bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2025–01–12
48 papers selected by
Viktor Korolchuk, Newcastle University
  1. Cargo hitchhiking autophagy - a hybrid autophagy pathway utilized in yeast.
  2. Hepatitis C Virus NS5A Activates Mitophagy Through Cargo Receptor and Phagophore Formation.
  3. Autophagy intersection: Unraveling the role of the SNARE complex in lysosomal fusion in Alzheimer's disease.
  4. Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase.
  5. Molecular Mechanisms Underlying Initiation and Activation of Autophagy.
  6. Exercise-driven cellular autophagy: A bridge to systematic wellness.
  7. Serinc2 antagonizes pressure overload-induced cardiac hypertrophy via regulating the amino acid/mTORC1 signaling pathway.
  8. Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.
  9. Phase separation of initiation hubs on cargo is a trigger switch for selective autophagy.
  10. Structure of the WIPI3/ATG16L1 Complex Reveals the Molecular Basis for the Recruitment of the ATG12~ATG5-ATG16L1 Complex by WIPI3.
  11. Crosstalk between ferroptosis and autophagy: broaden horizons of cancer therapy.
  12. PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology.
  13. Deciphering the Power of Resveratrol in Mitophagy: From Molecular Mechanisms to Therapeutic Applications.
  14. ATG8 delipidation is not universally critical for autophagy in plants.
  15. Breaking the cellular defense: the role of autophagy evasion in Francisella virulence.
  16. Dietary cinnamon promotes longevity and extends healthspan via mTORC1 and autophagy signaling.
  17. Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.
  18. Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines.
  19. Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.
  20. Mitophagy in Doxorubicin-Induced Cardiotoxicity: Insights into Molecular Biology and Novel Therapeutic Strategies.
  21. Mesencephalic astrocyte-derived neurotrophic factor inhibits neuroinflammation through autophagy-mediated α-synuclein degradation.
  22. Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord.
  23. Controversial Roles of Autophagy in Adenomyosis and Its Implications for Fertility Outcomes-A Systematic Review.
  24. Inhibition of Unc-51-like-kinase is mitoprotective during Pseudomonas aeruginosa infection in corneal epithelial cells.
  25. TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.
  26. Amino Acid Metabolism and Autophagy in Atherosclerotic Cardiovascular Disease.
  27. Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function.
  28. CCAAT/Enhancer-Binding Protein Beta Nitration Participates in Hyperhomocysteinemia-Induced Cardiomyocyte Autophagic Flux Blockage by Inhibiting Transcription Factor EB Transcription.
  29. Hantaan virus glycoprotein Gc induces NEDD4-dependent PTEN ubiquitination and degradation to escape the restriction of autophagosomes and facilitate viral propagation.
  30. ATG9 promotes autophagosome formation through interaction with LC3.
  31. Acidosis induces autophagic cell death through ASIC1-mediated Akt/mTOR signaling in HT22 neurons.
  32. Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation.
  33. Ubiquitination of TFEB increased intestinal permeability to aggravate metabolic dysfunction-associated steatohepatitis.
  34. RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis.
  35. Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment.
  36. Targeting mTOR Kinase with Natural Compounds: Potent ATP-Competitive Inhibition Through Enhanced Binding Mechanisms.
  37. Impact of LITAF on Mitophagy and Neuronal Damage in Epilepsy via MCL-1 Ubiquitination.
  38. Structure-Activity Relationship Studies of an Autophagy Inhibitor That Targets the ATG14L-Beclin1 Protein-Protein Interaction Reveal Modifications That Improve Potency and Solubility and Maintain Selectivity.
  39. Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.
  40. Autophagy mediated by ROS-AKT-FoxO pathway is required for intestinal regeneration in echinoderms.
  41. Mitochondrial phosphatase PPTC7 promotes EGFR recycling by facilitating VPS4A endosomal localization.
  42. Spermidine Enhances Mitochondrial Bioenergetics in Young and Aged Human-Induced Pluripotent Stem Cell-Derived Neurons.
  43. Tax1bp1 enhances bacterial virulence and promotes inflammatory responses during Mycobacterium tuberculosis infection of alveolar macrophages.
  44. Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.
  45. The Effect of Quercetin on Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Beclin1, P62, and LC3: An Experimental Study.
  46. Modulating mTOR-dependent astrocyte substate transitions to alleviate neurodegeneration.
  47. Chemically engineered antibodies for autophagy-based receptor degradation.
  48. Elevated p16Ink4a Expression Enhances Tau Phosphorylation in Neurons Differentiated From Human-Induced Pluripotent Stem Cells.
  1. Autophagy. 2025 Jan 05. 1-13
    Cargo hitchhiking autophagy - a hybrid autophagy pathway utilized in yeast.
    Katrina F Cooper.
      Macroautophagy is a catabolic process that maintains cellular homeostasis by recycling intracellular material through the use of double-membrane vesicles called autophagosomes. In turn, autophagosomes fuse with vacuoles (in yeast and plants) or lysosomes (in metazoans), where resident hydrolases degrade the cargo. Given the conservation of autophagy, Saccharomyces cerevisiae is a valuable model organism for deciphering molecular details that define macroautophagy pathways. In yeast, macroautophagic pathways fall into two subclasses: selective and nonselective (bulk) autophagy. Bulk autophagy is predominantly upregulated following TORC1 inhibition, triggered by nutrient stress, and degrades superfluous random cytosolic proteins and organelles. In contrast, selective autophagy pathways maintain cellular homeostasis when TORC1 is active by degrading damaged organelles and dysfunctional proteins. Here, selective autophagy receptors mediate cargo delivery to the vacuole. Now, two groups have discovered a new hybrid autophagy mechanism, coined cargo hitchhiking autophagy (CHA), that uses autophagic receptor proteins to deliver selected cargo to phagophores built in response to nutrient stress for the random destruction of cytosolic contents. In CHA, various autophagic receptors link their cargos to lipidated Atg8, located on growing phagophores. In addition, the sorting nexin heterodimer Snx4-Atg20 assists in the degradation of cargo during CHA, possibly by aiding the delivery of cytoplasmic cargos to phagophores and/or by delaying the closure of expanding phagophores. This review will outline this new mechanism, also known as Snx4-assisted autophagy, that degrades an assortment of cargos in yeast, including transcription factors, glycogen, and a subset of ribosomal proteins.
    Keywords:  Atg45; Hab1; Ksp1; cargo hitchhiking autophagy; receptor proteins
    DOI:  https://doi.org/10.1080/15548627.2024.2447207
  2. Pathogens. 2024 Dec 23. pii: 1139. [Epub ahead of print]13(12):
    Hepatitis C Virus NS5A Activates Mitophagy Through Cargo Receptor and Phagophore Formation.
    Yuan-Chao Hsiao, Chih-Wei Chang, Chau-Ting Yeh, Po-Yuan Ke.
      Chronic HCV infection is a risk factor for end-stage liver disease, leading to a major burden on public health. Mitophagy is a specific form of selective autophagy that eliminates mitochondria to maintain mitochondrial integrity. HCV NS5A is a multifunctional protein that regulates the HCV life cycle and may induce host mitophagy. However, the molecular mechanism by which HCV NS5A activates mitophagy remains largely unknown. Here, for the first time, we delineate the dynamic process of HCV NS5A-activated PINK1/Parkin-dependent mitophagy. By performing live-cell imaging and CLEM analyses of HCV NS5A-expressing cells, we demonstrate the degradation of mitochondria within autophagic vacuoles, a process that is dependent on Parkin and ubiquitin translocation onto mitochondria and PINK1 stabilization. In addition, the cargo receptors of mitophagy, NDP52 and OPTN, are recruited to the mitochondria and required for HCV NS5A-induced mitophagy. Moreover, ATG5 and DFCP1, which function in autophagosome closure and phagophore formation, are translocated near mitochondria for HCV NS5A-induced mitophagy. Furthermore, autophagy-initiating proteins, including ATG14 and ULK1, are recruited near the mitochondria for HCV NS5A-triggered mitophagy. Together, these findings demonstrate that HCV NS5A may induce PINK1/Parkin-dependent mitophagy through the recognition of mitochondria by cargo receptors and the nascent formation of phagophores close to mitochondria.
    Keywords:  HCV; HCV NS5A; cargo receptor; mitophagy; phagophore
    DOI:  https://doi.org/10.3390/pathogens13121139
  3. J Alzheimers Dis. 2025 Jan 09. 13872877241307403
    Autophagy intersection: Unraveling the role of the SNARE complex in lysosomal fusion in Alzheimer's disease.
    Siyu Li, Yangyang Wang, Xiao Liang, Yu Li.
      Autophagy is a fundamental cellular process critical for maintaining neuronal health, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD). This review explores the intricate role of the SNARE complex in the fusion of autophagosomes with lysosomes, a crucial step in autophagic flux. Disruptions in this fusion process, often resulting from aberrant SNARE complex function or impaired lysosomal acidification, contribute to the pathological accumulation of autophagosomes and lysosomes observed in AD. We examine the composition, regulation, and interacting molecules of the SNARE complex, emphasizing its central role in autophagosome-lysosome fusion. Furthermore, we discuss the potential impact of specific SNARE protein mutations and the broader implications for neuronal health and disease progression. By elucidating the molecular mechanisms underlying SNARE-mediated autophagic fusion, we aim to highlight therapeutic targets that could restore autophagic function and mitigate the neurodegenerative processes characteristic of AD.
    Keywords:  Alzheimer's disease; SNARE proteins; autophagosome-lysosome fusion; autophagy
    DOI:  https://doi.org/10.1177/13872877241307403
  4. Autophagy. 2025 Jan 11. 1-20
    Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase.
    Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, Cheng Cao.
      The vacuolar-type H+-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V1 domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68 phosphorylation in ATP6V1B2 facilitates the recruitment of the ATP6V1D subunit into the V1 subcomplex of V-ATPase, therefore potentiating the assembly of the V1 subcomplex with the membrane-embedded V0 subcomplex to form the integrated functional V-ATPase. ABL1 inhibition or depletion impairs V-ATPase assembly and lysosomal acidification, resulting in an increased lysosomal pH, a decreased lysosomal hydrolase activity, and consequently, the suppressed degradation of lumenal cargo during macroautophagy/autophagy. Consistently, the efficient removal of damaged mitochondrial residues during mitophagy is also impeded by ABL1 deficiency. Our findings suggest that ABL1 is a crucial autophagy regulator that maintains the adequate lysosomal acidification required for both physiological conditions and stress responses.Abbreviation: ANOVA: analysis of variance; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRK: CRK proto-oncogene, adaptor protein; CTSD: cathepsin D; DMSO: dimethylsulfoxide; EBSS: Earle's balanced salt solution; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GST: glutathione S-transferase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PD: Parkinson disease; PLA: proximity ligation assay; RFP: red fluorescent protein; WT: wild-type.
    Keywords:  ABL1; V-ATPase; kinase; lysosome; phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2024.2448913
  5. Biomolecules. 2024 Nov 27. pii: 1517. [Epub ahead of print]14(12):
    Molecular Mechanisms Underlying Initiation and Activation of Autophagy.
    Zhixiao Wei, Xiao Hu, Yumeng Wu, Liming Zhou, Manhan Zhao, Qiong Lin.
      Autophagy is an important catabolic process to maintain cellular homeostasis and antagonize cellular stresses. The initiation and activation are two of the most important aspects of the autophagic process. This review focuses on mechanisms underlying autophagy initiation and activation and signaling pathways regulating the activation of autophagy found in recent years. These findings include autophagy initiation by liquid-liquid phase separation (LLPS), autophagy initiation in the endoplasmic reticulum (ER) and Golgi apparatus, and the signaling pathways mediated by the ULK1 complex, the mTOR complex, the AMPK complex, and the PI3KC3 complex. Through the review, we attempt to present current research progress in autophagy regulation and forward our understanding of the regulatory mechanisms and signaling pathways of autophagy initiation and activation.
    Keywords:  atg9a; autophagy initiation; liquid–liquid phase separation (LLPS); signaling pathways
    DOI:  https://doi.org/10.3390/biom14121517
  6. J Adv Res. 2025 Jan 03. pii: S2090-1232(24)00613-1. [Epub ahead of print]
    Exercise-driven cellular autophagy: A bridge to systematic wellness.
    Xiao-Han Zhou, Ya-Xi Luo, Xiu-Qing Yao.
       BACKGROUND: Exercise enhances health by supporting homeostasis, bolstering defenses, and aiding disease recovery. It activates autophagy, a conserved cellular process essential for maintaining balance, while dysregulated autophagy contributes to disease progression. Despite extensive research on exercise and autophagy independently, their interplay remains insufficiently understood.
    AIM OF REVIEW: This review explores the molecular mechanisms of exercise-induced autophagy in various tissues, focusing on key transduction pathways. It examines how different types of exercise trigger specific autophagic responses, supporting cellular balance and addressing systemic dysfunctions. The review also highlights the signaling pathways involved, their roles in protecting organ function, reducing disease risk, and promoting longevity, offering a clear understanding of the link between exercise and autophagy.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: Exercise-induced autophagy is governed by highly coordinated and dynamic pathways integrating direct and indirect mechanical forces and biochemical signals, linking physical activity to cellular and systemic health across multiple organ systems. Its activation is influenced by exercise modality, intensity, duration, and individual biological characteristics, including age, sex, and muscle fiber composition. Aerobic exercises primarily engage AMPK and mTOR pathways, supporting mitochondrial quality and cellular homeostasis. Anaerobic training activates PI3K/Akt signaling, modulating molecules like FOXO3a and Beclin1 to drive muscle autophagy and repair. In pathological contexts, exercise-induced autophagy enhances mitochondrial function, proteostasis, and tissue regeneration, benefiting conditions like sarcopenia, neurodegeneration, myocardial ischemia, metabolic disorders, and cancer. However, excessive exercise may lead to autophagic overactivation, leading to muscle atrophy or pathological cardiac remodeling. This underscores the critical need for balanced exercise regimens to maximize therapeutic efficacy while minimizing risks. Future research should prioritize identifying reliable biomarkers, optimizing exercise protocols, and integrating exercise with pharmacological strategies to enhance therapeutic outcomes.
    Keywords:  Autophagy; Exercise; Health; Macroautophagy; Physical activity; Well-being
    DOI:  https://doi.org/10.1016/j.jare.2024.12.036
  7. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 03. pii: S0925-4439(24)00644-6. [Epub ahead of print]1871(3): 167650
    Serinc2 antagonizes pressure overload-induced cardiac hypertrophy via regulating the amino acid/mTORC1 signaling pathway.
    Shuai Mao, Manqi Yang, Huimin Liu, Shun Wang, Man Liu, Shan Hu, Beilei Liu, Hao Ju, Zheyu Liu, Min Huang, Shuijing He, Mian Cheng, Gang Wu.
       BACKGROUND: Cardiac hypertrophy is characterized by the upregulation of fetal genes, increased protein synthesis, and enlargement of cardiac myocytes. The mechanistic target of rapamycin complex 1 (mTORC1), which responds to fluctuations in cellular nutrient and energy levels, plays a pivotal role in regulating protein synthesis and cellular growth. While attempts to inhibit mTORC1 activity, such as through the application of rapamycin and its analogs, have demonstrated limited efficacy, further investigation is warranted.
    METHODS AND RESULTS: Here, we show that Serinc2 expression is downregulated in the transverse aortic constriction (TAC)-induced hypertrophic myocardium. Both in vivo and in vitro, the reduction of Serinc2 expression results in pathological hypertrophic growth, whereas Serinc2 overexpression exhibits a protective effect. RNA sequencing analysis following Serinc2 knockdown reveals a transcriptomic shift toward a pro-hypertrophic profile and suggests a significant interplay between Serinc2, amino acid, mTOR, and the lysosome, a hub for mTOR activation. Moreover, we show that Serinc2 localizes to lysosomes and hinders mTORC1 recruitment to the lysosomal membrane in response to amino acid stimulation, playing a critical role in regulating amino acid signaling pathway involved in the activation of p70S6K, S6, and 4EBP1 in Hela cells. And its deficiency exacerbates mTORC1 activity and mTORC1-dependent subsequent protein synthesis, which can be abrogated by rapamycin. In line with our in vitro findings, Serinc2 knockout mice subjected to TAC surgery exhibit elevated phosphorylation of p70S6K and 4EBP1, while inhibition of mTORC1 signaling through amino acid deprivation prevents this activation and impedes the progression to pathological cardiac remodeling.
    CONCLUSIONS: We have illustrated that Serinc2 localizes to the lysosomal membrane and modulates amino acid /mTORC1 signaling in cardiomyocytes. Serinc2 therefore presents a potential therapeutic target for mitigating excessive protein synthesis and improving heart failure under hemodynamic stress.
    Keywords:  Amino acid; Cardiac hypertrophy; Lysosome; SERINC2; mTORC1
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167650
  8. Biomolecules. 2024 Dec 22. pii: 1649. [Epub ahead of print]14(12):
    Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.
    Lydia Shen, Ulf Dettmer.
      The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson's disease (PD), a brain disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Consequently, impaired mitochondrial quality control may play a key role in PD pathology. This is affirmed by work indicating that genes such as PRKN and PINK1, which participate in multiple mitochondrial processes, harbor PD-associated mutations. Furthermore, mitochondrial complex-I-inhibiting toxins like MPTP and rotenone are known to cause Parkinson-like symptoms. At the heart of PD is alpha-synuclein (αS), a small synaptic protein that misfolds and aggregates to form the disease's hallmark Lewy bodies. The specific mechanisms through which aggregated αS exerts its neurotoxicity are still unknown; however, given the vital role of both αS and mitochondria to PD, an understanding of how αS influences mitochondrial maintenance may be essential to elucidating PD pathogenesis and discovering future therapeutic targets. Here, the current knowledge of the relationship between αS and mitochondrial quality control pathways in PD is reviewed, highlighting recent findings regarding αS effects on mitochondrial biogenesis, dynamics, and autophagy.
    Keywords:  PGC-1α; PINK1/Parkin; Parkinson’s disease; mitochondrial dysfunction; mitochondrial fragmentation; mitophagy; α-synuclein
    DOI:  https://doi.org/10.3390/biom14121649
  9. Nat Cell Biol. 2025 Jan 07.
    Phase separation of initiation hubs on cargo is a trigger switch for selective autophagy.
    Mariya Licheva, Jeremy Pflaum, Riccardo Babic, Hector Mancilla, Jana Elsässer, Emily Boyle, David M Hollenstein, Jorge Jimenez-Niebla, Jonas Pleyer, Mio Heinrich, Franz-Georg Wieland, Joachim Brenneisen, Christopher Eickhorst, Johann Brenner, Shan Jiang, Markus Hartl, Sonja Welsch, Carola Hunte, Jens Timmer, Florian Wilfling, Claudine Kraft.
      Autophagy is a key cellular quality control mechanism. Nutrient stress triggers bulk autophagy, which nonselectively degrades cytoplasmic material upon formation and liquid-liquid phase separation of the autophagy-related gene 1 (Atg1) complex. In contrast, selective autophagy eliminates protein aggregates, damaged organelles and other cargoes that are targeted by an autophagy receptor. Phase separation of cargo has been observed, but its regulation and impact on selective autophagy are poorly understood. Here, we find that key autophagy biogenesis factors phase separate into initiation hubs at cargo surfaces in yeast, subsequently maturing into sites that drive phagophore nucleation. This phase separation is dependent on multivalent, low-affinity interactions between autophagy receptors and cargo, creating a dynamic cargo surface. Notably, high-affinity interactions between autophagy receptors and cargo complexes block initiation hub formation and autophagy progression. Using these principles, we converted the mammalian reovirus nonstructural protein µNS, which accumulates as particles in the yeast cytoplasm that are not degraded, into a neo-cargo that is degraded by selective autophagy. We show that initiation hubs also form on the surface of different cargoes in human cells and are key to establish the connection to the endoplasmic reticulum, where the phagophore assembly site is formed to initiate phagophore biogenesis. Overall, our findings suggest that regulated phase separation underscores the initiation of both bulk and selective autophagy in evolutionarily diverse organisms.
    DOI:  https://doi.org/10.1038/s41556-024-01572-y
  10. Cells. 2024 Dec 20. pii: 2113. [Epub ahead of print]13(24):
    Structure of the WIPI3/ATG16L1 Complex Reveals the Molecular Basis for the Recruitment of the ATG12~ATG5-ATG16L1 Complex by WIPI3.
    Xinyu Gong, Yingli Wang, Yuqian Zhou, Lifeng Pan.
      Macroautophagy deploys a wealth of autophagy-related proteins to synthesize the double-membrane autophagosome, in order to engulf cytosolic components for lysosome-dependent degradation. The recruitment of the ATG12~ATG5-ATG16L1 complex by WIPI family proteins is a crucial step in autophagosome formation. Nevertheless, the molecular mechanism by which WIPI3 facilitates the recruitment of the ATG12~ATG5-ATG16L1 complex remains largely unknown. Here, we uncover that WIPI3 can directly interact with the coiled-coil domain of ATG16L1. By determining the crystal structure of WIPI3 in complex with ATG16L1 coiled-coil, we elucidate the molecular basis underpinning the specific recruitment of the ATG12~ATG5-ATG16L1 complex by WIPI3. Moreover, we demonstrate that WIPI2 and WIPI3 are competitive for interacting with ATG16L1 coiled-coil, and ATG16L1 and ATG2 are mutually exclusive in binding to WIPI3. In all, our findings provide mechanistic insights into the WIPI3/ATG16L1 interaction, and are valuable for further understanding the activation mechanism of the ATG12~ATG5-ATG16L1 complex as well as the working mode of WIPI3 in autophagy.
    Keywords:  ATG16L1; WIPI3; alternative autophagy; autophagy; macroautophagy
    DOI:  https://doi.org/10.3390/cells13242113
  11. J Transl Med. 2025 Jan 06. 23(1): 18
    Crosstalk between ferroptosis and autophagy: broaden horizons of cancer therapy.
    Xingyu Liu, Halahati Tuerxun, Yixin Zhao, Yawen Li, Shuhui Wen, Xi Li, Yuguang Zhao.
      Ferroptosis and autophagy are two main forms of regulated cell death (RCD). Ferroptosis is a newly identified RCD driven by iron accumulation and lipid peroxidation. Autophagy is a self-degradation system through membrane rearrangement. Autophagy regulates the metabolic balance between synthesis, degradation and reutilization of cellular substances to maintain intracellular homeostasis. Numerous studies have demonstrated that both ferroptosis and autophagy play important roles in cancer pathogenesis and cancer therapy. We also found that there are intricate connections between ferroptosis and autophagy. In this article, we tried to clarify how different kinds of autophagy participate in the process of ferroptosis and sort out the common regulatory pathways between ferroptosis and autophagy in cancer. By exploring the complex crosstalk between ferroptosis and autophagy, we hope to broaden horizons of cancer therapy.
    Keywords:  Autophagy; Cancer therapy; Crosstalk; Ferroptosis
    DOI:  https://doi.org/10.1186/s12967-024-06059-w
  12. Autophagy. 2025 Jan 08.
    PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology.
    Chuang Zhang, Zhanpeng Huang, Xinyue Huang, Yanni Ma, Yifan Cao, Zhixiong Zhang, Rui Wang, Haigang Ren, Longtai Zheng, Chun-Feng Liu, Guanghui Wang.
      The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that PLK2 regulated SNCA pathology independently of S129. Overexpression of PLK2 promoted SNCA preformed fibril (PFF)-induced aggregation of wild-type SNCA and mutant SNCAS129A. Genetic or pharmacological inhibition of PLK2 attenuated SNCA deposition and neurotoxicity. Mechanistically, PLK2 exacerbated the propagation of SNCA pathology by impeding the clearance of SNCA aggregates by blocking macroautophagic/autophagic flux. We further showed that PLK2 phosphorylated S1098 of DCTN1 (dynactin 1), a protein that controls the movement of organelles, leading to impaired autophagosome-lysosome fusion. Furthermore, genetic suppression of PLK2 alleviated SNCA aggregation and motor dysfunction in vivo. Our findings suggest that PLK2 negatively regulates autophagy, promoting SNCA pathology, suggesting a role for PLK2 in PD.
    Keywords:  Autophagic flux; DCTN1; PLK2; autophagosome-lysosome fusion; parkinson disease
    DOI:  https://doi.org/10.1080/15548627.2024.2448914
  13. Phytother Res. 2025 Jan 04.
    Deciphering the Power of Resveratrol in Mitophagy: From Molecular Mechanisms to Therapeutic Applications.
    Hongmei Liu, Yixuan Song, Huan Wang, Ying Zhou, Min Xu, Jiaxun Xian.
      Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its therapeutic potential in various pathological conditions. This review explores how RES modulates mitophagy-the selective autophagic degradation of mitochondria essential for maintaining cellular homeostasis. RES promotes the initiation and execution of mitophagy by enhancing PINK1/Parkin-mediated mitochondrial clearance, reducing reactive oxygen species production, and mitigating apoptosis, thereby preserving mitochondrial integrity. Additionally, RES regulates mitophagy through the activation of key molecular targets such as AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), deacetylases (SIRT1 and SIRT3), and mitochondrial quality control (MQC) pathways, demonstrating substantial therapeutic effects in multiple disease models. We provide a detailed account of the biosynthetic pathways, pharmacokinetics, and metabolic characteristics of RES, focusing on its role in mitophagy modulation and implications for medical applications. Potential adverse effects associated with its clinical use are also discussed. Despite its promising therapeutic properties, the clinical application of RES is limited by issues of bioavailability and pharmacokinetic profiles. Future research should concentrate on enhancing RES bioavailability and developing derivatives that precisely modulate mitophagy, thereby unlocking new avenues for disease therapy.
    Keywords:  AMPK; PINK1/Parkin; SIRT1; disease intervention; mitophagy; resveratrol
    DOI:  https://doi.org/10.1002/ptr.8433
  14. Nat Commun. 2025 Jan 05. 16(1): 403
    ATG8 delipidation is not universally critical for autophagy in plants.
    Yong Zou, Jonas A Ohlsson, Sanjana Holla, Igor Sabljić, Jia Xuan Leong, Florentine Ballhaus, Melanie Krebs, Karin Schumacher, Panagiotis N Moschou, Simon Stael, Suayib Üstün, Yasin Dagdas, Peter V Bozhkov, Elena A Minina.
      Intracellular recycling via autophagy is governed by post-translational modifications of the autophagy-related (ATG) proteins. One notable example is ATG4-dependent delipidation of ATG8, a process that plays critical but distinct roles in autophagosome formation in yeast and mammals. Here, we aim to elucidate the specific contribution of this process to autophagosome formation in species representative of evolutionarily distant green plant lineages: unicellular green alga Chlamydomonas reinhardtii, with a relatively simple set of ATG genes, and a vascular plant Arabidopsis thaliana, harboring expanded ATG gene families. Remarkably, the more complex autophagy machinery of Arabidopsis renders ATG8 delipidation entirely dispensable for the maturation of autophagosomes, autophagic flux, and related stress tolerance; whereas autophagy in Chlamydomonas strictly depends on the ATG4-mediated delipidation of ATG8. Importantly, we also demonstrate the distinct impact of different Arabidopsis ATG8 orthologs on autophagosome formation, especially prevalent under nitrogen depletion, providing new insight into potential drivers behind the expansion of the ATG8 family in higher plants. Our findings underscore the evolutionary diversification of the molecular mechanism governing the maturation of autophagosomes in eukaryotic lineages and highlight how this conserved pathway is tailored to diverse organisms.
    DOI:  https://doi.org/10.1038/s41467-024-55754-1
  15. Front Cell Infect Microbiol. 2024 ;14 1523597
    Breaking the cellular defense: the role of autophagy evasion in Francisella virulence.
    Pavla Pavlik, Eva Velecka, Petra Spidlova.
      Many pathogens have evolved sophisticated strategies to evade autophagy, a crucial cellular defense mechanism that typically targets and degrades invading microorganisms. By subverting or inhibiting autophagy, these pathogens can create a more favorable environment for their replication and survival within the host. For instance, some bacteria secrete factors that block autophagosome formation, while others might escape from autophagosomes before degradation. These evasion tactics are critical for the pathogens' ability to establish and maintain infections. Understanding the mechanisms by which pathogens avoid autophagy is crucial for developing new therapeutic strategies, as enhancing autophagy could bolster the host's immune response and aid in the elimination of pathogenic bacteria. Francisella tularensis can manipulate host cell pathways to prevent its detection and destruction by autophagy, thereby enhancing its virulence. Given the potential for F. tularensis to be used as a bioterrorism agent due to its high infectivity and ability to cause severe disease, research into how this pathogen evades autophagy is of critical importance. By unraveling these mechanisms, new therapeutic approaches could be developed to enhance autophagic responses and strengthen host defense against this and other similarly evasive pathogens.
    Keywords:  Francisella; autophagy; bacterial pathogenesis; host-pathogen interaction; virulence
    DOI:  https://doi.org/10.3389/fcimb.2024.1523597
  16. Aging Cell. 2025 Jan 06. e14448
    Dietary cinnamon promotes longevity and extends healthspan via mTORC1 and autophagy signaling.
    Yuling Guo, Qing Zhang, Bi Zhang, Tong Pan, Elizabeth A Ronan, Anthony Huffman, Yongqun He, Ken Inoki, Jianfeng Liu, X Z Shawn Xu.
      Cinnamon, renowned for its aromatic flavor, represents one of the most widely used spices worldwide. Cinnamon is also considered beneficial to human health with therapeutic potential for treating various diseases, ranging from diabetes and cancer to neurodegenerative diseases. However, the mechanisms underlying cinnamon's health benefits remain elusive. It is also unclear whether cinnamon has any role in aging. Using C. elegans as a model, here we show that feeding worms cinnamaldehyde (CA), the active ingredient in cinnamon oil, prolongs longevity. CA also promotes stress resistance and reduces β-Amyloid toxicity in a C. elegans model of Alzheimer's disease. Mechanistically, CA exerts its beneficial effects through mTORC1 and autophagy signaling. Interestingly, CA promotes longevity by inducing a dietary restriction-like state without affecting food intake, suggesting CA as a dietary restriction mimetic. In human cells, CA exerts a similar effect on mTORC1 and autophagy signaling, suggesting a conserved mechanism. Our results demonstrate that dietary cinnamon promotes both lifespan and healthspan and does so by regulating mTORC1 and autophagy signaling.
    Keywords:   C. elegans ; aging; lifespan; longevity
    DOI:  https://doi.org/10.1111/acel.14448
  17. Biomolecules. 2024 Nov 30. pii: 1537. [Epub ahead of print]14(12):
    Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.
    Hao Chen, Kaitlyn Hinz, Chen Zhang, Yssa Rodriguez, Sha Neisha Williams, Mengwei Niu, Xiaowen Ma, Xiaojuan Chao, Alexandria L Frazier, Kenneth E McCarson, Xiaowan Wang, Zheyun Peng, Wanqing Liu, Hong-Min Ni, Jianhua Zhang, Russell H Swerdlow, Wen-Xing Ding.
      Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. The purpose of this study is to explore whether chronic alcohol consumption worsens the age-related decline in TFEB-mediated lysosomal biogenesis in the brain and exacerbates cognitive decline associated with aging. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month-old) and aged (23-month-old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. Morris Water and Barnes Maze spatial memory tasks were used to characterize the effects of aging and chronic alcohol exposure (mice fed alcohol for 4 weeks). The aged mice showed worse spatial memory acquisition in both tests. Alcohol feeding slightly impaired spatial memory in the young mice, but had little effect or even slightly improved spatial memory acquisition in the aged mice. In conclusion, aging produces greater reductions in brain autophagy flux and impairment of spatial memory than alcohol consumption.
    Keywords:  autophagy; lipid; lysosome; mitochondria; tau aggregation
    DOI:  https://doi.org/10.3390/biom14121537
  18. Cells. 2024 Dec 15. pii: 2069. [Epub ahead of print]13(24):
    Distinct UPR and Autophagic Functions Define Cell-Specific Responses to Proteotoxic Stress in Microglial and Neuronal Cell Lines.
    Helena Domínguez-Martín, Elena Gavilán, Celia Parrado, Miguel A Burguillos, Paula Daza, Diego Ruano.
      Autophagy is a catabolic process involved in different cellular functions. However, the molecular pathways governing its potential roles in different cell types remain poorly understood. We investigated the role of autophagy in the context of proteotoxic stress in two central nervous system cell types: the microglia-like cell line BV2 and the neuronal-like cell line N2a. Proteotoxic stress, induced by proteasome inhibition, produced early apoptosis in BV2 cells, due in part to a predominant activation of the PERK-CHOP pathway. In contrast, N2a cells showcased greater resistance and robust induction of the IRE1α-sXbp1 arm of the UPR. We also demonstrated that proteotoxic stress activated autophagy in both cell lines but with different kinetics and cellular functions. In N2a cells, autophagy restored cellular proteostasis, while in BV2 cells, it participated in regulating phagocytosis. Finally, proteotoxic stress predominantly activated the mTORC2-AKT-FOXO1-β-catenin pathway in BV2 cells, while N2a cells preferentially induced the PDK1-AKT-FOXO3 axis. Collectively, our findings suggest that proteotoxic stress triggers cell-specific responses in microglia and neurons, with different physiological outcomes.
    Keywords:  autophagy; microglia; neurons; phagocytosis; proteasome; proteostasis; proteotoxic stress
    DOI:  https://doi.org/10.3390/cells13242069
  19. Cell Rep. 2025 Jan 07. pii: S2211-1247(24)01542-0. [Epub ahead of print]44(1): 115191
    Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis.
    Kylie R VanDerMolen, Martin A Newman, Peter C Breen, Yunjing Gao, Laura A Huff, Robert H Dowen.
      Organisms allocate energetic resources between essential cellular processes to maintain homeostasis and, in turn, maximize fitness. The nutritional regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in Caenorhabditis elegans. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor TRA-1/GLI, but rather via non-canonical signaling that engages mammalian target of rapamycin complex 2 (mTORC2). Hh mutants display impaired lipid homeostasis, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we find that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation to modulate lipid homeostasis. Our findings reveal a non-canonical role for Hh signaling in lipid metabolism via regulation of core homeostatic pathways.
    Keywords:  C. elegans; CP: Metabolism; Hedgehog; LIN-29; autophagy; growth; hepatocytes; lipid metabolism; mTORC2; p38; vitellogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2024.115191
  20. Biomolecules. 2024 Dec 17. pii: 1614. [Epub ahead of print]14(12):
    Mitophagy in Doxorubicin-Induced Cardiotoxicity: Insights into Molecular Biology and Novel Therapeutic Strategies.
    Heng Zhang, Saiyang Xie, Wei Deng.
      Doxorubicin is a chemotherapeutic drug utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity, including cardiac dilation and heart failure. Mitophagy, a cargo-specific form of autophagy, is specifically used to eliminate damaged mitochondria in autophagosomes through hydrolytic degradation following fusion with lysosomes. Recent advances have unveiled a major role for defective mitophagy in the etiology of DOX-induced cardiotoxicity. Moreover, specific interventions targeting this mechanism to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX-induced cardiotoxicity. However, clinical translation is challenging because of the unclear mechanisms of action and the potential for pharmacological adverse effects. This review aims to offer fresh perspectives on the role of mitophagy in the development of DOX-induced cardiotoxicity and investigate potential therapeutic strategies that focus on this mechanism to improve clinical management.
    Keywords:  cardiotoxicity; doxorubicin; mitochondria; mitophagy; treatment
    DOI:  https://doi.org/10.3390/biom14121614
  21. Arch Gerontol Geriatr. 2024 Dec 31. pii: S0167-4943(24)00413-8. [Epub ahead of print]131 105738
    Mesencephalic astrocyte-derived neurotrophic factor inhibits neuroinflammation through autophagy-mediated α-synuclein degradation.
    Kai-Ge Zhou, Yi-Bin Huang, Zi-Wen Zhu, Ming Jiang, Ling-Jing Jin, Qiang Guan, Lu-Lu Tian, Jing-Xing Zhang.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder marked by the progressive loss of dopamine neurons in the substantia nigra. α-synuclein (SNCA) aggregation-induced microglia activation and neuroinflammation play vital role in the pathology of PD. Our previous studies showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) could inhibit SNCA accumulation and Lipopolysaccharides (LPS)-induced neuroinflammation, but the specific molecular mechanism remains unclear. In this study, we showed that knock-down the expression of MANF leads to the up-regulation of inflammatory factor tumor necrosis factor-α (TNF-α). Exogenous MANF protein inhibits LPS-induced neuroinflammation in BV2 cells. Additionally, our results indicated that knock-down of the expression of MANF triggered autophagic pathway dysfunction, while exogenous addition of MANF protein or using adeno-associated virus 8 (AAV8) mediated MANF over-expression could activate the autophagic system and subsequently suppress SNCA accumulation. Furthermore, using autophagy inhibitor to block autophagic flux, we found that MANF prevented neuroinflammation by autophagy-mediated SNCA degradation. Collectively, this study indicated that MANF has potential therapeutic value for PD. Autophagy and its role in MANF-mediated anti-inflammatory properties may provide new sights that target SNCA pathology in PD.
    Keywords:  Autophagy; Neuroinflammation; Parkinson's disease; α-synuclein
    DOI:  https://doi.org/10.1016/j.archger.2024.105738
  22. Immunol Res. 2025 Jan 07. 73(1): 27
    Inactivation of ATG13 stimulates chronic demyelinating pathologies in muscle-serving nerves and spinal cord.
    Molly E Drosen, Sarojini Bulbule, Gunnar Gottschalk, Daniel Peterson, Linda Adrienne Allen, Leggy A Arnold, Avik Roy.
      Chronic muscle fatigue is a condition characterized by debilitating muscle weakness and pain. Based on our recent finding to study the potential effect of mTOR on ATG13 inactivation in chronic muscle fatigue, we report that biweekly oral administration with MHY1485, a potent inducer of mTOR, develops chronic illness in mice resulting in severe muscle weakness. As a mechanism, we observed that MHY1485 feeding impaired ATG13-dependent autophagy, caused the infiltration of inflammatory M1 macrophages (Mφ), upregulated IL6 and RANTES by STAT3 activation, and augmented demyelination in muscle-serving nerve fibers. Interestingly, these mice displayed worsened muscle fatigue during 2-day post-treadmill exercise, suggesting the critical role of chronic mTOR activation in potential PEM pathogenesis. Interestingly, ATG13-repressor mice exhibited enhanced infiltration of M1Mφ cells, STAT3 activation, demyelination of nerve fibers, and PEM-like symptoms, suggesting the potential role of ATG13 impairment in post-exertional fatigue. HIGHLIGHTS: The potential role of mTOR activation in post-exertional fatigue is highlighted. As a molecular mechanism, mTOR activation augments autophagy impairment via ATG13 inactivation. Autophagy impairment induces IL-6 and RANTES via STAT3, demyelinates nerves in the muscle and spinal cord. ATG13 repressor mice (Tg-ATG13) displayed inflammatory demyelination and post-treadmill fatigue.
    Keywords:  Chronic demyelinating pathologies; ME/CFS; MTOR-ATG13 crosstalk
    DOI:  https://doi.org/10.1007/s12026-024-09557-7
  23. J Clin Med. 2024 Dec 10. pii: 7501. [Epub ahead of print]13(24):
    Controversial Roles of Autophagy in Adenomyosis and Its Implications for Fertility Outcomes-A Systematic Review.
    Julie Vervier, Marlyne Squatrito, Michelle Nisolle, Laurie Henry, Carine Munaut.
      Background/Objectives: Adenomyosis is a benign condition where ectopic endometrial glandular tissue is found within the uterine myometrium. Its impact on women's reproductive outcomes is substantial, primarily due to defective decidualization, impaired endometrial receptivity, and implantation failure. The exact pathogenesis of the disease remains unclear, and the role of autophagy in adenomyosis and its associated infertility is not well understood. The aim of this systematic review was to conduct an exhaustive search of the literature to clarify the role of autophagy in the pathogenesis of adenomyosis. Methods: A systematic search was conducted in Medline, Embase, and Scopus databases up to the date of 20 August 2024. We included all English-written publications assessing the role of autophagy in the pathogenesis of adenomyosis. Results: Seventeen eligible articles were identified, including reviews and experimental studies involving human samples and murine models. The results showed that the role of autophagy in adenomyosis is controversial, with studies showing both increased and decreased levels of autophagy in adenomyosis. Conclusions: Autophagy plays a dual role in cell survival and death. Increased autophagy might support the survival and proliferation of ectopic endometrial cells, while decreased autophagy could prevent cell death, leading to abnormal growth. Oxidative stress may trigger pro-survival autophagy, mitigating apoptosis and promoting cellular homeostasis. Hormonal imbalances disrupt normal autophagic activity, potentially impairing endometrial receptivity and decidualization and contributing to infertility. The balance of autophagy is crucial in adenomyosis, with its dual role contributing to the complexity of the disease. Limitations: A few studies have been conducted with heterogeneous populations, limiting comparative analyses.
    Keywords:  adenomyosis; endometriosis interna; macroautophagy
    DOI:  https://doi.org/10.3390/jcm13247501
  24. mSphere. 2025 Jan 10. e0053724
    Inhibition of Unc-51-like-kinase is mitoprotective during Pseudomonas aeruginosa infection in corneal epithelial cells.
    Rajalakshmy Ayilam Ramachandran, Rossella Titone, Joelle T Abdallah, Mahad Rehman, Mou Cao, Hamid Baniasadi, Danielle M Robertson.
      Pseudomonas aeruginosa (PA) is an opportunistic gram-negative pathogen that can infect the cornea, leading to permanent vision loss. Autophagy is a cannibalistic process that drives cytoplasmic components to the lysosome for degradation and/or recycling. Autophagy has been shown to play a key role in the removal of intracellular pathogens and, as such, is an important component of the innate immune response. Autophagy is intimately linked to mitochondria, organelles that mediate energy homeostasis, immune signaling, and cell death. Using a combination of biochemical and imaging approaches, we investigated the effects of PA on autophagy and host cell mitochondria in relation to pro-inflammatory cytokine expression. Using a standard invasive test strain of PA, we show that PA infection triggers dephosphorylation of the mechanistic target of rapamycin in corneal epithelial cells, leading to the induction of autophagy through ULK1/2. This was associated with robust mitochondrial depolarization, changes in mitochondrial ultrastructure, and an increase in IL-6 and IL-8 secretion. PA infection was also associated with an increase in purine metabolism by host cells. Treatment with the ULK1/2 inhibitor, MRT68921, which blocks phagophore formation, attenuated levels of intracellular PA in corneal epithelial cells. Unexpectedly, treatment of cells with MRT68921 blocked PA-induced mitochondrial depolarization and downregulated purine and pyrimidine metabolism. While MRT68921 attenuated the PA-induced increase in IL-6, it further increased IL-8 and neutrophil chemotaxis. This was associated with the nuclear internalization of NFκB. Taken together, these findings highlight a novel mechanism whereby the inhibition of ULK1/2 activity confers mitoprotection during PA infection in corneal epithelial cells.IMPORTANCEPseudomonas aeruginosa (PA) is a common pathogen that can cause severe disease in man. In the eye, PA infection can lead to blindness. In this study, we show that PA induces autophagy, a mechanism whereby cells recycle damaged proteins and organelles. PA infection further depolarizes mitochondria, leading to the release of pro-inflammatory mediators. Unexpectedly, the inhibition of ULK1/2, an enzyme involved in the early stages of autophagy, not only inhibits autophagy but enhances mitochondrial polarization. This leads to a reduction in intracellular levels of PA and changes in the inflammatory milieu. Together, these data suggest that the inhibition of ULK1/2 may be mitoprotective in corneal epithelial cells during PA infection.
    Keywords:  Pseudomonas; autophagy; cornea; infection; mitochondria
    DOI:  https://doi.org/10.1128/msphere.00537-24
  25. Genes Dis. 2025 Mar;12(2): 101429
    TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.
    Xin He, Mulan Chen, Yepeng Fan, Bin Wu, Zhifang Dong.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.
    Keywords:  Autophagy; Mitochondrial biogenesis; Mitophagy; Parkinson's disease; TFE3; α-synuclein
    DOI:  https://doi.org/10.1016/j.gendis.2024.101429
  26. Biomolecules. 2024 Dec 06. pii: 1557. [Epub ahead of print]14(12):
    Amino Acid Metabolism and Autophagy in Atherosclerotic Cardiovascular Disease.
    Yuting Wu, Irem Avcilar-Kücükgöze, Donato Santovito, Dorothee Atzler.
      Cardiovascular disease is the most common cause of mortality globally, accounting for approximately one out of three deaths. The main underlying pathology is atherosclerosis, a dyslipidemia-driven, chronic inflammatory disease. The interplay between immune cells and non-immune cells is of great importance in the complex process of atherogenesis. During atheroprogression, intracellular metabolic pathways, such as amino acid metabolism, are master switches of immune cell function. Autophagy, an important stress survival mechanism involved in maintaining (immune) cell homeostasis, is crucial during the development of atherosclerosis and is strongly regulated by the availability of amino acids. In this review, we focus on the interplay between amino acids, especially L-leucine, L-arginine, and L-glutamine, and autophagy during atherosclerosis development and progression, highlighting potential therapeutic perspectives.
    Keywords:  amino acids; atherosclerosis; autophagy; cardiovascular disease
    DOI:  https://doi.org/10.3390/biom14121557
  27. Elife. 2025 Jan 07. pii: RP100928. [Epub ahead of print]13
    Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function.
    Masroor Ahmad Paddar, Fulong Wang, Einar S Trosdal, Emily Hendrix, Yi He, Michelle R Salemi, Michal Mudd, Jingyue Jia, Thabata Duque, Ruheena Javed, Brett S Phinney, Vojo Deretic.
      ATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here, we show that ATG5 associates with retromer's core components VPS26, VPS29, and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors.
    Keywords:  active tuberculosis; atg8ylation; autophagy; cell biology; glucose transport; human; latent tuberculosis; membrane transport; mouse
    DOI:  https://doi.org/10.7554/eLife.100928
  28. Antioxid Redox Signal. 2025 Jan 09.
    CCAAT/Enhancer-Binding Protein Beta Nitration Participates in Hyperhomocysteinemia-Induced Cardiomyocyte Autophagic Flux Blockage by Inhibiting Transcription Factor EB Transcription.
    Jiayin Chai, Jiahui Xu, Shangyue Zhang, Wenjing Yan, Shuai Chen, Xinyu Zhu, Chenghua Luo, Wen Wang.
      Aims: Autophagy is a protective mechanism of cardiomyocytes. Hyperhomocysteinemia (HHcy) elevates oxidative and nitrosative stress levels, leading to an abnormal increase in nitration protein, possibly leading to abnormal autophagy regulation in cardiomyocytes. However, the regulatory effect of HHcy on autophagy at the post-translational modification level is still unclear. Here, we aimed to explore the regulatory mechanism of HHcy on transcription factor EB (TFEB) and nitration of CCAAT/enhancer-binding protein beta (C/EBPβ), a transcriptional repressor of Tfeb, on autophagy in cardiomyocytes. Results: In this study, we established the HHcy rat model by feeding a 2.5% (w/w) methionine diet. The nitration level of C/EBPβ was increased in HHcy, which promoted the entry of C/EBPβ into the nucleus, enhanced the transcriptional suppressive effect of C/EBPβ on Tfeb, and induced insufficient autophagy in cardiomyocytes. Furthermore, we confirmed that the Tyr 274 site of C/EBPβ could undergo nitration induced by HHcy. Once C/EBPβ was nitrated on the Tyr 274 site, the nuclear translocation of C/EBPβ and transcription suppressor function of C/EBPβ on Tfeb were enhanced. Innovation and Conclusion: We find that C/EBPβ is a transcriptional repressor of Tfeb, and HHcy induces the nitration at the Tyr 274 site of C/EBPβ, leading to autophagic flux blockage in cardiomyocytes. These data indicated that nitrated C/EBPβ might be a potential therapeutic target against HHcy-induced autophagy insufficiency of cardiomyocytes. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  C/EBPβ; TFEB; autophagy; hyperhomocysteinemia; nitration
    DOI:  https://doi.org/10.1089/ars.2023.0517
  29. FASEB J. 2025 Jan 15. 39(1): e70295
    Hantaan virus glycoprotein Gc induces NEDD4-dependent PTEN ubiquitination and degradation to escape the restriction of autophagosomes and facilitate viral propagation.
    Shuang Lu, Shuliang Chen, Yuqing Zhang, Xiaoli Mou, Mingyang Li, Shaowei Zhu, Xingyuan Chen, Tomas M Strandin, Yale Jiang, Zhoufu Xiang, Yuanyuan Liu, Hairong Xiong, Deyin Guo, Liangjun Chen, Yirong Li, Wei Hou, Fan Luo.
      Hantaan virus (HTNV) infection causes severe hemorrhagic fever with renal syndrome (HFRS) in humans and the infectious process can be regulated by autophagy. The phosphatase and tensin homolog (PTEN) protein has antiviral effects and plays a critical role in the autophagy pathway. However, the relationship between PTEN and HTNV infection is not clear and whether PTEN-regulated autophagy involves in HTNV replication is unknown. Here, we identified that HTNV infection inhibits PTEN expression in vitro and in vivo. The HTNV glycoprotein Gc promotes PTEN ubiquitination and degradation through 26S-proteasome pathway via the E3 ubiquitin ligase NEDD4. In addition, knockdown of PTEN prevents autophagy and increases HTNV production, while overexpression of PTEN induces autophagosome formation which can wrap HTNV particles, thus leading to restrain the production of progeny viruses. Altogether, our findings reveal the role of PTEN in HTNV infection by autophagy, highlighting the potential importance of PTEN and autophagy in the treatment of HFRS diseases.
    Keywords:  HFRS; Hantaan virus; NEDD4; PTEN; autophagy; ubiquitination
    DOI:  https://doi.org/10.1096/fj.202401916R
  30. Biochem Biophys Res Commun. 2024 Dec 27. pii: S0006-291X(24)01790-X. [Epub ahead of print]747 151254
    ATG9 promotes autophagosome formation through interaction with LC3.
    Peiqi Xu, Ting Zhang, Fangfang Yu, Lixia Guo, Yanan Yang.
      The autophagosome is a double-membrane organelle that executes macroautophagy. Previous studies have shown that the autophagosome formation is driven by autophagy-related genes, among which ATG9 is the only conserved transmembrane protein and has been shown to play a critical role in the autophagosome formation. However, how ATG9 binds to the growing autophagosome membrane has remained uncertain. Herein, we report that ATG9 binds to LC3, an essential membrane component of the autophagosome, thereby allowing ATG9 to incorporate into the autophagosome membrane. Mechanistically, we show that ATG9 interacts with LC3 through its UIM motives, which bind to the UDS site of LC3. Interrupting such UIM-UDS interaction abolishes the autophagosome association of ATG9 and suppresses the autophagosome formation. Collectively, our findings reveal a novel mechanism regulating autophagosome biogenesis and suggest that the interaction of ATG9 with LC3 is critical for ATG9 binding to the growing autophagosome membrane.
    Keywords:  ATG9; Autophagosome; LC3; UDS; UIM
    DOI:  https://doi.org/10.1016/j.bbrc.2024.151254
  31. Toxicology. 2025 Jan 03. pii: S0300-483X(25)00001-0. [Epub ahead of print] 154045
    Acidosis induces autophagic cell death through ASIC1-mediated Akt/mTOR signaling in HT22 neurons.
    Miao Guo, Ming-Yue Qiu, Lin Zeng, Ya-Xiong Nie, Ya-Ling Tang, Yan Luo, Hong-Feng Gu.
      Although it has been confirmed that acid-sensing ion channel 1 (ASIC1) plays a critical role in acidosis-induced neuronal injury and death, its underlying mechanisms remain largely unclear. In the present study, we investigated the involvement of ASIC1 in acidosis-induced neuronal death and its underlying mechanisms in HT22 neurons. The neurons were cultured in acidic medium to mimic extracellular acidosis. Cell viability and death, autophagy, ASIC1 expression, and the phosphorylation of Akt and mTOR were evaluated. Our results demonstrated that acidosis markedly increased the cell death rate, which was profoundly reversed by 3-MA (an autophagy inhibitor) but exacerbated by rapamycin (an autophagy activator). Moreover, our results indicated that acidosis induced excessive autophagy by increasing the expression and translocation of ASIC1, and decreasing the phosphorylation of the Akt and mTOR proteins. Intriguingly, inhibiting the activation of ASIC1 with its blocker PcTx-1 not only significantly decreased acidosis-induced neurotoxicity but also markedly compromised acidosis-induced autophagy and Akt/mTOR signaling inactivation, as evidenced by a decrease in the neuronal death rate, LC3Ⅱ/LC3Ⅰ ratio, and autophagosome number as well as p62 degradation and an increase in the phosphorylation of Akt and mTOR. Collectively, these results indicate that acidosis exerts its cytotoxic effects on HT22 neurons by inducing autophagic cell death through the ASIC1-related Akt/mTOR signaling pathway.
    Keywords:  ASIC1; Acidosis; Akt/mTOR; autophagic cell death; autophagy; neuron
    DOI:  https://doi.org/10.1016/j.tox.2025.154045
  32. Clin Exp Pharmacol Physiol. 2025 Mar;52(3): e70010
    Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation.
    Ping Wang, Jiaxin Li, Chun Guang Li, Xian Zhou, Xiaolong Chen, Minghua Zhu, Hongjiang Wang.
      Exercise activates autophagy and lysosome system in skeletal muscle, which are known to play an important role in metabolic adaptation. However, the mechanism of exercise-activated autophagy and lysosome system in obese insulin resistance remains covert. In this study, we investigated the role of exercise-induced activation of autophagy and lysosome system in improving glucose metabolism of skeletal muscle. Male C57BL/6 mice were randomly divided into five groups: the chow diet (CD) group, the high-fat diet (HFD) group, the high-fat diet plus exercise (HFD-E) group and the HFD-E treated with calcineurin inhibitor FK506 (HFD-E-F) or saline (HFD-E-S) groups. The mice in exercise groups (HFD-E, HFD-E-F and HFD-E-S) were subjected to aerobic treadmill exercise (speed at 12 m/min for 1 h per session, 0° slope, 5 days per week for 12 weeks). Mice of HFD-E-F group were intraperitoneally administered FK506 (1 mg/kg), once each day for 2 weeks before the end of exercise. Expressions pTFEB, T-TFEB and autophagy-lysosome markers, including Beclin1, LC3, ULK1, SQSTM1, LAMP1, CTSD and CTSL proteins in gastrocnemius muscle were analysed. We demonstrated that HFD induced insulin resistance and decreased autophagy-lysosomal proteins and the exercise significantly increased transcription factor EB (TFEB) translocation from the cytoplasm to the nucleus, restored the impaired autophagy-lysosomal-related protein expressions, and improved glucose metabolism. The increase in TFEB nuclear translocation was partly blocked by the calcineurin inhibitor FK506. Our results suggest that exercise promotes autophagy and lysosome restoration by regulating calcineurin-mediated TFEB nuclear translocation, ultimately alleviating HFD-induced insulin resistance in mice skeletal muscle.
    Keywords:  TFEB; autophagy and lysosome dysfunction; exercise; insulin resistance
    DOI:  https://doi.org/10.1111/1440-1681.70010
  33. Hepatology. 2025 Jan 10.
    Ubiquitination of TFEB increased intestinal permeability to aggravate metabolic dysfunction-associated steatohepatitis.
    Donghai Liu, Lang Chen, Zai Wang, Zecheng Li, Lihong Liu, Liang Peng.
       BACKGROUND AND AIMS: Increased intestinal permeability exacerbates the development of metabolic dysfunction associated steatohepatitis (MASH), but the underlying mechanisms remain unclear. Autophagy is important for maintaining normal intestinal permeability. Here, we investigated the impact of intestinal transcription factor EB (TFEB), a key regulator of autophagy, in intestinal permeability and MASH progression.
    METHODS: TFEB expression was analyzed in the proximal colon of 45 individuals with metabolic dysfunction associated steatotic liver disease and 23 healthy controls. We utilized immunoprecipitation-mass spectrometry toidentify TFEB-interacting proteins. Intestine-specific Tfeb knockout mice were generated by mating Tfebfl/fl mice with Villin-Cre mice. The mice were fed a high-fat, high-sucrose diet, and assessments were performed to evaluate intestinal permeability and MASH progression.
    RESULTS: Intestinal TFEB levels were reduced in MASH patients and negatively correlated with intestinal permeability and hepatic toxicity. Intestine-specific TFEB deficiency increased intestinal permeability and worsened MASH severity, whereas moderate TFEB overexpression conferred protective effects. Mechanistically, the E3 ligase TRIP12 promotes the ubiquitination and degradation of nuclear TFEB, thereby inhibiting autophagic flux to aggravate intestinal barrier impairment and subsequently promote MASH progression. Importantly, a peptide PT1 designed to block the TRIP12-TFEB interaction reduced MASH progression.
    CONCLUSIONS: The ubiquitination of TFEB plays a pivotal role in increasing intestinal permeability and promoting the progression of MASH by inhibiting autophagy. Intestinal TFEB may represent a novel therapeutic target for the treatment of MASH.
    DOI:  https://doi.org/10.1097/HEP.0000000000001214
  34. EMBO J. 2025 Jan 06.
    RHEB neddylation by the UBE2F-SAG axis enhances mTORC1 activity and aggravates liver tumorigenesis.
    Fengwu Zhang, Xiufang Xiong, Zhijian Li, Haibo Wang, Weilin Wang, Yongchao Zhao, Yi Sun.
      Small GTPase RHEB is a well-known mTORC1 activator, whereas neddylation modifies cullins and non-cullin substrates to regulate their activity, subcellular localization and stability. Whether and how RHEB is subjected to neddylation modification remains unknown. Here, we report that RHEB is a substrate of NEDD8-conjugating E2 enzyme UBE2F. In cell culture, UBE2F depletion inactivates mTORC1, inhibiting cell cycle progression, cell growth and inducing autophagy. Mechanistically, UBE2F cooperates with E3 ligase SAG in neddylation of RHEB at K169 to enhance its lysosome localization and GTP-binding affinity. Furthermore, liver-specific Ube2f knockout attenuates steatosis and tumorigenesis induced by Pten loss in an mTORC1-dependent manner, suggesting a causal role of UBE2F in liver tumorigenesis. Finally, UBE2F expression levels and mTORC1 activity correlate with patient survival in hepatocellular carcinoma. Collectively, our study identifies RHEB as neddylation substrate of the UBE2F-SAG axis, and highlights the UBE2F-SAG axis as a potential target for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma.
    Keywords:  Liver Steatosis and Tumorigenesis; Neddylation; RHEB; UBE2F; mTORC1
    DOI:  https://doi.org/10.1038/s44318-024-00353-5
  35. Acta Neuropathol Commun. 2025 Jan 04. 13(1): 2
    Gain-of-function ANXA11 mutation cause late-onset ALS with aberrant protein aggregation, neuroinflammation and autophagy impairment.
    Qing Liu, Ye Sun, Baodong He, Haodong Chen, Lijing Wang, Gaojie Wang, Kang Zhang, Ximeng Zhao, Xinzhe Zhang, Dongchao Shen, Xue Zhang, Liying Cui.
      Mutations in the ANXA11 gene, encoding an RNA-binding protein, have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the underlying in vivo mechanisms remain unclear. This study examines the clinical features of ALS patients harboring the ANXA11 hotspot mutation p.P36R, characterized by late-onset motor neuron disease and occasional multi-system involvement. To elucidate the pathogenesis, we developed a knock-in mouse model carrying the p.P36R mutation. In both heterozygous and homozygous mutant mice, ANXA11 protein levels were comparable to those in wild-type. Both groups exhibited late-onset motor dysfunction at approximately 10 months of age, with similar survival rates to wild-type (> 24 months) and no signs of dementia. Pathological analysis revealed early abnormal aggregates in spinal cord motor neurons, cortical neurons, and muscle cells of homozygous mice. From 2 months of age, we observed mislocalized ANXA11 aggregates, SQSTM1/p62-positive inclusions, and cytoplasmic TDP-43 mislocalization, which intensified with disease progression. Importantly, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions. Electron microscopy of the gastrocnemius muscle uncovered myofibrillar abnormalities, including sarcomeric disorganization, Z-disc dissolution, and subsarcolemmal electron-dense structures within autophagic vacuoles. Autophagic flux, initially intact at 2 months, was impaired by 9 months, as evidenced by decreased Beclin-1 and LC3BII/I levels and increased SQSTM1/p62 expression, coinciding with mTORC1 hyperactivation. Significant motor neuron loss and neuroinflammation were detected by 9 months, with marked muscle dystrophy apparent by 12 months compared to wild-type controls. These findings implicate the gain-of-function ANXA11 mutation drives late-onset motor neuron disease by early presymptomatic proteinopathy, progressive neuronal degeneration, neuroinflammation, and autophagic dysfunction.
    Keywords:  ANXA11; Amyotrophic lateral sclerosis; Autophagy; Mouse model; Neuroinflammation; TDP-43 proteinopathy
    DOI:  https://doi.org/10.1186/s40478-024-01919-4
  36. Pharmaceuticals (Basel). 2024 Dec 12. pii: 1677. [Epub ahead of print]17(12):
    Targeting mTOR Kinase with Natural Compounds: Potent ATP-Competitive Inhibition Through Enhanced Binding Mechanisms.
    Sulaiman K Marafie, Eman Alshawaf, Fahd Al-Mulla, Jehad Abubaker, Anwar Mohammad.
      Background/Objectives: The mammalian target of the rapamycin (mTOR) signaling pathway is a central regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling contributes to many human diseases, including cancer, diabetes, and obesity. Therefore, inhibitors against mTOR's catalytic kinase domain (KD) have been developed and have shown significant antitumor activities, making it a promising therapeutic target. The ATP-KD interaction is particularly important for mTOR to exert its cellular functions, and such inhibitors have demonstrated efficient attenuation of overall mTOR activity. Methods: In this study, we screened the Traditional Chinese Medicine (TCM) database, which enlists natural products that capture the relationships between drugs targets and diseases. Our aim was to identify potential ATP-competitive agonists that target the mTOR-KD and compete with ATP to bind the mTOR-KD serving as potential potent mTOR inhibitors. Results: We identified two compounds that demonstrated interatomic interactions similar to those of ATP-mTOR. The conformational stability and dynamic features of the mTOR-KD bound to the selected compounds were tested by subjecting each complex to 200 ns molecular dynamic (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA) to extract free binding energies. We show the effectiveness of both compounds in forming stable complexes with the mTOR-KD, which is more effective than the mTOR-KD-ATP complex with more robust binding affinities. Conclusions: This study implies that both compounds could serve as potential therapeutic inhibitors of mTOR, regulating its function and, therefore, mitigating human disease progression.
    Keywords:  ATP; kinase domain; mTOR; mTOR inhibitors; molecular simulation; natural compounds
    DOI:  https://doi.org/10.3390/ph17121677
  37. CNS Neurosci Ther. 2025 Jan;31(1): e70191
    Impact of LITAF on Mitophagy and Neuronal Damage in Epilepsy via MCL-1 Ubiquitination.
    Fuli Min, Zhaofei Dong, Shuisheng Zhong, Ze Li, Hong Wu, Sai Zhang, Linming Zhang, Tao Zeng.
       OBJECTIVE: This study aims to investigate how the E3 ubiquitin ligase LITAF influences mitochondrial autophagy by modulating MCL-1 ubiquitination, and its role in the development of epilepsy.
    METHODS: Employing single-cell RNA sequencing (scRNA-seq) to analyze brain tissue from epilepsy patients, along with high-throughput transcriptomics, we identified changes in gene expression. This was complemented by in vivo and in vitro experiments, including protein-protein interaction (PPI) network analysis, western blotting, and behavioral assessments in mouse models.
    RESULTS: Neuronal cells in epilepsy patients exhibited significant gene expression alterations, with increased activity in apoptosis-related pathways and decreased activity in neurotransmitter-related pathways. LITAF was identified as a key upregulated factor, inhibiting mitochondrial autophagy by promoting MCL-1 ubiquitination, leading to increased neuronal damage. Knockdown experiments in mouse models further confirmed that LITAF facilitates MCL-1 ubiquitination, aggravating neuronal injury.
    CONCLUSION: Our findings demonstrate that LITAF regulates MCL-1 ubiquitination, significantly impacting mitochondrial autophagy and contributing to neuronal damage in epilepsy. Targeting LITAF and its downstream mechanisms may offer a promising therapeutic strategy for managing epilepsy.
    Keywords:  LPS‐induced TNF‐alpha factor; MCL1; epilepsy; mitochondrial autophagy; neuroprotection; ubiquitination regulation
    DOI:  https://doi.org/10.1111/cns.70191
  38. J Med Chem. 2025 Jan 06.
    Structure-Activity Relationship Studies of an Autophagy Inhibitor That Targets the ATG14L-Beclin1 Protein-Protein Interaction Reveal Modifications That Improve Potency and Solubility and Maintain Selectivity.
    Ryan S Hippman, Qiwen Gao, Andrea Arrieche Suarez, Victoria Soliz, Ivan Pavlinov, Gautami Sonarikar, Leslie N Aldrich.
      Autophagy, a recycling process in eukaryotes, contributes to tumor growth and metastasis by alleviating cellular stress and facilitating survival and chemoresistance. The development of small molecules that selectively inhibit this pathway has proven challenging and is required to determine if autophagy inhibition can be harnessed as an effective therapeutic strategy in cancer. Compound 19 was previously identified as a selective autophagy inhibitor that targets the ATG14L-Beclin1 protein-protein interaction, which regulates the formation, localization, and function of VPS34 Complex I to initiate autophagy. Importantly, Compound 19 does not inhibit the UVRAG-Beclin1 protein-protein interaction in VPS34 Complex II that regulates vesicle trafficking, thus overcoming a major limitation of targeting VPS34 lipid kinase activity. Subsequent development of strategies to synthesize Compound 19 analogues has enabled the evaluation of structure-activity relationships, revealing key regions and moieties that impact the properties of Compound 19 and impart selectivity for VPS34 Complex I over Complex II.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c02312
  39. EMBO J. 2025 Jan 06.
    Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.
    Viviana Buonomo, Kateryna Lohachova, Alessio Reggio, Sara Cano-Franco, Michele Cillo, Lucia Santorelli, Rossella Venditti, Elena Polishchuk, Ivana Peluso, Lorene Brunello, Carmine Cirillo, Sara Petrosino, Malan Silva, Rossella De Cegli, Sabrina Di Bartolomeo, Cesare Gargioli, Paolo Swuec, Mirko Cortese, Alexandra Stolz, Ramachandra M Bhaskara, Paolo Grumati.
      Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, is an important regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER is reorganized. Knocking out both FAM134B isoforms in myotubes results in an aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine-tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells.
    Keywords:  Autophagy; Endoplasmic Reticulum; FAM134B; Myogenesis; Reticulophagy
    DOI:  https://doi.org/10.1038/s44318-024-00356-2
  40. Cell Commun Signal. 2025 Jan 07. 23(1): 8
    Autophagy mediated by ROS-AKT-FoxO pathway is required for intestinal regeneration in echinoderms.
    Chuili Zeng, Ming Guo, Ke Xiao, Chenghua Li.
      Autophagy is essential for maintaining material balance and energy circulation and plays a critical role as a regulatory mechanism in tissue regeneration. However, current studies primarily describe this phenotype, with limited exploration of its molecular mechanisms. In this study, we provided the first evidence that autophagy is required for intestinal regeneration in Apostichopus japonicus and identified a previously unrecognized regulatory mechanism involved in this process. We observed that autophagy activation was significantly associated with enhanced regeneration, and its upregulation was shown to be regulated by reactive oxygen species (ROS) bursts. Mechanistically, ROS induced the dephosphorylation of Forkhead box protein O (FoxO) through AjAKT dephosphorylation. The dephosphorylated AjFoxO translocated to the nucleus, where it bound to the promoters of AjLC3 and AjATG4, inducing their transcription. This study highlights the ROS-AjAKT-AjFoxO-AjATG4/AjLC3 pathway as a novel regulatory mechanism underlying autophagy-mediated intestinal regeneration in echinoderms, providing a reference for studying regenerative processes and cytological mechanisms in economically important echinoderms.
    Keywords:   Apostichopus japonicus ; Autophagy; Forkhead box protein O; Intestine regeneration
    DOI:  https://doi.org/10.1186/s12964-024-01993-0
  41. J Cell Sci. 2025 Jan 08. pii: jcs.263676. [Epub ahead of print]
    Mitochondrial phosphatase PPTC7 promotes EGFR recycling by facilitating VPS4A endosomal localization.
    Rahul Baroi, Hilal Ahmad Reshi, SubbaReddy Maddika.
      PPTC7 is a mitochondrial phosphatase that is essential for mitochondrial biogenesis, metabolism, protein content maintenance and transport. While the mitochondrial roles of PPTC7 are well-characterized, its roles outside the mitochondria are unclear. Here we identified a non-mitochondrial role for PPTC7 in regulating epidermal growth factor receptor (EGFR) trafficking. PPTC7 interacts with and dephosphorylates VPS4A, a critical ESCRT and multivesicular body-associated protein. PPTC7-mediated dephosphorylation of VPS4A at Serine 335 is required for VPS4A stability and its early endosomal localization. Either loss of PPTC7 or presence of constitutively phosphorylated VPS4A leads to defective recycling of EGFR, thus leading to EGFR re-routing to lysosomes for degradation. Further, we demonstrate that PPTC7-VPS4A-dependent EGFR recycling promotes the AKT signaling pathway thus enhancing cell proliferation and migration. Overall, our studies unveil an important mechanism where the PPTC7-VPS4A complex orchestrates an endosomal switch to promote EGFR recycling.
    Keywords:  EGFR; Endosome; Mitogen signaling; PPTC7; Receptor recycling; VPS4A
    DOI:  https://doi.org/10.1242/jcs.263676
  42. Antioxidants (Basel). 2024 Dec 04. pii: 1482. [Epub ahead of print]13(12):
    Spermidine Enhances Mitochondrial Bioenergetics in Young and Aged Human-Induced Pluripotent Stem Cell-Derived Neurons.
    Leonora Szabo, Imane Lejri, Amandine Grimm, Anne Eckert.
      The accumulation of damaged mitochondria has long been considered a hallmark of the aging process. Among various factors, age-related mitochondrial alterations comprise bioenergetic impairments and disturbances in reactive oxygen species (ROS) control, thereby negatively affecting mitochondrial performance and ultimately accelerating aging. Previous studies have revealed that polyamine spermidine appears to exert health-protective and lifespan-promoting effects. Notably, recent findings have also described a spermidine-induced improvement in age-associated mitochondrial dysfunction, but the beneficial effects of spermidine on aged mitochondria have not been entirely examined yet. Here, we show that spermidine positively regulates several parameters related to mitochondrial bioenergetics and mitochondrial redox homeostasis in young and aged human-induced pluripotent stem cell-derived neurons. We report that spermidine treatment increases adenosine triphosphate production and mitochondrial membrane potential, which is accompanied by an attenuation in mitochondrial ROS levels in both age groups. Furthermore, we demonstrate a spermidine-mediated amelioration in mitochondrial respiration in both young and aged neurons. Overall, our findings suggest that nutritional spermidine supplementation might represent an attractive therapeutic approach to enhance mitochondrial function, consequently decelerating aging.
    Keywords:  aging; bioenergetics; induced pluripotent stem cell-derived neurons; mitochondria; oxidative stress; spermidine
    DOI:  https://doi.org/10.3390/antiox13121482
  43. bioRxiv. 2024 Dec 16. pii: 2024.12.16.628616. [Epub ahead of print]
    Tax1bp1 enhances bacterial virulence and promotes inflammatory responses during Mycobacterium tuberculosis infection of alveolar macrophages.
    Jeffrey Chin, Nalin Abeydeera, Teresa Repasy, Rafael Rivera-Lugo, Gabriel Mitchell, Vinh Q Nguyen, Weihao Zheng, Alicia Richards, Danielle L Swaney, Nevan J Krogan, Joel D Ernst, Jeffery S Cox, Jonathan M Budzik.
      Crosstalk between autophagy, host cell death, and inflammatory host responses to bacterial pathogens enables effective innate immune responses that limit bacterial growth while minimizing coincidental host damage. Mycobacterium tuberculosis ( Mtb ) thwarts innate immune defense mechanisms in alveolar macrophages (AMs) during the initial stages of infection and in recruited bone marrow-derived cells during later stages of infection. However, how protective inflammatory responses are achieved during Mtb infection and the variation of the response in different macrophage subtypes remain obscure. Here, we show that the autophagy receptor Tax1bp1 plays a critical role in enhancing inflammatory cytokine production and increasing the susceptibility of mice to Mtb infection. Surprisingly, although Tax1bp1 restricts Mtb growth during infection of bone marrow-derived macrophages (BMDMs) (Budzik et al. 2020) and terminates cytokine production in response to cytokine stimulation or viral infection, Tax1bp1 instead promotes Mtb growth in AMs, neutrophils, and a subset of recruited monocyte-derived cells from the bone marrow. Tax1bp1 also leads to increases in bacterial growth and inflammatory responses during infection of mice with Listeria monocytogenes , an intracellular pathogen that is not effectively targeted to canonical autophagy. In Mtb- infected AMs but not BMDMs, Tax1bp1 enhances necrotic-like cell death early after infection, reprogramming the mode of host cell death to favor Mtb replication in AMs. Tax1bp1's impact on host cell death is a mechanism that explains Tax1bp1's cell type-specific role in the control of Mtb growth. Similar to Tax1bp1- deficiency in AMs, the expression of phosphosite-deficient Tax1bp1 restricts Mtb growth. Together, these results show that Tax1bp1 plays a crucial role in linking the regulation of autophagy, cell death, and pro-inflammatory host responses and enhancing susceptibility to bacterial infection.
    Author Summary: Although macrophages are the first innate immune cells to encounter Mycobacterium tuberculosis during infection, M. tuberculosis has evolved the ability to persist in them. Recent studies highlight that some types of macrophages are more permissive to M. tuberculosis replication and survival than others, but the mechanisms for cell type-specific differences in M. tuberculosis growth are only beginning to be understood. We found that the host factor, Tax1bp1 (Tax-1 binding protein 1), supports M. tuberculosis growth during animal infection and in specific subsets of innate immune cells, including alveolar macrophages while restricting M. tuberculosis in bone marrow-derived macrophages. We also found that Tax1bp1 has a similar phenotype in enhancing the pathogenesis of another intracellular pathogen, Listeria monocytogenes. Compared to bone marrow-derived macrophages, in alveolar macrophages, Tax1bp1 enhances the release of inflammatory mediators and leads to necrotic-like host cell death, which is known to enhance M. tuberculosis growth. Phosphorylation of Tax1bp1 in alveolar macrophages promotes M. tuberculosis growth. Our research highlights that Tax1bp1 is a host target for host-directed therapy against M. tuberculosis and controls host responses to M. tuberculosis in a cell type-specific manner.
    DOI:  https://doi.org/10.1101/2024.12.16.628616
  44. Nature. 2025 Jan;637(8045): E11-E14
    Amino acids and KLHL22 do not activate mTORC1 via DEPDC5 degradation.
    Max L Valenstein, Pranav V Lalgudi, Jibril F Kedir, Kendall J Condon, Anna Platzek, Daniel G Freund, Martin S Taylor, Yunhan Xu, Raghu R Chivukula, David M Sabatini.
      
    DOI:  https://doi.org/10.1038/s41586-024-07974-0
  45. Nutrients. 2024 Dec 11. pii: 4282. [Epub ahead of print]16(24):
    The Effect of Quercetin on Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Beclin1, P62, and LC3: An Experimental Study.
    Ioannis Katsaros, Maria Sotiropoulou, Michail Vailas, Fotini Papachristou, Paraskevi Papakyriakopoulou, Marirena Grigoriou, Nikolaos Kostomitsopoulos, Alexandra Giatromanolaki, Georgia Valsami, Alexandra Tsaroucha, Dimitrios Schizas.
      Background/Objectives: Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder with no established pharmacotherapy. Quercetin, a polyphenolic flavonoid, demonstrates potential hepatoprotective effects but has limited bioavailability. This study evaluates the impact of quercetin on NAFLD and assesses the roles of autophagy-related proteins in disease progression. Methods: Forty-seven male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce NAFLD, followed by quercetin treatment for 4 weeks. Mice were divided into baseline, control, and two quercetin groups, receiving low (10 mg/kg) and high (50 mg/kg) doses. Liver histology was scored using the NAFLD Activity Score (NAS). Immunohistochemistry and immunoblotting were performed to analyze autophagy markers. Results: Quercetin-treated groups showed significant reductions in NAS compared to controls (p = 0.011), mainly in steatosis and steatohepatitis. Immunohistochemistry indicated increased expression of autophagy markers LCA and p62 in quercetin groups. Western blot analysis revealed significant elevations in LC3A in the treated groups, suggesting improved autophagic activity and lipid degradation. Conclusions: Quercetin effectively reduces NAFLD severity and modulates autophagy-related proteins. These findings suggest that quercetin enhances autophagic flux, supporting its therapeutic potential for NAFLD. Additional research is needed to clarify the molecular mechanisms of quercetin and to determine the optimal dosing for clinical application.
    Keywords:  Beclin1; LC3; MASLD; NAFLD; SQSTM1; autophagy; p62; quercetin
    DOI:  https://doi.org/10.3390/nu16244282
  46. Nat Aging. 2025 Jan 08.
    Modulating mTOR-dependent astrocyte substate transitions to alleviate neurodegeneration.
    Liansheng Zhang, Zhengzheng Xu, Zhiheng Jia, Shicheng Cai, Qiang Wu, Xingyu Liu, Xinde Hu, Tao Bai, Yongyu Chen, Tianwen Li, Zhen Liu, Bin Wu, Jianhong Zhu, Haibo Zhou.
      Traditional approaches to studying astrocyte heterogeneity have mostly focused on analyzing static properties, failing to identify whether subtypes represent intermediate or final states of reactive astrocytes. Here we show that previously proposed neuroprotective and neurotoxic astrocytes are transitional states rather than distinct subtypes, as revealed through time-series multiomic sequencing. Neuroprotective astrocytes are an intermediate state of the transition from a nonreactive to a neurotoxic state in response to neuroinflammation, a process regulated by the mTOR signaling pathway. In Alzheimer's disease (AD) and aging, we observed an imbalance in neurotoxic and neuroprotective astrocytes in animal models and human patients. Moreover, targeting mTOR in astrocytes with rapamycin or shRNA mitigated astrocyte neurotoxic effects in neurodegenerative mouse models. Overall, our study uncovers a mechanism through which astrocytes exhibit neuroprotective functions before becoming neurotoxic under neuroinflammatory conditions and highlights mTOR modulation specifically in astrocytes as a potential therapeutic strategy for neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s43587-024-00792-z
  47. Nat Chem Biol. 2025 Jan 09.
    Chemically engineered antibodies for autophagy-based receptor degradation.
    Binghua Cheng, Meiqing Li, Jiwei Zheng, Jiaming Liang, Yanyan Li, Ruijing Liang, Hui Tian, Zeyu Zhou, Li Ding, Jian Ren, Wenli Shi, Wenjie Zhou, Hailiang Hu, Long Meng, Ke Liu, Lintao Cai, Ximing Shao, Lijing Fang, Hongchang Li.
      Cell surface receptor-targeted protein degraders hold promise for drug discovery. However, their application is restricted because of the complexity of creating bifunctional degraders and the reliance on specific lysosome-shuttling receptors or E3 ubiquitin ligases. To address these limitations, we developed an autophagy-based plasma membrane protein degradation platform, which we term AUTABs (autophagy-inducing antibodies). Through covalent conjugation with polyethylenimine (PEI), the engineered antibodies acquire the capacity to degrade target receptors through autophagy. The degradation activities of AUTABs are self-sufficient, without necessitating the participation of lysosome-shuttling receptors or E3 ubiquitin ligases. The broad applicability of this platform was then illustrated by targeting various clinically important receptors. Notably, combining specific primary antibodies with a PEI-tagged secondary nanobody also demonstrated effective degradation of target receptors. Thus, our study outlines a strategy for directing plasma membrane proteins for autophagic degradation, which possesses desirable attributes such as ease of generation, independence from cell type and broad applicability.
    DOI:  https://doi.org/10.1038/s41589-024-01803-1
  48. Aging Cell. 2025 Jan 05. e14472
    Elevated p16Ink4a Expression Enhances Tau Phosphorylation in Neurons Differentiated From Human-Induced Pluripotent Stem Cells.
    Kristopher Holloway, Kashfia Neherin, Yingduo Song, Kazuhito Sato, Andrew Houston, Feng Chen, Li Ding, Hong Zhang.
      Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer's disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a doxycycline-inducible system to trigger p16 up-regulation in human-induced pluripotent stem cells (iPSCs) and neurons differentiated from iPSCs. We demonstrated that up-regulated p16 expression in iPSCs reduces cell proliferation, down-regulates cell cycle genes, and up-regulates genes involved in focal adhesion, interferon α response and PI3K-Akt signaling. Our approach enables temporal control of p16 induction upon differentiation from iPSCs to neurons. In differentiated cortical neurons, we found that up-regulation of p16 increases tau phosphorylation at Ser202/Thr205 and Thr231 in a cell-autonomous manner, while amyloid beta secretion is not affected. These data suggest a critical role of p16 in regulating tau phosphorylation in neurons, and thereby contributing to pathological progression of AD. As pathological tau tangles have been shown to induce p16 expression, our studies suggest a positive feedback loop between p16 and tau to exacerbate tau pathologies.
    Keywords:  Alzheimer's disease; aging; cellular senescence; disease modeling; p16Ink4a; tau
    DOI:  https://doi.org/10.1111/acel.14472
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