cognitive deficits in two distinct AD mouse models. By integrating synchronized dual autophagy activation with targeted biomimetic delivery, AR@ENV represents a promising therapeutic candidate for AD. Moreover, the MiLi-FE platform offers a versatile and scalable approach for delivering diverse therapeutics to the central nervous system, extending its potential applicability to a range of neurological disorders.

DOI: https://doi.org/10.1038/s41392-025-02453-y
J Cell Sci. 2025 Nov 03. pii: jcs.263920. [Epub ahead of print]

Endoplasmic reticulum protein FAM134B acts as a regulator of mitochondrial morphology.

Sebabrata Maity, Anwesha Dutta Gupta, Izaz Monir Kamal, Rajdeep Das, Rupsha Mondal, Arpit Tyagi, Deepak Sharma, Joy Chakraborty, Saikat Chakrabarti, Oishee Chakrabarti.

  The endoplasmic reticulum (ER) and mitochondria are known to affect myriad cellular mechanisms. More recently, dynamic association between them has been identified in different eukaryotes; these interactions vary in their composition and involvement in regulation of intracellular machineries. FAM134B or RETREG1, originally identified as an oncogene, regulates ER membrane shape and curvature. It is a key ER-phagy or reticulophagy receptor, which promotes autophagy of not only the ER but also simultaneous dual autophagy of ER and mitochondria. While it is known that FAM134B can potentiate contact with mitochondria, its direct involvement in affecting mitochondrial dynamics remains unexplored. Here we show that FAM134B can interact with the canonical fission-promoting protein, DRP1. Functional depletion of FAM134B leads to local Actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in hyperfusion. A decrease in FAM134B levels is observed with aging in rat brains, cell and mouse models of Parkinson's disease and patient-derived samples. Our study establishes FAM134B as the ER partner that helps in maintaining mitochondrial morphology and dynamics.

Keywords:  DRP1; FAM134B; Fission; Mitochondrial hyperfusion

DOI:  https://doi.org/10.1242/jcs.263920
Nature. 2025 Nov 05.

Secretome translation shaped by lysosomes and lunapark-marked ER junctions.

Heejun Choi, Ya-Cheng Liao, Young J Yoon, Jonathan Grimm, Nan Wang, Luke D Lavis, Robert H Singer, Jennifer Lippincott-Schwartz.

The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome density and translation efficiency of secretome mRNAs near lysosomes, an effect that was dependent on eIF2-mediated initiation and was reversed by the integrated stress response inhibitor ISRIB. Lysosome-associated translation was further modulated by nutrient status: amino acid deprivation enhanced lysosome-proximal translation, whereas lysosomal pH neutralization suppressed it. These findings identify a mechanism by which ER junctional proteins and lysosomal activity cooperatively pattern secretome mRNA translation, linking ER architecture and nutrient sensing to the production of secretory and membrane proteins.

DOI: https://doi.org/10.1038/s41586-025-09718-0
Acta Neuropathol Commun. 2025 Nov 04. 13(1): 223

Transaldolase 1 impacts Parkinson's disease pathogenesis via metabolic reprogramming and autophagy-lysosomal pathway.

Zixin Tan, Huimin Hu, Hao Chen, Yuwan Lin, Miaomiao Zhou, Wenlong Zhang, Pingyi Xu, Xiang Chen.

  Parkinson's disease (PD) progression involves dopaminergic neurodegeneration and pathological α-synuclein aggregation, processes linked to metabolic dysregulation and autophagy-lysosomal pathway (ALP) impairment. Transaldolase1 (TAL1) is a key enzyme of the pentose phosphate pathway. While elevated TAL1 protein levels have been observed in postmortem substantia nigra of PD patients, the enzyme's functional role in disease pathogenesis remains undefined. In this study, we explored the role of TAL1 in PD-related pathologies using MPTP-induced and AAV-A53T mouse models. We demonstrate that TAL1 upregulation is associated with dopaminergic neuron degeneration across both experimental models. TAL1 knockdown activated TFEB-mediated transcription of autophagy-lysosomal genes (Ctsb, Ctsd, Lamp1, Becn1, and Map1Lc3b). In addition, targeted metabolomics revealed that TAL1 knockdown modulates the energy pathways, especially in the TCA cycle, and glycolysis. The neuroprotective effects were mediated through AMPK/mTORC1 pathway activation, evidenced by increased AMP levels, p-AMPK/AMPK ratios, and downstream ALP enhancement. Importantly, TAL1 inhibition improved locomotor function in AAV-A53T mice and normalized stride length in footprint analysis. Pathological experiments confirmed reduced phospho-α-synuclein level and preserved the neuron loss in substantia nigra. Our findings highlight TAL1 as a regulator of autophagy-lysosomal function and energy metabolism in PD-related experimental models, where its inhibition restores the degradation of α-synuclein through coordinated activation of autophagy-lysosomal clearance and energetic reprogramming. These results suggest that targeting TAL1 may offer a potential therapeutic approach to mitigate PD-associated neuropathology.

Keywords:  Autophagy-lysosomal pathway; Metabolic reprogramming; Parkinson’s disease; Transaldolase1

DOI:  https://doi.org/10.1186/s40478-025-02133-6
Blood. 2025 Nov 05. pii: blood.2025030061. [Epub ahead of print]

PIKfyve inhibition in myeloma disrupts autophagy and the lysosome, increasing MHC expression and cholesterol metabolism.

Cecilia Bonolo De Campos, Ruijuan He, Tessa Josephine Pelino, Dor David Abelman, Zhihua Li, Daniel K C Lee, Ding Yan Wang, Michael St Paul, Jeffrey Bruce, Craig D Simpson, Leanne Wybenga-Groot, Michael F Moran, Rodger E Tiedemann, Trevor Pugh, Tak W Mak, Olga Issakova, Nikolai Sepetov, Suzanne Trudel, A Keith Stewart.

We previously reported a chemo-genomics screen that unexpectedly identified Phosphatidylinositol-3-phosphate 5 kinase (PIKfyve) as a vulnerable target in multiple myeloma (MM). PIKfyve is an essential regulator of lysosomal function and autophagy. Given the high basal necessity of autophagy in MM for sustainable immunoglobulin synthesis, targeting autophagy holds clinical potential as a novel therapeutic avenue. Here, we report the development and characterization of PIK001 and analogues, potent and selective novel small-molecule inhibitors of PIKfyve. PIK001 demonstrated potent anti-MM activity in vitro, as well as synergistic activity with established anti-MM agents (including venetoclax and selinexor), while retaining efficacy in lenalidomide-resistant models. Multi-omic characterization of isogenic cell lines sensitive / resistant to PIK001 identified a catalytic domain mutation (PIKFYVEN1939K) and heterogenous alterations in autophagy capabilities. Importantly, we noted that PIK001 exposure also resulted in significantly increased cholesterol metabolism and upregulation of MHC Class I expression, with potential implications in tumor immunity. Beyond MM, PIKfyve inhibition also shows selective cytotoxicity in acute myeloid leukemia, melanoma, and renal cancer, highlighting broader therapeutic potential. These findings establish PIKfyve inhibition as a valid target for MM and other hematologic malignancies, provide insights into mechanisms of sensitivity and resistance, and a compelling foundation for further pre-clinical (particularly with respect to the role of cholesterol metabolism and tumor immunity) and clinical development.

DOI: https://doi.org/10.1182/blood.2025030061
Autophagy Rep. 2025 ;4(1): 2574355

CNX:FAM134B-driven ERLAD of ATZ polymers proceeds via enhanced formation of VAPA:ORP1L:RAB7 contact sites between ER and endolysosomes.

Elisa Fasana, Ilaria Fregno, Maurizio Molinari.

  Membrane contact sites (MCS) between organelles maintain the proximity required for controlled exchange of small molecules and ions yet preventing fusion events that would compromise organelles' identity and integrity. Here, by investigating the intracellular fate of the disease-causing Z-variant of alpha1 antitrypsin (ATZ), we report on a novel function of MCS between the endoplasmic reticulum (ER) and RAB7/LAMP1-positive endolysosomes in ER-to-lysosome-associated degradation (ERLAD). For this function, the VAPA:ORP1L:RAB7 multi-protein complex forming MCS between the ER and endolysosomes engages, in an ERLAD client-driven manner, the misfolded protein segregation complex formed by the lectin chaperone calnexin (CNX), the ER-phagy receptor FAM134B, and the ubiquitin-like protein LC3. Generation of this supramolecular complex facilitates the membrane fusion events regulated by the SNARE proteins STX17 and VAMP8 that ensure efficient delivery of ATZ polymers from their site of generation, the ER, to the site of their intracellular clearance, the degradative RAB7/LAMP1-positive endolysosomes.

Keywords:  Calnexin (CNX); ER-phagy; ER-to-Lysosome-Associated Degradation (ERLAD); Endoplasmic Reticulum (ER); FAM134B; Membrane Contact Sites (MCS); ORP1L; RAB7; VAPA; endolysosomes

DOI:  https://doi.org/10.1080/27694127.2025.2574355
Nat Struct Mol Biol. 2025 Nov 06.

Caught in the act: how a brake on cell growth is anchored to lysosomes.

DOI: https://doi.org/10.1038/s41594-025-01709-z