bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–10–06
fifty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. The role of PINK1-Parkin in mitochondrial quality control.
  2. TDRD3 functions as a selective autophagy receptor with dual roles in autophagy and modulation of stress granule stability.
  3. Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain.
  4. Migratory autolysosome disposal mitigates lysosome damage.
  5. Evolutionary conservation and metabolic significance of autophagy in algae.
  6. Reassessing kinetin's effect on PINK1 and mitophagy.
  7. LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR.
  8. Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
  9. Membrane tension sensing formin-binding protein 1 is a neuronal nutrient stress-responsive Golgiphagy receptor.
  10. mTOR is an essential gate in adapting the functional response of ovine trophoblast cells under stress-inducing environments.
  11. Autophagy as a Guardian of Vascular Niche Homeostasis.
  12. Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and vici syndrome patients.
  13. An artificial peptide inhibits autophagy through calcineurin-TFEB pathway.
  14. Orchestrating AMPK/mTOR signaling to initiate melittin-induced mitophagy: A neuroprotective strategy against Parkinson's disease.
  15. Is Autophagy a Friend or Foe in SARS-CoV-2 Infection?
  16. Impact of O -GlcNAcylation elevation on mitophagy and glia in the dentate gyrus.
  17. The novel TFEB agonist desloratadine ameliorates hepatic steatosis by activating the autophagy-lysosome pathway.
  18. Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.
  19. Dinotoms possess two evolutionary distinct autophagy-related ubiquitin-like conjugation systems.
  20. Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
  21. CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion.
  22. HSV-2 Manipulates Autophagy through Interferon Pathway: A Strategy for Viral Survival.
  23. Hyperuricemia Facilitates Uric Acid-Mediated Vascular Endothelial Cell Damage by Inhibiting Mitophagy.
  24. The Role of the SIRT1-mTOR Signaling Pathway in Regulating Autophagy in Sevoflurane-Induced Apoptosis of Fetal Rat Brain Neurons.
  25. Autophagy-related lncRNAs and exosomal lncRNAs in colorectal cancer: focusing on lncRNA-targeted strategies.
  26. Low protein diet protects the liver from Salmonella Typhimurium-mediated injury by modulating the mTOR/autophagy axis in macrophages.
  27. Cerliponase alfa decreases Aβ load and alters autophagy- related pathways in mouse hippocampal neurons exposed to fAβ1-42.
  28. Elucidating the effective age for dietary restriction and the key metabolites involved.
  29. JPH203 alleviates peritoneal fibrosis via inhibition of amino acid-mediated mTORC1 signaling.
  30. Neuronal LAMP2A-mediated reduction of adenylyl cyclases induces acute neurodegenerative responses and neuroinflammation after ischemic stroke.
  31. Autophagy plays an antiviral defence role against tomato spotted wilt orthotospovirus and is counteracted by viral effector NSs.
  32. The activation of autophagy by molecular hydrogen is functionally associated with osmotic tolerance in Arabidopsis.
  33. Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs).
  34. Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome.
  35. Targeting NCAPD2 as a Therapeutic Strategy for Crohn's Disease: Implications for Autophagy and Inflammation.
  36. Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?
  37. SEC31a-ATG9a Interaction Mediates the Recruitment of COPII Vesicles for Autophagosome Formation.
  38. Autophagy and its role in gastrointestinal diseases.
  39. TRPV2 calcium channel promotes breast cancer progression potential by activating autophagy.
  40. Inhibition of ACSS2 triggers glycolysis inhibition and nuclear translocation to activate SIRT1/ATG5/ATG2B deacetylation axis, promoting autophagy and reducing malignancy and chemoresistance in ovarian cancer.
  41. The Negative Impact of Prolonged Desiccation on the Recovery of Selaginella bryopteris: Insights Into Autophagy and Cellular Protection Strategies.
  42. The Autophagy Receptor SQSTM1/p62 Is a Restriction Factor of HCMV Infection.
  43. Nrf2 Connects Cellular Autophagy and Vascular Senescence in Atherosclerosis: A Mini-Review.
  44. Tumor Dormancy Within the Lymphovascular Embolus Is Regulated by Multiple Metabolism-signaling Pathways.
  45. Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets.
  46. Crosstalk Between Innate Immunity and Autophagy in Viral Myocarditis Leading to Dilated Cardiomyopathy.
  47. Tetrahydropalmatine promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate atherosclerosis.
  48. METTL3-mediated m6A modification of SIRT1 mRNA affects the progression of diabetic cataracts through cellular autophagy and senescence.
  49. Modified (2'-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway.
  50. Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling.
  51. Autophagy defects at weaning impair complement-dependent synaptic pruning and induce behavior deficits.
  52. Lysosomal Proteases and Their Inhibitors.
  53. Prevention of medication-related osteonecrosis of the jaw in mice by adipose-derived stem cells associated with activated autophagic flux.
  54. Nuclear envelope budding inhibition slows down progerin-induced aging process.
  55. Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research.
  56. The metabolic sensor AMPK: Twelve enzymes in one.
  57. Identification of the GABARAP binding determinant in PI4K2A.
  58. USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway.
  59. SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
  1. Nat Cell Biol. 2024 Oct 02.
    The role of PINK1-Parkin in mitochondrial quality control.
    Derek P Narendra, Richard J Youle.
      Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is widely distributed throughout a highly branched axonal arbor. Here we review the current understanding of the role of PINK1-Parkin in the quality control of mitophagy, including sensing of mitochondrial distress by PINK1, activation of Parkin by PINK1 to induce mitophagy, and the physiological relevance of the PINK1-Parkin pathway.
    DOI:  https://doi.org/10.1038/s41556-024-01513-9
  2. bioRxiv. 2024 Sep 22. pii: 2024.09.22.614367. [Epub ahead of print]
    TDRD3 functions as a selective autophagy receptor with dual roles in autophagy and modulation of stress granule stability.
    Matthew Deater, Richard E Lloyd.
      Tudor Domain Containing 3 (TDRD3) is a methylarginine-reader protein that functions as a scaffold in the nucleus facilitating transcription, however TDRD3 is also recruited to stress granules (SGs) during the Integrated Stress Response (ISR) although its function therein remains largely unknown. We previously showed that TDRD3 is a novel antiviral restriction factor that is cleaved by virus 2A protease, and plays complex modulatory roles in both interferon and inflammatory signaling during stress and enterovirus infections. Here we have found that TDRD3 contains structural motifs similar to known selective autophagy receptors such as p62/SQSTM1, sharing ubiquitin associated domains (UBA) and LC3 interacting regions (LIR) that anchor cargo destined for autophagosomes to activated LC3 protein coating autophagosome membranes. This is of interest since enteroviruses hijack autophagy machinery to facilitate formation of viral replication factories, virus assembly and egress from the infected cell. Here we explored possible roles of TDRD3 in autophagy, hypothesizing that TDRD3 may function as a specialized selective autophagy receptor. We found that KO of TDRD3 in HeLa cells significantly reduces starvation induced autophagy, while its reintroduction restores it in a dose-dependent manner. Autophagy receptors are degraded during autophagy and expression levels decrease during this time. We found that TDRD3 levels decrease to the same extent as the autophagy receptor p62/SQSTM1 during autophagy, indicating autophagy-targeted turnover in that role. Knockout of TDRD3 or G3BP1 did not make significant changes in overall cell localization of LC3B or p62/SQSTM1, but did result in greater concentration of Lamp2 phagosome marker for phagosomes and phagolysosomes. To test the potential roles of TDRD3 in autophagic processes, we created a series of deletion mutants of TDRD3 lacking either UBA domain or the various LIR motifs that are predicted to interact with LC3B. Microscopic examination of starved cells expressing these variants of TDRD3 showed ΔLIR-TDRD3 had defects in colocalization with LC3B or Lamp2. Further, super resolution microscopy revealed ring structures with TDRD3 interfacing with p62/SQSTM1. In examination of arsenite induced stress granules we found recruitment of TDRD3 variants disrupted normally tight SG condensation, altered the decay rate of SGs upon release from stress and the kinetics of SG formation. We found evidence that the LIR3 motif on TDRD3 is involved in TDRD3 interaction with LC3B in coIP experiments, colocalization studies, and that this motif plays a key role in TDRD3 recruitment to SGs and SG resolution. Overall, these data support a functional role of TDRD3 in selective autophagy in a mode similar to p62/SQSTM1, with specific roles in SG stability and turnover. Enterovirus cleavage of TDRD3 likely affects both antiviral and autophagic responses that the virus controls for replication.
    DOI:  https://doi.org/10.1101/2024.09.22.614367
  3. Int J Mol Sci. 2024 Sep 18. pii: 10042. [Epub ahead of print]25(18):
    Assembly of mTORC3 Involves Binding of ETV7 to Two Separate Sequences in the mTOR Kinase Domain.
    Jun Zhan, Frank Harwood, Sara Ten Have, Angus Lamond, Aaron H Phillips, Richard W Kriwacki, Priyanka Halder, Monica Cardone, Gerard C Grosveld.
      mTOR plays a crucial role in cell growth by controlling ribosome biogenesis, metabolism, autophagy, mRNA translation, and cytoskeleton organization. It is a serine/threonine kinase that is part of two distinct extensively described protein complexes, mTORC1 and mTORC2. We have identified a rapamycin-resistant mTOR complex, called mTORC3, which is different from the canonical mTORC1 and mTORC2 complexes in that it does not contain the Raptor, Rictor, or mLST8 mTORC1/2 components. mTORC3 phosphorylates mTORC1 and mTORC2 targets and contains the ETS transcription factor ETV7, which binds to mTOR and is essential for mTORC3 assembly in the cytoplasm. Tumor cells that assemble mTORC3 have a proliferative advantage and become resistant to rapamycin, indicating that inhibiting mTORC3 may have a therapeutic impact on cancer. Here, we investigate which domains or amino acid residues of ETV7 and mTOR are involved in their mutual binding. We found that the mTOR FRB and LBE sequences in the kinase domain interact with the pointed (PNT) and ETS domains of ETV7, respectively. We also found that forced expression of the mTOR FRB domain in the mTORC3-expressing, rapamycin-resistant cell line Karpas-299 out-competes mTOR for ETV7 binding and renders these cells rapamycin-sensitive in vivo. Our data provide useful information for the development of molecules that prevent the assembly of mTORC3, which may have therapeutic value in the treatment of mTORC3-positive cancer.
    Keywords:  ETV7; mTOC3; mTOR; rapamycin
    DOI:  https://doi.org/10.3390/ijms251810042
  4. J Cell Biol. 2024 Dec 02. pii: e202403195. [Epub ahead of print]223(12):
    Migratory autolysosome disposal mitigates lysosome damage.
    Takami Sho, Ying Li, Haifeng Jiao, Li Yu.
      Lysosomes, essential for intracellular degradation and recycling, employ damage-control strategies such as lysophagy and membrane repair mechanisms to maintain functionality and cellular homeostasis. Our study unveils migratory autolysosome disposal (MAD), a response to lysosomal damage where cells expel LAMP1-LC3 positive structures via autolysosome exocytosis, requiring autophagy machinery, SNARE proteins, and cell migration. This mechanism, crucial for mitigating lysosomal damage, underscores the role of cell migration in lysosome damage control and facilitates the release of small extracellular vesicles, highlighting the intricate relationship between cell migration, organelle quality control, and extracellular vesicle release.
    DOI:  https://doi.org/10.1083/jcb.202403195
  5. Philos Trans R Soc Lond B Biol Sci. 2024 Nov 18. 379(1914): 20230368
    Evolutionary conservation and metabolic significance of autophagy in algae.
    Juliette Laude, Matteo Scarsini, Charlotte Nef, Chris Bowler.
      Autophagy is a highly conserved 'self-digesting' mechanism used in eukaryotes to degrade and recycle cellular components by enclosing them in a double membrane compartment and delivering them to lytic organelles (lysosomes or vacuoles). Extensive studies in plants have revealed how autophagy is intricately linked to essential aspects of metabolism and growth, in both normal and stress conditions, including cellular and organelle homeostasis, nutrient recycling, development, responses to biotic and abiotic stresses, senescence and cell death. However, knowledge regarding autophagic processes in other photosynthetic organisms remains limited. In this review, we attempt to summarize the current understanding of autophagy in algae from a metabolic, molecular and evolutionary perspective. We focus on the composition and conservation of the autophagy molecular machinery in eukaryotes and discuss the role of autophagy in metabolic regulation, cellular homeostasis and stress adaptation in algae. This article is part of the theme issue 'The evolution of plant metabolism'.
    Keywords:  ATG; algae; autophagy; metabolism; phytoplankton; stress
    DOI:  https://doi.org/10.1098/rstb.2023.0368
  6. Autophagy. 2024 Sep 29. 1-2
    Reassessing kinetin's effect on PINK1 and mitophagy.
    Zhong Yan Gan, David Komander, Sylvie Callegari.
      Substantial evidence indicates that a decline in mitochondrial health contributes to the development of Parkinson disease. Accordingly, therapeutic stimulation of mitophagy, the autophagic turnover of dysfunctional mitochondria, is a promising approach to treat Parkinson disease. An attractive target in such a setting is PINK1, a protein kinase that initiates the mitophagy cascade. Previous reports suggest that PINK1 kinase activity can be enhanced by kinetin triphosphate (KTP), an enlarged ATP analog that acts as an alternate phosphate donor for PINK1 during phosphorylation. However, the mechanism of how KTP could exert such an effect on PINK1 was unclear. In a recent study, we demonstrate that contrary to previous thinking, KTP cannot be used by PINK1. Nucleotide-bound PINK1 structures indicate that KTP would clash with the back of PINK1's ATP binding pocket, and enlarging this pocket by mutagenesis is required to enable PINK1 to use KTP. Strikingly, mutation shifts PINK1's nucleotide preference from ATP to KTP. Similar results could be demonstrated in cells with kinetin, a membrane-permeable precursor of KTP. These results overturn the previously accepted mechanism of how kinetin enhances mitophagy and indicate that kinetin and its derivatives instead function through a currently unidentified mechanism.
    Keywords:  Mitophagy; PINK1; parkin; parkinson’s disease; protein kinase; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2024.2395144
  7. Nature. 2024 Oct 02.
    LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR.
    Charles Bayly-Jones, Christopher J Lupton, Alastair C Keen, Shuqi Dong, Chantel Mastos, Wentong Luo, Chunyi Qian, Gareth D Jones, Hari Venugopal, Yong-Gang Chang, Ronald J Clarke, Michelle L Halls, Andrew M Ellisdon.
      Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability1. LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1)2. However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation.
    DOI:  https://doi.org/10.1038/s41586-024-08012-9
  8. EMBO J. 2024 Oct 04.
    Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
    Anna Rappe, Helena A Vihinen, Fumi Suomi, Antti J Hassinen, Homa Ehsan, Eija S Jokitalo, Thomas G McWilliams.
      Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility to neurodegeneration. Here, we define the longitudinal dynamics of basal mitophagy and macroautophagy across neuronal and non-neuronal cell types within the intact aging mouse brain in vivo. Quantitative profiling of reporter mouse cohorts from young to geriatric ages reveals cell- and tissue-specific alterations in mitophagy and macroautophagy between distinct subregions and cell populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia and interneurons. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.
    Keywords:  Aging; Autophagy; Brain; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1038/s44318-024-00241-y
  9. Metabolism. 2024 Sep 26. pii: S0026-0495(24)00268-3. [Epub ahead of print] 156040
    Membrane tension sensing formin-binding protein 1 is a neuronal nutrient stress-responsive Golgiphagy receptor.
    Smita Saha, Anirban Mandal, Akash Ranjan, Debasish Kumar Ghosh.
       BACKGROUND: Nutrient stress-responsive neuronal homeostasis relies on intricate autophagic mechanisms that modulate various organelle integrity and function. The selective autophagy of the Golgi, known as Golgiphagy, regulates secretory processes by modulating vesicle trafficking during nutrient starvation.
    RESULTS: In this study, we explored a genetic screen of BAR-domain-containing proteins to elucidate the role of formin-binding protein 1 (FNBP1) as a Golgiphagy receptor in modulating Golgi dynamics in response to varying nutrient availability in neurons. Mapping the systems network of FNBP1 and its interacting proteins reveals the putative involvement of FNBP1 in autophagy and Golgi-associated processes. While nutrient depletion causes Golgi fragmentation, FNBP1 preferentially localizes to the fragmented Golgi membrane through its 284FEDYTQ289 motif during nutrient stress. Simultaneously, FNBP1 engages in molecular interactions with LC3B through a conserved 131WKQL134 LC3 interacting region, thereby sequestering the fragmented Golgi membrane in neuronal autophagosomes. Increased aggregation of GM130, abnormal clumping of RAB11-positive secretory granules, and enhanced senescent death of FNBP1-depleted starved neurons indicate disruptions of neuronal homeostasis under metabolic stress.
    CONCLUSION: The identification of FNBP1 as a nutrient stress-responsive Golgiphagy receptor expands our insights into the molecular mechanisms underlying Golgiphagy, establishing the crosstalk between nutrient sensing and membrane tension-sensing regulatory autophagic processes of Golgi turnover in neurons.
    Keywords:  Formin-binding protein 1; Golgi fragmentation; Golgiphagy; Golgiphagy receptor; Neuron; Nutrient stress
    DOI:  https://doi.org/10.1016/j.metabol.2024.156040
  10. Placenta. 2024 Sep 19. pii: S0143-4004(24)00654-4. [Epub ahead of print]158 14-22
    mTOR is an essential gate in adapting the functional response of ovine trophoblast cells under stress-inducing environments.
    Irene Viola, Paolo Accornero, Isabella Manenti, Silvia Miretti, Mario Baratta, Paola Toschi.
       INTRODUCTION: During the early stage of pregnancy trophoblast cells adapt to adverse uterine environments characterized by oxygen and nutrient deprivation. Autophagy is an intracellular degradation process that aims to promote cell survival in response to stressful conditions. Autophagy activation passes through the mechanistic target of rapamycin (mTOR), also known as a placental nutrient sensor. Here, we tested the hypothesis that ovine trophoblast cells may adapt to a suboptimal environment through an mTOR dependent regulation of cell survival with relevant implications for key placental functionality.
    METHODS: Primary ovine trophoblast cells subjected to mTOR inhibitor and low-nutrient conditions were used to explore how autophagy affects cellular functionality and expression of solute carriers' genes (SLCs).
    RESULTS: Autophagy activation was confirmed both in rapamycin-treated and low-nutrient conditions, through the detection of specific autophagic markers. However, p-mTOR activation seems to be severely modified only following rapamycin treatment whereas 24h of starvation allowed p-mTOR reactivation. Starvation promoted migration compared to normal culture conditions whereas all trophoblast functional activities were decreased in rapamycin treatment. Interestingly in both conditions, the autophagy-activated environment did not affect the progesterone release. mRNA expression of amino acid transporters remains largely undisturbed except for SLC43A2 and SLC38A4 which are downregulated in starved and rapamycin-treated cells, respectively.
    DISCUSSION: The study demonstrates that sheep trophoblast cells can adapt to adverse conditions in the early stage of placentation by balancing, in an mTOR dependent manner, nutrient recycling and transport with relevant effects for in vitro functional properties, which could potentially impact conceptus development and survival.
    Keywords:  Autophagy; Early pregnancy; Nutrients; Sheep; Trophoblast; mTOR
    DOI:  https://doi.org/10.1016/j.placenta.2024.09.011
  11. Int J Mol Sci. 2024 Sep 20. pii: 10097. [Epub ahead of print]25(18):
    Autophagy as a Guardian of Vascular Niche Homeostasis.
    Konstantin Dergilev, Alexandre Gureenkov, Yelena Parfyonova.
      The increasing burden of vascular dysfunction on healthcare systems worldwide results in higher morbidity and mortality rates across pathologies, including cardiovascular diseases. Vasculopathy is suggested to be caused by the dysregulation of vascular niches, a microenvironment of vascular structures comprising anatomical structures, extracellular matrix components, and various cell populations. These elements work together to ensure accurate control of the vascular network. In recent years, autophagy has been recognized as a crucial regulator of the vascular microenvironment responsible for maintaining basic cell functions such as proliferation, differentiation, replicative senescence, and apoptosis. Experimental studies indicate that autophagy activation can be enhanced or inhibited in various pathologies associated with vascular dysfunction, suggesting that autophagy plays both beneficial and detrimental roles. Here, we review and assess the principles of autophagy organization and regulation in non-tumor vascular niches. Our analysis focuses on significant figures in the vascular microenvironment, highlighting the role of autophagy and summarizing evidence that supports the systemic or multiorgan nature of the autophagy effects. Finally, we discuss the critical organizational and functional aspects of the vasculogenic niche, specifically in relation to autophagy. The resulting dysregulation of the vascular microenvironment contributes to the development of vascular dysfunction.
    Keywords:  autophagy; vascular niche; vascular regeneration
    DOI:  https://doi.org/10.3390/ijms251810097
  12. Autophagy. 2024 Sep 29.
    Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and vici syndrome patients.
    Celine Deneubourg, Hormos Salimi Dafsari, Simon Lowe, Aitana Martinez-Cotrina, David Mazaud, Seo Hyun Park, Virginia Vergani, Amanda Almacellas Barbanoj, Reza Maroofian, Luisa Averdunk, Ehsan Ghayoor-Karimiani, Sandeep Jayawant, Cyril Mignot, Boris Keren, Renate Peters, Arveen Kamath, Lauren Mattas, Sumit Verma, Arpana Silwal, Felix Distelmaier, Henry Houlden, Gabriele Lignani, Adam Antebi, James Jepson, Heinz Jungbluth, Manolis Fanto.
      Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions.
    Keywords:  Autophagy; Drosophila; EPG5; behavior; epilepsy; vici syndrome
    DOI:  https://doi.org/10.1080/15548627.2024.2405956
  13. Biochim Biophys Acta Mol Cell Res. 2024 Sep 29. pii: S0167-4889(24)00196-4. [Epub ahead of print] 119853
    An artificial peptide inhibits autophagy through calcineurin-TFEB pathway.
    Yumeng Yang, Yanan Li, Hanxiao Shang, Yueyang Liu, Wenying Li, Limin Chen, Na Cheng, Yuchen Zhang, Nan Zhang, Yanxia Yin, Li Tong, Zhimei Li, Jingyu Yang, Jing Luo.
      We previously reported that a bioactive peptide (pep3) can potently inhibit the enzyme activity of purified calcineurin (CN). In this paper, we further demonstrate that transfected pep3 can strongly inhibit CN enzyme activity in HEK293 cells. Transcription factor EB (TFEB) plays an important role in the autophagy-lysosome pathway (ALP) as one of the substrates of CN, so we study the effect of pep3 on the CN-TFEB-ALP pathway. Pep3 can significantly inhibit the mRNA levels of the TFEB downstream genes and the expression of the autophagy-associated proteins, and autophagy flux in HEK293 cells. We also validated the inhibitory effect of pep3 on autophagy in mice. These findings may provide a new idea for discovering more CN inhibitors and autophagy inhibitory drugs.
    Keywords:  Autophagy-lysosome pathway; Calcineurin; Inhibitor; Pep3; Transcription factor EB
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119853
  14. Int J Biol Macromol. 2024 Sep 27. pii: S0141-8130(24)06928-9. [Epub ahead of print]281(Pt 1): 136119
    Orchestrating AMPK/mTOR signaling to initiate melittin-induced mitophagy: A neuroprotective strategy against Parkinson's disease.
    Mingran Chen, Xue Wang, Shuangyan Bao, Dexiao Wang, Jie Zhao, Qian Wang, Chaojie Liu, Haiong Zhao, Chenggui Zhang.
      Apitherapy has a long history in treating Parkinson's disease (PD) in humans, with evidence suggesting that bee venom (BV) can mitigate Parkinson's symptoms. Central to BV's effects is melittin (MLT), a principal peptide whose neuroprotective mechanisms in PD are not fully understood. The study investigated the effects of MLT on an experimental PD model in mice and dopaminergic neuron cells, induced by MPTP or MPP+. We concentrate on the autophagic response elicited by MLT during PD pathogenesis. The findings showed that MLT was shown to protect against MPP+/MPTP cytotoxicity and preserve tyrosine hydroxylase (TH) levels, indicating neuronal safeguarding. Remarkably, MLT instigated mitophagy, enhancing mitochondrial homeostasis in MPP+-exposed SH-SY5Y cells. Further, MLT's promotion of mitophagy was confirmed to be AMPK/mTOR signaling-dependent. Validation using Bafilomycin A1, an autophagy inhibitor, confirmed MLT's neuroprotective role, with autophagy inhibition negating MLT's benefits and reducing TH preservation. These findings illuminate MLT's therapeutic potential, particularly its modulation of mitochondrial dysfunction in PD pathology. Our research advances the understanding of MLT's mechanistic action, emphasizing its role in mitochondrial autophagy and AMPK/mTOR signaling, offering a novel perspective beyond the symptomatic relief associated with BV.
    Keywords:  AMPK/mTOR signaling pathway; Dopaminergic neuron; Melittin; Mitophagy; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136119
  15. Viruses. 2024 Sep 20. pii: 1491. [Epub ahead of print]16(9):
    Is Autophagy a Friend or Foe in SARS-CoV-2 Infection?
    Asifa Khan, Jiaxin Ling, Jinlin Li.
      As obligate parasites, viruses need to hijack resources from infected cells to complete their lifecycle. The interaction between the virus and host determines the viral infection process, including viral propagation and the disease's outcome. Understanding the interaction between the virus and host factors is a basis for unraveling the intricate biological processes in the infected cells and thereby developing more efficient and targeted antivirals. Among the various fundamental virus-host interactions, autophagy plays vital and also complicated roles by directly engaging in the viral lifecycle and functioning as an anti- and/or pro-viral factor. Autophagy thus becomes a promising target against virus infection. Since the COVID-19 pandemic, there has been an accumulation of studies aiming to investigate the roles of autophagy in SARS-CoV-2 infection by using different models and from distinct angles, providing valuable information for systematically and comprehensively dissecting the interplay between autophagy and SARS-CoV-2. In this review, we summarize the advancements in the studies of the interaction between SARS-CoV-2 and autophagy, as well as detailed molecular mechanisms. We also update the current knowledge on the pharmacological strategies used to suppress SARS-CoV-2 replication through remodeling autophagy. These extensive studies on SARS-CoV-2 and autophagy can advance our understanding of virus-autophagy interaction and provide insights into developing efficient antiviral therapeutics by regulating autophagy.
    Keywords:  SARS-CoV-2; antivirals; autophagy; autophagy modulator; incomplete autophagy; virophagy
    DOI:  https://doi.org/10.3390/v16091491
  16. bioRxiv. 2024 Sep 20. pii: 2024.09.19.613771. [Epub ahead of print]
    Impact of O -GlcNAcylation elevation on mitophagy and glia in the dentate gyrus.
    Joshua Kramer, John C Chatham, Martin E Young, Victor Darley-Usmar, Jianhua Zhang.
      O -GlcNAcylation is a dynamic and reversible protein post-translational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O -GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative disease. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of OGA with thiamet G which leads to elevation of protein O -GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP positive astrocytes and is significantly decreased in response to elevated O -GlcNAcylation. Furthermore, with increased O -GlcNAcylation, the levels of astrocyte makers GFAP and S100B, and microglial cell marker IBA1 were decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O -GlcNAc pathway.
    DOI:  https://doi.org/10.1101/2024.09.19.613771
  17. Front Pharmacol. 2024 ;15 1449178
    The novel TFEB agonist desloratadine ameliorates hepatic steatosis by activating the autophagy-lysosome pathway.
    Jieru Lin, Chunhuan Huang, Jingye Zhao, Lu Li, Zhenwei Wu, Tingyu Zhang, Yuyin Li, Wei Li, Baoqiang Guo, Zhenxing Liu, Aipo Diao.
      The autophagy-lysosome pathway plays an essential role in promoting lipid catabolism and preventing hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). Transcription factor EB (TFEB) enhances the autophagy-lysosome pathway by regulating the expression of genes related to autophagy and lysosome biogenesis. Therefore, targeting TFEB provides a novel strategy for the treatment of lipid metabolic diseases. In this study, the antiallergic drug desloratadine was screened and identified as a novel TFEB agonist. Desloratadine effectively induced translocation of TFEB to the nucleus and promoted autophagy and lysosome biogenesis. Desloratadine-induced TFEB activation was dependent on AMPK rather than mTORC1. Moreover, desloratadine treatment enhanced clearance of lipid droplets in cells induced by fatty acids oleate and palmitate. Furthermore, high-fat diet (HFD) induced obesity mouse model experiments indicated treatment with desloratadine markedly reduced the body weight of HFD-fed mice, as well as the levels of hepatic triglycerides and total cholesterol, serum glutamic pyruvic transaminase and glutamic-oxaloacetic transaminase. Oil red O staining showed the liver fat was significantly reduced after desloratadine treatment, and H&E staining analysis demonstrated hepatocellular ballooning was improved. In addition, autophagy and lysosomal biogenesis was stimulated in the liver of desloratadine treated mice. Altogether, these findings demonstrate desloratadine ameliorates hepatic steatosis through activating the TFEB-mediated autophagy-lysosome pathway, thus desloratadine has an exciting potential to be used to treat fatty liver disease.
    Keywords:  TFEB agonist; autophagy; desloratadine; hepatic steatosis; lysosome; obesity
    DOI:  https://doi.org/10.3389/fphar.2024.1449178
  18. Nat Commun. 2024 Oct 04. 15(1): 8622
    Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy.
    Amy-Jayne Hutchings, Bita Hambrecht, Alexander Veh, Neha Jadhav Giridhar, Abdolhossein Zare, Christina Angerer, Thorben Ohnesorge, Maren Schenke, Bhuvaneish T Selvaraj, Siddharthan Chandran, Jared Sterneckert, Susanne Petri, Bettina Seeger, Michael Briese, Christian Stigloher, Thorsten Bischler, Andreas Hermann, Markus Damme, Michael Sendtner, Patrick Lüningschrör.
      Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.
    DOI:  https://doi.org/10.1038/s41467-024-52875-5
  19. Protist. 2024 Sep 21. pii: S1434-4610(24)00059-2. [Epub ahead of print]175(6): 126067
    Dinotoms possess two evolutionary distinct autophagy-related ubiquitin-like conjugation systems.
    Euki Yazaki, Tadaaki Uehara, Hirokazu Sakamoto, Yuji Inagaki.
      Autophagy is an intracellular degradation mechanism by which cytoplasmic materials are delivered to and degraded in the lysosome-fused autophagosome (autolysosome) and proposed to have been established at an early stage of eukaryotic evolution. Dinoflagellates harboring endosymbiotic diatoms (so-called "dinotoms"), which retain their own nuclei and mitochondria in addition to plastids, have been investigated as an intermediate toward the full integration of a eukaryotic phototroph into the host-controlled organelle (i.e., plastid) through endosymbiosis. Pioneering studies systematically evaluated the degree of host governance on several metabolic pathways in the endosymbiotic diatoms (ESDs). However, little attention has been paid to the impact of the endosymbiotic lifestyle on the autophagy operated in the ESDs. In this study, we searched for ATG3, ATG4, ATG5, ATG7, ATG8, ATG10, and ATG12, which are required for autophagosome formation, in the RNA-seq data from dinotoms Durinskia baltica and Kryptoperidinium foliaceum. We detected two evolutionally distinct sets of the ATG proteins in the dinotom species, one affiliated with the dinoflagellate homologs and the other with the diatom homologs in phylogenetic analyses. The results suggest that the ATG proteins descended from the diatom taken up by the dinoflagellate host persist for autophagosome formation and, most likely, autophagy.
    Keywords:  ATG12; ATG8; Autophagy; Diatoms; Dinoflagellates; Endosymbiosis
    DOI:  https://doi.org/10.1016/j.protis.2024.126067
  20. Int J Mol Sci. 2024 Sep 20. pii: 10116. [Epub ahead of print]25(18):
    Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
    Chong Zhao, Yonghao Wu, Shuaiqi Zhu, Haiying Liu, Shuai Xu.
      Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.
    Keywords:  irisin; mitochondrial quality control; musculoskeletal health; myokine; osteoporosis; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms251810116
  21. Nat Commun. 2024 Oct 02. 15(1): 8519
    CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion.
    Hyunjin Rho, Seungyeon Kim, Seung Up Kim, Jeong Won Kim, Sang Hoon Lee, Sang Hoon Park, Freddy E Escorcia, Joon-Yong Chung, Jaewhan Song.
      The fusion of autophagosomes and lysosomes is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). Here, we generate a hepatocyte-specific CHIP knockout (H-KO) mouse model that develops NAFLD more rapidly in response to a high-fat diet (HFD) or high-fat, high-fructose diet (HFHFD). The accumulation of P62 and LC3 in the livers of H-KO mice and CHIP-depleted cells indicates the inhibition of autophagosome-lysosome fusion. AAV8-mediated overexpression of CHIP in the murine liver slows the progression of NAFLD induced by HFD or HFHFD feeding. Mechanistically, CHIP induced K63- and K27-linked polyubiquitination at the lysine 198 residue of STX17, resulting in increased STX17-SNAP29-VAMP8 complex formation. The STX17 K198R mutant was not ubiquitinated by CHIP; it interfered with its interaction with VAMP8, rendering STX17 incapable of inhibiting steatosis development in mice. These results indicate that a signaling regulatory mechanism involving CHIP-mediated non-degradative ubiquitination of STX17 is necessary for autophagosome-lysosome fusion.
    DOI:  https://doi.org/10.1038/s41467-024-53002-0
  22. Viruses. 2024 Aug 29. pii: 1383. [Epub ahead of print]16(9):
    HSV-2 Manipulates Autophagy through Interferon Pathway: A Strategy for Viral Survival.
    Debashree Dass, Anwesha Banerjee, Kishore Dhotre, Vaishnavi Sonawane, Ashwini More, Anupam Mukherjee.
      Autophagy, an evolutionarily conserved cellular process, influences the regulation of viral infections. While the existing understanding indicates that Herpes Simplex Virus type 2 (HSV-2) maintains a basal level of autophagy to support its viral yield, the precise pathways governing the induction of autophagy during HSV-2 infection remain unknown. Therefore, this study aims to explore the role of type I interferons (IFN-I) in modulating autophagy during HSV-2 infection and to decode the associated signaling pathways. Our findings revealed an interplay wherein IFN-I regulates the autophagic response during HSV-2 infection. Additionally, we investigated the cellular pathways modulated during this complex process. Exploring the intricate network of signaling events involved in autophagy induction during HSV-2 infection holds promising therapeutic implications. Identifying these pathways advances our understanding of host-virus interactions and holds the foundation for developing targeted therapeutic strategies against HSV-2. The insight gained from this study provides a platform for exploring potential therapeutic targets to restrict HSV-2 infections, addressing a crucial need in antiviral research.
    Keywords:  HSV-2; JAK-STAT pathway; MAPK pathway; autophagy; interferon pathway
    DOI:  https://doi.org/10.3390/v16091383
  23. Cell Biochem Biophys. 2024 Sep 28.
    Hyperuricemia Facilitates Uric Acid-Mediated Vascular Endothelial Cell Damage by Inhibiting Mitophagy.
    Gang Wu, Jun Liu, Guirong Ma, Qiuyu Wei, Xinghui Song.
      Hyperuricemia remains an elusive factor in the pathogenesis of vascular endothelial injury. This study elucidates the role of hydroxychloroquine (HCQ) in the context of uric acid (UA)-induced vascular endothelial cell damage. Human umbilical vein endothelial cells (HUVECs) were exposed to varying UA concentrations (6 mg/dL to 50 mg/dL) for 48 h, or to 50 mg/dL UA for different time points (6 to 72 h). We observed a concentration- and time-dependent inhibition of cell proliferation, particularly at 40 mg/dL and 50 mg/dL UA. The autophagy marker LC3 exhibited reduced fluorescence intensity post-UA treatment, along with decreased expression of LC3-II/LC3I, beclin1, and p62, indicating impaired autophagy. The mechanistic exploration revealed that HCQ, in conjunction with the mitochondrial autophagy inhibitor Cyclosporine A (CsA), exacerbated the inhibitory effects of UA on HUVEC autophagy. This was evidenced by a further reduction in mitochondrial autophagy-related proteins and diminished fluorescence of LC3-II/LC3-I and Parkin, culminating in suppressed cell proliferation and accelerated cell senescence and apoptosis. Conversely, the co-treatment with the mitochondrial autophagy inducer carbonyl cyanide m-chlorophenyl hydrazine (CCCP) and HCQ mitigated the detrimental effects of UA on HUVEC autophagy. This intervention led to increased expression of PINK1, Parkin, Bnip3, and Nix, along with enhanced fluorescence of LC3-II/LC3-I and Parkin, effectively inhibiting cell senescence and apoptosis while promoting cell proliferation. In conclusion, our findings underscore the pivotal role of HCQ in modulating UA-mediated vascular endothelial cell damage through the inhibition of mitophagy, providing novel insights into the therapeutic potential of targeting HCQ in the management of hyperuricemia-associated vascular complications.
    Keywords:  Human umbilical vein endothelial cells; Hydroxychloroquine; Hyperuricemia; Mitophagy
    DOI:  https://doi.org/10.1007/s12013-024-01512-5
  24. Front Biosci (Landmark Ed). 2024 Sep 20. 29(9): 324
    The Role of the SIRT1-mTOR Signaling Pathway in Regulating Autophagy in Sevoflurane-Induced Apoptosis of Fetal Rat Brain Neurons.
    Yihui Li, Cheng Xiao, Yuting Tan, Sheng Jing.
       BACKGROUND: Isoflurane is a commonly used general anesthetic widely employed in clinical surgeries. Recent studies have indicated that isoflurane might induce negative impacts on the nervous system, notably by triggering neuronal apoptosis. This process is pivotal to the development and emergence of neurological disorders; its misregulation could result in functional deficits and the initiation of diseases within nervous system. However, the potential molecular mechanism of isoflurane on the neuronal apoptosis remains fully unexplored. This study aims to investigate the regulatory role of the sirtuin 1-mechanistic target of rapamycin (SIRT1-mTOR) signaling pathway in autophagy during isoflurane-induced apoptosis of fetal rat brain neuronal cells.
    METHODS: Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, real-time quantitative polymerase chain reaction (qPCR), and Western blot were utilized to evaluate the apoptotic status of hippocampal tissue cells in fetal mice after sevoflurane exposure. Our further investigation was commenced with flow cytometry, immunofluorescence, qPCR, and Western blot to determine the impact of autophagy on sevoflurane-induced apoptosis in these neurons. On the other hand, we conducted an additional set of analyses, including flow cytometric analysis, qPCR, and Western blot, to further elucidate the neuroprotective potential of autophagy in neural cells of fetal mice subjected to sevoflurane-induced apoptosis.
    RESULTS: Our findings indicated that a 3% sevoflurane treatment led to a significant rise in apoptosis among fetal rat hippocampal tissue cells and neurons. Levels of apoptosis-associated proteins, cleaved-caspase-3 and Bcl-2 associated X protein (Bax), were found to be markedly higher, coinciding with an enhancement in autophagy as evidenced by increased microtubule-associated proteins 1A/1B-light chain 3 (LC3) and decreased p62 expression. Concurrently, there was a notable up-regulation of sirtuin 1 (SIRT1) and a down-regulation of mechanistic target of rapamycin (mTOR) expression. In conclusion, our research elucidated the pivotal function of cellular autophagy in an apoptosis induced by sevoflurane in fetal rat nerve cells. Through experimental manipulation, we observed that interference with SIRT1 resulted in a reduction of both cleaved-caspase-3 and Bax levels. This intervention also beget a diminished expression of the autophagy-associated factor LC3 and an up-regulation of p62. Furthermore, inhibition against mTOR reversed the effects induced by SIRT1 interference, suggesting a complex interplay amid these regulatory pathways.
    CONCLUSIONS: SIRT1 possesses a capacity to modulate apoptosis in the hippocampal neurons of fetal rats triggered by sevoflurane, with mTOR functioning as an inhibitory factor within this signaling pathway.
    Keywords:  SIRT1-mTOR signaling pathway; cerebral nerve cell apoptosis; nerve cells autophagy; sevoflurane
    DOI:  https://doi.org/10.31083/j.fbl2909324
  25. Cancer Cell Int. 2024 Sep 28. 24(1): 328
    Autophagy-related lncRNAs and exosomal lncRNAs in colorectal cancer: focusing on lncRNA-targeted strategies.
    Yan Dong, Yiwei He, Yanna Geng, Meimei Wei, Xiaomei Zhou, Jianlun Lian, Jamal Hallajzadeh.
      Autophagy is a cellular process that involves the degradation and recycling of cellular components, including damaged proteins and organelles. It is an important mechanism for maintaining cellular homeostasis and has been implicated in various diseases, including cancer. Long non-coding RNAs (lncRNAs) are a class of RNA molecules that do not code for proteins but instead play regulatory roles in gene expression. Emerging evidence suggests that lncRNAs can influence autophagy and contribute to the development and progression of colorectal cancer (CRC). Several lncRNAs have been identified as key players in modulating autophagy in CRC. The dysregulation of autophagy and non-coding RNAs (ncRNAs) in CRC suggests a complex interplay between these two factors in the pathogenesis of the disease. Modulating autophagy may sensitize cancer cells to existing therapies or improve the efficacy of new treatment approaches. Additionally, targeting specific lncRNAs involved in autophagy regulation could potentially be used as a therapeutic intervention to inhibit tumor growth, metastasis, and overcome drug resistance in CRC. In this review, a thorough overview is presented, encompassing the functions and underlying mechanisms of autophagy-related lncRNAs in a range of critical areas within tumor biology. These include cell proliferation, apoptosis, migration, invasion, drug resistance, angiogenesis, and radiation resistance.
    Keywords:  Autophagy; Colorectal cancer; Exosomal long non-coding RNAs; Long non-coding RNAs
    DOI:  https://doi.org/10.1186/s12935-024-03503-1
  26. Commun Biol. 2024 Sep 30. 7(1): 1219
    Low protein diet protects the liver from Salmonella Typhimurium-mediated injury by modulating the mTOR/autophagy axis in macrophages.
    Edyta E Wojtowicz, Katherine Hampton, Mar Moreno-Gonzalez, Charlotte L Utting, Yuxuan Lan, Paula Ruiz, Gemma Beasy, Caitlin Bone, Charlotte Hellmich, Rebecca Maynard, Luke Acton, Matthew Markham, Linda Troeberg, Andrea Telatin, Robert A Kingsley, Iain C Macaulay, Stuart A Rushworth, Naiara Beraza.
      Western diets are the underlying cause of metabolic and liver diseases. Recent trend to limit the consumption of protein-rich animal products has become more prominent. This dietary change entails decreased protein consumption; however, it is still unknown how this affects innate immunity. Here, we studied the influence of a low protein diet (LPD) on the liver response to bacterial infection in mice. We found that LPD protects from Salmonella enterica serovar Typhimurium (S. Typhimurium)-induced liver damage. Bulk and single-cell RNA sequencing of murine liver cells showed reduced inflammation and upregulation of autophagy-related genes in myeloid cells in mice fed with LPD after S. Typhimurium infection. Mechanistically, we found reduced activation of the mammalian target of rapamycin (mTOR) pathway, whilst increased phagocytosis and activation of autophagy in LPD-programmed macrophages. We confirmed these observations in phagocytosis and mTOR activation in metabolically programmed human peripheral blood monocyte-derived macrophages. Together, our results support the causal role of dietary components on the fitness of the immune system.
    DOI:  https://doi.org/10.1038/s42003-024-06932-w
  27. Life Sci. 2024 Oct 01. pii: S0024-3205(24)00695-7. [Epub ahead of print]357 123105
    Cerliponase alfa decreases Aβ load and alters autophagy- related pathways in mouse hippocampal neurons exposed to fAβ1-42.
    Selma Kose, Elif Cinar, Hilal Akyel, Canan Cakir-Aktas, Banu Cahide Tel, Hulya Karatas, Pelin Kelicen-Ugur.
      Extracellular aggregation of amyloid-beta (Aβ) in the brain plays a central role in the onset and progression of Alzheimer's disease (AD). Moreover, intraneuronal accumulation of Aβ via oligomer internalization might play an important role in the progression of AD. Deficient autophagy, which is a lysosomal degradation process, occurs during the early stages of AD. Tripeptidyl peptidase-1 (TPP1) functions as a lysosomal enzyme, and TPP1 gene mutations are associated with type 2 late infantile neuronal ceroid lipofuscinosis (LINCL). Nevertheless, there is little information about the role of TPP1 in the pathogenesis of AD; therefore, the present study aimed to measure the decrease in intraneuronal Aβ accumulation by a recombinant analog of the TPP1 enzyme, cerliponase alfa (CER) (Brineura®), and to determine whether autophagy pathways play a role in this decrease. In this study, endogenous Aβ accumulation was induced by fAβ1-42 (a toxic fragment of full-length Aβ) exposure, and mouse hippocampal neuronal cells (HT-22) were treated with CER (human recombinant rhTPP1 1 mg mL-1). Soluble Aβ, TPP1, and the proteins involved in autophagy, including mammalian target of rapamycin (p-mTOR/mTOR), p62/sequestosome-1 (p62/SQSTM1), and microtubule-associated protein 1 A/1B-light chain 3 (LC3), were evaluated using western blotting. The sirtuin-1, beclin-1, and Atg5 genes were also studied using RT-PCR. Aβ and TPP1 localizations were observed via immunocytochemistry. CER reduced the Aβ load in HT-22 cells by inducing TPP1 expression and converting pro-TPP1 into the mature form. Furthermore, exposure to CER and fAβ1-42 induced the autophagy-regulatory/related pathways in HT-22 cells and exposure to CER alone increased sirtuin-1 activity. Based on the present findings, we suggest that augmentation of TPP1 with enzyme replacement therapy may be a potential therapeutic option for the treatment of AD.
    Keywords:  Alzheimer's disease; Autophagy; Cerliponase alfa; TPP1
    DOI:  https://doi.org/10.1016/j.lfs.2024.123105
  28. Exp Gerontol. 2024 Oct 01. pii: S0531-5565(24)00247-X. [Epub ahead of print] 112601
    Elucidating the effective age for dietary restriction and the key metabolites involved.
    Jazween Loo, Geetha Gunasekaran, Jen Kit Tan, Jo Aan Goon.
      Dietary restriction (DR) extends lifespan in various species, but its effect at different ages, especially when started later, is unclear. This study used Caenorhabditis elegans to explore the impact of DR at different ages. Worms were divided into control and DR groups, with daily survival monitored. To confirm the occurrence of DR, the expression of DR-sensitive genes namely acdh-1, pyk-1, pck-2 and cts-1 were determined using RT-qPCR. Liquid chromatography mass spectrometry (LC-MS) was employed to observe the changes in metabolites affected by DR. The results indicated that young worms subjected to mild DR displayed the longest lifespan, highlighting the effectiveness of initiating DR at a young age. Increased expression of acdh-1 and pck-2 suggests activation of beta-oxidation and gluconeogenesis, while decreased cts-1 expression indicates a reduced citric acid cycle, further supporting the observed effects of DR in these worms. Metabolomic results indicated that DR decreased the activity of mechanistic Target of Rapamycin (mTOR) and the synthesis of amino acids namely leucine, tyrosine and tryptophan to conserve energy for cell repair and survival. DR also decreased levels of N-acetyl-L-methionine and S-adenosyl-methionine (SAM) in methionine metabolism, thereby promoting autophagy, reducing inflammation, and facilitating the removal of damaged cells and proteins. In conclusion, initiating dietary restriction early in life extends the lifespan by modulating amino acid metabolism and enhancing the autophagy pathway, thereby maintaining cellular wellbeing.
    Keywords:  C. elegans; Dietary restriction; Effective age; LC-MS; Lifespan; PCA
    DOI:  https://doi.org/10.1016/j.exger.2024.112601
  29. Biochem Biophys Res Commun. 2024 Sep 04. pii: S0006-291X(24)01192-6. [Epub ahead of print]734 150656
    JPH203 alleviates peritoneal fibrosis via inhibition of amino acid-mediated mTORC1 signaling.
    Tiangang Wu, Zanzhe Yu, Junhao Dai, Jiayang Li, Fengling Ning, Xin Liu, Nan Zhu, Xuemei Zhang.
       BACKGROUND AND AIMS: The mesothelial-mesenchymal transition (MMT) of mesothelial cells has been recognized as a critical process during progression of peritoneal fibrosis (PF). Despite its crucial role in amino acid transport and metabolism, the involvement of L-type amino acid transporter 1 (LAT1) and the potential therapeutic role of its inhibitor, JPH203, in fibrotic diseases remain unexplored. Considering the paucity of research on amino acid-mediated mTORC1 activation in PF, our study endeavors to elucidate the protective effects of JPH203 against PF and explore the involvement of amino acid-mediated mTORC1 signaling in this context.
    METHODS: We established the transforming growth factor beta 1 (TGF-β1) induced MMT model in primary human mesothelial cells and the peritoneal dialysis fluid (PDF) induced PF model in mice. The therapeutic effects of JPH203 on PF were then examined on these two models by real-time quantitative polymerase chain reaction, western blotting, immunofluorescence staining, Masson's trichrome staining, H&E staining, picro-sirius red staining, and immunohistochemistry. The involvement of amino acid-mediated mTORC1 signaling was screened by RNA sequencing and further verified by western blotting in vitro.
    RESULTS: LAT1 was significantly upregulated and JPH203 markedly attenuated fibrotic phenotype both in vitro and in vivo. RNA-seq unveiled a significant enrichment of mTOR signaling pathway in response to JPH203 treatment. Western blotting results indicated that JPH203 alleviates PF by inhibiting amino acid-mediated mTORC1 signaling, which differs from the direct inhibition observed with rapamycin.
    CONCLUSION: JPH203 alleviates PF by inhibiting amino acid-mediated mTORC1 signaling.
    Keywords:  JPH203; LAT1; Peritoneal fibrosis; RNA-Seq; mTORC1
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150656
  30. Cell Death Differ. 2024 Sep 28.
    Neuronal LAMP2A-mediated reduction of adenylyl cyclases induces acute neurodegenerative responses and neuroinflammation after ischemic stroke.
    Dingfang Shi, Yunhao Bai, Ruiling Long, Jing Xia, Wenxuan Xu, Dongshen Qin, Xuejun Yang, Ming Ding, Xiao-Yu Hou.
      Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY-cAMP-PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY-PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes.
    DOI:  https://doi.org/10.1038/s41418-024-01389-0
  31. Mol Plant Pathol. 2024 Oct;25(10): e70012
    Autophagy plays an antiviral defence role against tomato spotted wilt orthotospovirus and is counteracted by viral effector NSs.
    Xingwang Zhang, Hao Hong, Jiaoling Yan, Yulong Yuan, Mingfeng Feng, Qinhai Liu, Yanxiao Zhao, Tongqing Yang, Shen Huang, Chunli Wang, Ruizhen Zhao, Wenyu Zuo, Suyu Liu, Zixuan Ding, Changjun Huang, Zhongkai Zhang, Jiban Kumar Kundu, Xiaorong Tao.
      Autophagy, an intracellular degradation process, has emerged as a crucial innate immune response against various plant pathogens, including viruses. Tomato spotted wilt orthotospovirus (TSWV) is a highly destructive plant pathogen that infects over 1000 plant species and poses a significant threat to global food security. However, the role of autophagy in defence against the TSWV pathogen, and whether the virus counteracts this defence, remains unknown. In this study, we report that autophagy plays an important role in antiviral defence against TSWV infection; however, this autophagy-mediated defence is counteracted by the viral effector NSs. Transcriptome profiling revealed the up-regulation of autophagy-related genes (ATGs) upon TSWV infection. Blocking autophagy induction by chemical treatment or knockout/down of ATG5/ATG7 significantly enhanced TSWV accumulation. Notably, the TSWV nucleocapsid (N) protein, a major component of the viral replication unit, strongly induced autophagy. However, the TSWV nonstructural protein NSs was able to effectively suppress N-induced autophagy in a dose-dependent manner. Further investigation revealed that NSs inhibited ATG6-mediated autophagy induction. These findings provide new insights into the defence role of autophagy against TSWV, a representative segmented negative-strand RNA virus, as well as the tospoviral pathogen counterdefence mechanism.
    Keywords:  TSWV; antiviral defence; autophagy; counterdefence; nonstructural protein NSs; nucleocapsid protein
    DOI:  https://doi.org/10.1111/mpp.70012
  32. Free Radic Biol Med. 2024 Sep 27. pii: S0891-5849(24)00690-7. [Epub ahead of print]225 63-74
    The activation of autophagy by molecular hydrogen is functionally associated with osmotic tolerance in Arabidopsis.
    Yihua Zhang, Pengfei Cheng, Yueqiao Wang, Xing Lu, Wenrong Yao, Longna Li, Ke Jiang, Wenbiao Shen.
      The role of molecular hydrogen (H2) in autophagy during inflammatory response is controversial in mammalian cells. Although the stimulation of H2 production in response to osmotic stress was observed in plants, its synthetic pathway and the interrelationship between its induction and plant autophagy remain unclear. Here, the induction of autophagy was observed in Arabidopsis upon osmotic stress, assessing by the autophagosome formation and autophagy-related genes expression. Above responses were intensified by H2 fumigation. Meanwhile, the reduction in seedling growth and roots vigor was obviously abolished, accompanied by reestablishing redox balance. These H2 responses were markedly impaired in T-DNA knockout lines atg2, atg5, and atg18. Further evidence showed that the increased endogenous H2 synthesis by genetic manipulation, not only stimulated autophagosome formation, but also triggered various plant responses toward osmotic stress. By contrast, these responses were obviously abolished by the disruption of endogenous H2 synthesis with the addition of 2,6-dichloroindophenol sodium salt. Together, the integrated genetic and molecular evidence clearly illustrated the requirement of autophagy activation in H2 control of plant osmotic tolerance.
    Keywords:  Arabidopsis thaliana; Autophagy; Cell death; Molecular hydrogen; Osmotic stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.043
  33. Biomolecules. 2024 Sep 01. pii: 1096. [Epub ahead of print]14(9):
    Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs).
    Kumudesh Mishra, Or Kakhlon.
      Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control, generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades, thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSDs.
    Keywords:  autophagy and mitophagy; glycogen storage disorders; mitochondrial dysfunction; myopathy; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/biom14091096
  34. Mitochondrion. 2024 Oct 01. pii: S1567-7249(24)00130-2. [Epub ahead of print] 101972
    Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome.
    Keshari Sriwastawa, Ashutosh Kumar.
      Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction is reported as a key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes, as well as functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide stable and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy.
    Keywords:  Diabetes; Diabetic neuropathy; Inflammasome; Mitochondria; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2024.101972
  35. Inflamm Bowel Dis. 2024 Sep 28. pii: izae211. [Epub ahead of print]
    Targeting NCAPD2 as a Therapeutic Strategy for Crohn's Disease: Implications for Autophagy and Inflammation.
    Hao Ge, Can Wang, Haoran Zhao, Hao Chen, Yuxia Gong, Lichao Qiao, Yi Zhang, Ping Liu, Bolin Yang.
       BACKGROUND: Our earlier studies identified that non-SMC condensin I complex subunit D2 (NCAPD2) induces inflammation through the IKK/NF-κB pathway in ulcerative colitis. However, its role in the development of Crohn's disease (CD) and the specific molecular mechanism still need to be further studied.
    METHODS: NCAPD2 expression in clinical ileal CD mucosa vs normal mucosa was examined, alongside its correlation with CD patients' clinical characteristics via their medical records. The biological function and molecular mechanism of NCAPD2 in CD were explored using a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD mouse model, along with immunofluorescence, western blot, quantitative real-time PCR, immunohistochemistry, hematoxylin and eosin staining, and cell functional analysis.
    RESULTS: NCAPD2 was overexpressed in CD tissues and significantly correlated with disease activity in CD patients (P = .016). In a TNBS-induced CD mouse model, NCAPD2 knockdown inhibited the development of TNBS-induced intestinal inflammation in mice. In addition, we found that NCAPD2 inhibited autophagy. Mechanistically, NCAPD2 promoted the phosphorylation of mammalian target of the rapamycin (mTOR) and its direct effector S6K and downregulated the expression of autophagy-related proteins Beclin1, LC3II, and Atg5. In addition, NCAPD2 activates the NF-κB signaling pathway, and the downstream inflammatory factors are continuously released, leading to the persistence of inflammation.
    CONCLUSIONS: Our results show that NCAPD2 suppresses autophagy and worsens intestinal inflammation by modulating mTOR signaling and impacting the NF-κB pathway, suggesting a critical role in CD progression. Targeting NCAPD2 could be a promising therapeutic approach to stop CD advancement.
    Keywords:  CD; NCAPD2; autophagy; mTOR/NF-κB pathway
    DOI:  https://doi.org/10.1093/ibd/izae211
  36. Bioessays. 2024 Oct 04. e2400023
    Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?
    Zoë P Van Acker, Thomas Leroy, Wim Annaert.
      Neurodegenerative diseases encompass a spectrum of conditions characterized by the gradual deterioration of neurons in the central and peripheral nervous system. While their origins are multifaceted, emerging data underscore the pivotal role of impaired mitochondrial functions and endolysosomal homeostasis to the onset and progression of pathology. This article explores whether mitochondrial dysfunctions act as causal factors or are intricately linked to the decline in endolysosomal function. As research delves deeper into the genetics of neurodegenerative diseases, an increasing number of risk loci and genes associated with the regulation of endolysosomal and autophagy functions are being identified, arguing for a downstream impact on mitochondrial health. Our hypothesis centers on the notion that disturbances in endolysosomal processes may propagate to other organelles, including mitochondria, through disrupted inter-organellar communication. We discuss these views in the context of major neurodegenerative diseases including Alzheimer's and Parkinson's diseases, and their relevance to potential therapeutic avenues.
    Keywords:  lysosomal homeostasis; mitochondrial homeostasis; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/bies.202400023
  37. Adv Sci (Weinh). 2024 Oct 03. e2405127
    SEC31a-ATG9a Interaction Mediates the Recruitment of COPII Vesicles for Autophagosome Formation.
    Jiaming Nie, Shaoyang Ma, Linyue Wu, Ye Li, Jiao Cao, Meng Li, Peter Mei, Paul R Cooper, Ang Li, Dandan Pei.
      Autophagy plays an important role in determining stem-cell differentiation. During the osteogenic differentiation of mesenchymal stem cells (MSCs), autophagosome formation is upregulated but the reason is unknown. A long-standing quest in the autophagy field is to find the membrane origin of autophagosomes. In this study, cytoplasmic coat protein complex II (COPII) vesicles, endoplasmic reticulum-derived vesicles responsible for the transport of storage proteins to the Golgi, are demonstrated to be a critical source of osteoblastic autophagosomal membrane. A significant correlation between the number of COPII vesicle and the autophagy level is identified in the rat bone tissues. Disruption of COPII vesicles restrained osteogenesis and decreased the number and size of autophagosomes. SEC31a (an outer coat protein of COPII vesicle) is found to be vital to regulate COPII vesicle-dependent autophagosome formation via interacting with ATG9a of autophagosomal seed vesicles. The interference of Sec31a inhibited autophagosome formation and osteogenesis in vitro and in vivo. These results identified a novel mechanism of autophagosome formation in osteogenic differentiation of stem cells and identified SEC31a as a critical protein that mediates the interplay between COPII and ATG9a vesicles. These findings broaden the understanding of the regulatory mechanism in the osteogenic differentiation of MSCs.
    Keywords:  ATG9a; COPII vesicles; SEC31a; autophagosome formations; osteogenesis
    DOI:  https://doi.org/10.1002/advs.202405127
  38. World J Gastroenterol. 2024 Sep 28. 30(36): 4014-4020
    Autophagy and its role in gastrointestinal diseases.
    Bo-Zong Shao, Wen-Gang Zhang, Zhen-Yu Liu, En-Qiang Linghu.
      Gastrointestinal disorders encompass a spectrum of conditions affecting various organs within the digestive system, such as the esophagus, stomach, colon, rectum, pancreas, liver, small intestine, and bile ducts. The role of autophagy in the etiology and progression of gastrointestinal diseases has garnered significant attention. This paper seeks to evaluate the impact and mechanisms of autophagy in gastrointestinal disorders by synthesizing recent research findings. Specifically, we delve into inflammation-related gastrointestinal conditions, including ul-cerative colitis, Crohn's disease, and pancreatitis, as well as gastrointestinal cancers such as esophageal, gastric, and colorectal cancers. Additionally, we provide commentary on a recent publication by Chang et al in the World Journal of Gastroenterology. Our objective is to offer fresh perspectives on the mechanisms and therapeutic approaches for these gastrointestinal ailments. This review aims to offer new perspectives on the mechanisms and therapeutic strategies for gastrointestinal disorders by critically analyzing relevant publications. As discussed, the role of autophagy in gastrointestinal diseases is complex and, at times, contentious. To harness the full therapeutic potential of autophagy in treating these conditions, more in-depth research is imperative.
    Keywords:  Autophagy; Cancer; Inflammation; Inflammatory bowel disease; Pancreatitis
    DOI:  https://doi.org/10.3748/wjg.v30.i36.4014
  39. Cancer Cell Int. 2024 Sep 27. 24(1): 324
    TRPV2 calcium channel promotes breast cancer progression potential by activating autophagy.
    Qing Li, Huixian Li, Ruiwen Zhu, William Chi Shing Cho, Xiaoqiang Yao, Fung Ping Leung, Gary Tse, Lai Kwok Leung, Wing Tak Wong.
      Breast cancer, the most prevalent and aggressive tumor affecting women, requires identification of disease determinants to facilitate the development of effective therapeutic strategies. Transient receptor potential vanilloid 2 (TRPV2), an ion channel highly permeable for calcium (Ca2+), is implicated in physiological and pathological processes. Nevertheless, the role of TRPV2 in breast cancer remains poorly elucidated. In this study, we found high levels of TRPV2 expression associated with advanced malignancy, thereby suggesting its potential as a biomarker for breast cancer staging. We demonstrated that TRPV2 activation promotes breast cancer cell proliferation, migration, and invasion, while silencing of TRPV2 suppresses breast cancer progression, highlighting the oncogenic role of TRPV2. Moreover, we reveal that TRPV2 facilitates cancer progression by modulating the CaMKKβ/AMPK/ULK1-autophagic axis through mediating calcium influx, providing new insights into TRPV2 as a novel therapeutic target for breast cancer treatment.
    Keywords:  AMPK; Autophagy; Breast cancer; CaMKKβ; Calcium channel; TRPV2; ULK1
    DOI:  https://doi.org/10.1186/s12935-024-03506-y
  40. Metabolism. 2024 Oct 01. pii: S0026-0495(24)00269-5. [Epub ahead of print] 156041
    Inhibition of ACSS2 triggers glycolysis inhibition and nuclear translocation to activate SIRT1/ATG5/ATG2B deacetylation axis, promoting autophagy and reducing malignancy and chemoresistance in ovarian cancer.
    Jiang Yang, Haoyu Wang, Bingshu Li, Jingchun Liu, Xiaoyi Zhang, Ying Wang, Jiaxin Peng, Likun Gao, Xinqi Wang, Siyuan Hu, Wenyi Zhang, Li Hong.
       BACKGROUND: Metabolic reprogramming is a hallmark of cancer, characterized by a high dependence on glycolysis and an enhanced utilization of acetate as an alternative carbon source. ACSS2 is a critical regulator of acetate metabolism, playing a significant role in the development and progression of various malignancies. ACSS2 facilitates the conversion of acetate to acetyl-CoA, which participates in multiple metabolic pathways and functions as an epigenetic regulator of protein acetylation, thereby modulating key cellular processes such as autophagy. However, the roles and intrinsic connections of ACSS2, glycolysis, protein acetylation, and autophagy in ovarian cancer (OC) remain to be elucidated.
    BASIC PROCEDURES: Utilizing clinical specimens and online databases, we analysed the expression of ACSS2 in OC and its relationship with clinical prognosis. By knocking down ACSS2, we evaluated its effects on the malignant phenotype, acetate metabolism, glycolysis, and autophagy. The metabolic alterations in OC cells were comprehensively analysed using Seahorse assays, transmission electron microscopy, membrane potential measurements, and stable-isotope labeling techniques. CUT&TAG and co-immunoprecipitation techniques were employed to explore the deacetylation of autophagy-related proteins mediated by ACSS2 via SIRT1. Additionally, through molecular docking, transcriptome sequencing, and metabolomics analyses, we validated the pharmacological effects of paeonol on ACSS2 and the glycolytic process in OC cells. Finally, both in vitro and in vivo experiments were performed to investigate the impact of paeonol on autophagy and its anti-OC effects mediated through the ACSS2/SIRT1 deacetylation axis.
    MAIN FINDINGS: ACSS2 is significantly upregulated in OC and is associated with poor prognosis. Knockdown of ACSS2 inhibits OC cells proliferation, migration, invasion, angiogenesis, and platinum resistance, while reducing tumour burden in vivo. Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2. This glycolytic reduction promotes the translocation of ACSS2 from the cytoplasm to the nucleus, leading to increased expression of the deacetylase SIRT1. SIRT1 mediates the deacetylation of autophagy-related proteins, such as ATG5 and ATG2B, thereby significantly activating autophagy in OC cells and exerting antitumor effects. Paeonol inhibits acetate metabolism and glycolysis in OC cells by targeting ACSS2. Paeonol activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation axis, demonstrating inhibition of OC in vitro and in vivo.
    PRINCIPAL CONCLUSIONS: Pae can serve as an effective, low-toxicity, multi-targeted drug targeting ACSS2 and glycolysis. It activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation signalling cascade, thereby exerting anti-OC effects. Our study provides new insights into the malignant mechanisms of OC and offers a novel strategy for its treatment.
    Keywords:  ACSS2; Autophagy; Glycolysis; Ovarian cancer; Paeonol; SIRT1
    DOI:  https://doi.org/10.1016/j.metabol.2024.156041
  41. Plant Cell Environ. 2024 Oct 01.
    The Negative Impact of Prolonged Desiccation on the Recovery of Selaginella bryopteris: Insights Into Autophagy and Cellular Protection Strategies.
    Jismon Jose, Lakhani Amiben, B P Girish, Kakali Sen, T N V K V Prasad, Sujit Roy, Swarup Roy Choudhury.
      Desiccation tolerance is a complex biological phenomenon that allows certain plants to survive extreme dehydration and revive upon rehydration. Although significant progress has been made in understanding the physiological and molecular mechanisms involved in desiccation tolerance, recovery mechanisms after prolonged desiccation periods are enigmatic. Combining physiological, biochemical, transcriptomic and metabolomic approaches, we investigated the role of prolonged desiccation on recovery of Selaginella bryopteris. Prolonged desiccation causes a decline in the antioxidant system, leading to accumulation of ROS that hinder recovery by inducing cellular damage. Transcriptome and WGCNA analysis revealed the significance of protective proteins, alternative respiration and protein homeostasis in cellular protection and recovery after short and long-term desiccation. Metabolomic analysis exhibited an increased accumulation of antioxidant compounds, which can be substituted for antioxidant enzymes to maintain cellular protection during prolonged desiccation. The significant role of autophagy and autophagic components was evaluated by H2O2 treatment and phylogenetic analysis of ATG4 and ATG8, which unveiled their substantial role in desiccation tolerance and remarkable conservation of the autophagy-related genes across plant species. Our data demonstrated that prolonged desiccation leads to ROS-induced cell death by extensive autophagy due to enormous loss of protective proteins, antioxidant enzymes and energy resources during desiccation.
    Keywords:  ROS; Selaginella bryopteris; WGCNA; autophagy; cell death; cellular protection; desiccation tolerance; metabolomics; protein homeostasis; transcriptome
    DOI:  https://doi.org/10.1111/pce.15179
  42. Viruses. 2024 Sep 10. pii: 1440. [Epub ahead of print]16(9):
    The Autophagy Receptor SQSTM1/p62 Is a Restriction Factor of HCMV Infection.
    Nadine Krämer, Uxía Gestal Mato, Steffi Krauter, Nicole Büscher, Ahmad Afifi, Lina Herhaus, Luise Florin, Bodo Plachter, Christine Zimmermann.
      (1) Background: Intrinsic defense mechanisms are pivotal host strategies to restrict viruses already at early stages of their infection. Here, we addressed the question of how the autophagy receptor sequestome 1 (SQSTM1/p62, hereafter referred to as p62) interferes with human cytomegalovirus (HCMV) infection. (2) Methods: CRISPR/Cas9-mediated genome editing, mass spectrometry and the expression of p62 phosphovariants from recombinant HCMVs were used to address the role of p62 during infection. (3) Results: The knockout of p62 resulted in an increased release of HCMV progeny. Mass spectrometry revealed an interaction of p62 with cellular proteins required for nucleocytoplasmic transport. Phosphoproteomics further revealed that p62 is hyperphosphorylated at position S272 in HCMV-infected cells. Phosphorylated p62 showed enhanced nuclear retention, which is concordant with enhanced interaction with viral proteins relevant for genome replication and nuclear capsid egress. This modification led to reduced HCMV progeny release compared to a non-phosphorylated version of p62. (4) Conclusions: p62 is a restriction factor for HCMV replication. The activity of the receptor appears to be regulated by phosphorylation at position S272, leading to enhanced nuclear localization, viral protein degradation and impaired progeny production.
    Keywords:  SQSTM1/p62; autophagy receptor; host cell defense; human cytomegalovirus; optineurin
    DOI:  https://doi.org/10.3390/v16091440
  43. J Lipid Atheroscler. 2024 Sep;13(3): 292-305
    Nrf2 Connects Cellular Autophagy and Vascular Senescence in Atherosclerosis: A Mini-Review.
    Kai Wen Wai, Liang Ee Low, Bey Hing Goh, Wei Hsum Yap.
      Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor that maintains intracellular redox equilibrium, modulates the expression of antioxidant genes, scavenger receptors, and cholesterol efflux transporters, all of which contribute significantly to foam cell development and plaque formation. Nrf2 has recently emerged as a key regulator that connects autophagy and vascular senescence in atherosclerosis. Autophagy, a cellular mechanism involved in the breakdown and recycling of damaged proteins and organelles, and cellular senescence, a state of irreversible growth arrest, are both processes implicated in the pathogenesis of atherosclerosis. The intricate interplay of these processes has received increasing attention, shedding light on their cumulative role in driving the development of atherosclerosis. Recent studies have revealed that Nrf2 plays a critical role in mediating autophagy and senescence in atherosclerosis progression. Nrf2 activation promotes autophagy, which increases lipid clearance and prevents the development of foam cells. Meanwhile, the activation of Nrf2 also inhibits cellular senescence by regulating the expression of senescence markers to preserve cellular homeostasis and function and delay the progression of atherosclerosis. This review provides an overview of the molecular mechanisms through which Nrf2 connects cellular autophagy and vascular senescence in atherosclerosis. Understanding these mechanisms can provide insights into potential therapeutic strategies targeting Nrf2 to modulate cellular autophagy and vascular senescence, thereby preventing the progression of atherosclerosis.
    Keywords:  Atherosclerosis; Autophagy; Cellular senescence
    DOI:  https://doi.org/10.12997/jla.2024.13.3.292
  44. Anticancer Res. 2024 Oct;44(10): 4165-4173
    Tumor Dormancy Within the Lymphovascular Embolus Is Regulated by Multiple Metabolism-signaling Pathways.
    Yin Ye, Justin Wang, Jordan Dillard, Sanford H Barsky.
       BACKGROUND/AIM: Recently, we demonstrated that cancer dormancy is initiated within the lymphovascular tumor embolus and consists of decreased proliferation and lower mammalian target of rapamycin (mTOR) activity. In the present study, we investigated other intersecting metabolism-signaling pathways that may ultimately determine whether the lymphovascular tumor embolus remains dormant or undergoes cell death.
    MATERIALS AND METHODS: The present study exploited a singular patient-derived xenograft (PDX) of inflammatory breast cancer (Mary-X) that spontaneously forms high density spheroids, the in vitro equivalent of emboli. The AMPK metabolic checkpoint pathway, the mTOR nutrient-responsive cell growth pathway, the P13K/Akt intracellular quiescence regulating pathway, and the calpain-mediated E-cadherin proteolytic pathway responsible for spontaneous spheroid-genesis were also investigated, to determine their relative contributions to dormancy.
    RESULTS: The levels of phosphorylated AMPK proteins (AMPKα and β subunits) decreased gradually with the formation of MARY-X spheroids in vitro. Rapamycin down-regulated mTOR activity, yet dormancy persisted. LY294002, a PI3K/Akt inhibitor, completely abolished mTOR and induced spheroid disadherence and apoptosis. Compound C (AMPK inhibitor) up-regulated mTOR and induced spheroid disadherence and apoptosis. Increasing cellular metabolism led to cell death, even in enriched medium, whereas growing the spheroids in serum-free media (starvation) did not result in further mTOR inhibition, and dormancy was maintained.
    CONCLUSION: An increase in our understanding of dormancy from the standpoint of internal signaling pathways might ultimately provide clues to the external stimuli (starvation, hypoxia or other not yet understood phenomena) that act through these pathways to maintain or disrupt dormancy.
    Keywords:  5′ AMP-activated protein kinase; E-cadherin/N-terminal fragment-1; Inflammatory breast cancer; analysis of variance; apoptotic index; mammalian target of rapamycin; patient-derived xenograft; phosphoinositide 3-kinase
    DOI:  https://doi.org/10.21873/anticanres.17247
  45. Biomolecules. 2024 Sep 21. pii: 1190. [Epub ahead of print]14(9):
    Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets.
    Elena Conte, Brigida Boccanegra, Giorgia Dinoi, Michael Pusch, Annamaria De Luca, Antonella Liantonio, Paola Imbrici.
      Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively. Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation, and is stimulated by various energy sources and hormonal signaling pathways. Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC. Brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality. Even though several therapeutic options are available for the treatment of TSC, there is further need for a better understanding of the pathophysiological basis of the neurologic and other manifestations seen in TSC, and for novel therapeutic approaches. This review provides an overview of the main current therapies for TSC and discusses recent studies highlighting the repurposing of approved drugs and the emerging role of novel targets for future drug design.
    Keywords:  CLC-5; Kv1.1; everolimus; mTOR; tuberous sclerosis complex; vigabatrin
    DOI:  https://doi.org/10.3390/biom14091190
  46. Rev Med Virol. 2024 Nov;34(6): e2586
    Crosstalk Between Innate Immunity and Autophagy in Viral Myocarditis Leading to Dilated Cardiomyopathy.
    Chen Wang, Honglin Luo.
      Viral myocarditis, characterised by inflammation of the heart muscle, presents a significant challenge to global public health, particularly affecting younger individuals and often progressing to dilated cardiomyopathy (DCM), a leading cause of heart failure. Despite ongoing research efforts, viable treatments for this condition remain elusive. Recent studies have shed light on the complex interplay between the innate immune response and autophagy mechanisms, revealing their pivotal roles in the pathogenesis of viral myocarditis and subsequent DCM development. This review aims to delve into the recent advancements in understanding the molecular mechanisms and pathways that intersect innate immunity and autophagy in the context of viral myocarditis. Furthermore, it explores the potential therapeutic implications of these findings, offering insights into promising avenues for the management and treatment of this debilitating condition.
    Keywords:  autophagy; innate immunity; viral myocarditis
    DOI:  https://doi.org/10.1002/rmv.2586
  47. Histol Histopathol. 2024 Sep 06. 18809
    Tetrahydropalmatine promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate atherosclerosis.
    Hui Wang, Ke Ding, Jiaqi He, Jiahong Wang.
       BACKGROUND: Atherosclerosis (AS) is a chronic progressive arterial disease that is associated with macrophage autophagy and AMP-activated protein kinase (AMPK)/mechanistic target of the rapamycin (mTOR) pathway. Tetrahydropalmatine (THP) can activate AMPK-dependent autophagy. We aim to study the mechanism of macrophage autophagy mediated by THP in the treatment of AS via the AMPK/mTOR pathway.
    METHODS: High-fat diet apolipoprotein E-deficient mice and ox-LDL-induced RAW264.7 cells were used to mimic the AS model, then THP was administered. Cell viability was detected by MTT. Pathological aorta lesions were detected using Hematoxylin and Eosin, Masson, and oil red staining. Lipid metabolism indices and inflammatory factors were measured using ELISA. A transmission electron microscope was used to observe autophagosomes. Autophagy and AMPK/mTOR pathway protein expression was detected by immunofluorescence and Western blot. The AMPK inhibitor 9-β-d-Arabinofuranosyl Adenine (Ara-A) was used to validate the effect of THP. The mRNA expression of Beclin-1 and MCP-1 was detected by q-PCR.
    RESULTS: THP administration regulated lipid metabolism by lowering total cholesterol, triacylglycerol, low-density lipoprotein, and high-density lipoprotein levels, and suppressed aortic damage. THP suppressed aortic damage and regulated lipid metabolism by altering serum lipid levels. THP reduced inflammation and macrophage CD68 expression. Twenty μg/mL THP reduced cell viability. THP decreased cholesterol uptake and increased efflux, promoting autophagy. THP increased autophagosome number, LC3B expression, and autophagy markers p-AMPK/AMPK and LC3-II/LC3-I. THP also decreased p-mTOR/mTOR and P62. THP increased Beclin-1 mRNA expression and decreased MCP-1 mRNA expression. Ara-A reversed THP's effects.
    CONCLUSION: THP promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate AS.
    DOI:  https://doi.org/10.14670/HH-18-809
  48. J Transl Med. 2024 Sep 27. 22(1): 865
    METTL3-mediated m6A modification of SIRT1 mRNA affects the progression of diabetic cataracts through cellular autophagy and senescence.
    Su Dong, Jiajia Zhang, Yushan Fu, Gege Tang, Jianfeng Chen, Dawei Sun, Yanhua Qi, Nan Zhou.
       BACKGROUND: The increasing incidence of diabetes mellitus has established diabetic cataracts (DC) as a significant worldwide public health issue. The mechanisms underlying DC remain unknown, and effective prevention and treatment strategies are lacking. Accordingly, we aimed to explore the role and mechanism behind N6-methyladenosine (m6A) in DC progression.
    METHODS: Methyltransferase-like 3 (METTL3), p21, Beclin1, LC3, and p62 expression levels were measured in human tissues. This study assessed total m6A levels and common m6A-regulated biomarkers in both in vitro and in vivo DC models. Autophagy flux was detected in vitro through Ad-mCherry-GFP-LC3B and Monodansylcadaverine (MDC) staining. Cellular senescence was assessed utilizing the senescence-associated β-galactosidase (SA-β-Gal) assay. Furthermore, the effect of METTL3 on SIRT1 mRNA modification was demonstrated, and its mechanism was elucidated using RT-qPCR, western blot, RNA stability assays, and RIP analysis.
    RESULTS: METTL3, p21, and p62 expression levels were elevated in lens epithelial cells (LECs) from DC patients, while Beclin1 and LC3 levels were reduced. Silencing METTL3-mediated m6A modifications restored high-glucose-induced autophagy inhibition and prevented premature senescence in LECs. Notably, SIRT1720 and Metformin significantly enhanced autophagosome generation and delayed cellular senescence. The m6A-reading protein YTHDF2 bound to m6A modifications, and YTHDF2 silencing significantly reduced METTL3-mediated SIRT1 inactivation.
    CONCLUSIONS: METTL3 induces senescence in DC by destabilizing SIRT1 mRNA in an m6A-YTHDF2-dependent manner. The METTL3-YTHDF2-SIRT1 axis is a key target and potential pathogenic mechanism in DC.
    Keywords:  Autophagy; Cellular senescence; Diabetic cataract; METTL3; SIRT1; m6A
    DOI:  https://doi.org/10.1186/s12967-024-05691-w
  49. Bioorg Med Chem Lett. 2024 Oct 01. pii: S0960-894X(24)00382-2. [Epub ahead of print] 129980
    Modified (2'-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway.
    Ekaterina A Guseva, Polina N Kamzeeva, Sofya Y Sokolskaya, Georgy K Slushko, Evgeny S Belyaev, Boris P Myasnikov, Julia A Golubeva, Vera A Alferova, Petr V Sergiev, Andrey V Aralov.
      Autophagy is a conserved self-digestion process, which governs regulated degradation of cellular components. Autophagy is upregulated upon energy shortage sensed by AMP-dependent protein kinase (AMPK). Autophagy activators might be contemplated as therapies for metabolic neurodegenerative diseases and obesity, as well as cancer, considering tumor-suppressive functions of autophagy. Among them, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), a nucleoside precursor of the active phosphorylated AMP analog, is the most commonly used pharmacological modulator of AMPK activity, despite its multiple reported "off-target" effects. Here, we assessed the autophagy/mitophagy activation ability of a small set of (2'-deoxy)adenosine derivatives and analogs using a fluorescent reporter assay and immunoblotting analysis. The first two leader compounds, 7,8-dihydro-8-oxo-2'-deoxyadenosine and -adenosine, are nucleoside forms of major oxidative DNA and RNA lesions. The third, a derivative of inactive N6-methyladenosine with a metabolizable phosphate-masking group, exhibited the highest activity in the series. These compounds primarily contributed to the activation of AMPK and outperformed AICAr; however, retaining the activity in knockout cell lines for AMPK (ΔAMPK) and its upstream regulator SIRT1 (ΔSIRT1) suggests that AMPK is not a main cellular target. Overall, we confirmed the prospects of searching for autophagy activators among (2'-deoxy)adenosine derivatives and demonstrated the applicability of the phosphate-masking strategy for increasing their efficacy.
    Keywords:  Adenosine; Autophagy; DNA lesion; Phosphate; Prodrug; RNA lesion
    DOI:  https://doi.org/10.1016/j.bmcl.2024.129980
  50. Sci Rep. 2024 09 27. 14(1): 22147
    Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling.
    Takeru Akabane, Hiromori Sagae, Koen van Wijk, Shinichi Saitoh, Tomohiro Kimura, Satoshi Okano, Ken Kodama, Kiwamu Takahashi, Motowo Nakajima, Tohru Tanaka, Michiaki Takagi, Osamu Nakajima.
      Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that Alas1 heterozygous mice at 20-35 weeks (aged-A1+/-s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in A1+/-s and a sarcopenic phenotype in A1+/-s at 75-95 weeks (senile-A1+/-s). Senile-A1+/-s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged-A1+/-s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells (A1KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-A1+/-s and A1KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling.
    Keywords:  5-aminolevulinic acid; 5-aminolevulinic acid synthase 1 (ALAS1); Autophagy; Heme; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1038/s41598-024-73049-9
  51. J Neuroinflammation. 2024 Sep 27. 21(1): 239
    Autophagy defects at weaning impair complement-dependent synaptic pruning and induce behavior deficits.
    Xi Su, Guanyu Wang, Senqi Liu, Jinming Li, Minglong Shao, Yongfeng Yang, Meng Song, Yong Han, Wenqiang Li, Luxian Lv.
      Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA.
    Keywords:  Autophagy; Complement; Maternal immune activation; Schizophrenia; Synaptic pruning
    DOI:  https://doi.org/10.1186/s12974-024-03235-z
  52. Int J Mol Sci. 2024 Sep 19. pii: 10070. [Epub ahead of print]25(18):
    Lysosomal Proteases and Their Inhibitors.
    Vito Turk, Veronika Stoka.
      The discovery of the lysosome, a major cytoplasmic organelle, represents a breakthrough in the understanding of intracellular protein degradation processes-proteolysis [...].
    DOI:  https://doi.org/10.3390/ijms251810070
  53. J Dent Sci. 2024 Oct;19(4): 2106-2113
    Prevention of medication-related osteonecrosis of the jaw in mice by adipose-derived stem cells associated with activated autophagic flux.
    Xian Dong, Shuo Chen, Yang He, Yi Zhang.
       Background/purpose: Medication-related osteonecrosis of the jaw (MRONJ) represents a rare yet serious adverse reaction associated with the prolonged use of anti-bone resorptive or anti-angiogenic agents. This study aimed to investigate the impact and underlying mechanisms of adipose-derived stem cells (ADSCs) in preventing MRONJ in a mouse model.
    Materials and methods: Following tooth extraction in MRONJ mice, ADSCs or PBS were administered via the tail vein. The healing progress of gingival epithelium and the extraction socket was assessed using a stereoscopic microscope and histological analysis. Immunofluorescence was employed to examine markers associated with autophagy (LC3 and SQSTM1) and apoptosis (Cleaved-CASP 3). Statistical analysis involved unpaired Student's t-test and ANOVA on ABI Prism 7500, with P-values below 0.05 deemed statistically significant.
    Results: ADSCs enhanced gingival epithelium migration and facilitated new bone formation. In the MRONJ group, the expressions of autophagy-related protein LC3 and SQSTM1 in gingival epithelium were concurrently elevated, which indicated autophagic flux was impaired. Conversely, when treated with ADSCs, the expression of LC3 and SQSTM1 were downregulated, similarly to the Control group. Mechanically, zoledronate induced a deficiency of autophagosome-lysosome fusion in epithelial cells, while ADSCs supernatant could promote the autolysosomes formation. Furthermore, ADSCs rescued the number of autophagy-related apoptotic cells in the gingival epithelium of MRONJ.
    Conclusion: ADSCs could effectively prevent the occurrence of MRONJ, likely through the activation of autophagic flux and the inhibition of autophagy-related apoptosis in gingival epithelium. These findings enhanced the understanding of MRONJ pathogenesis and propose a potential therapeutic target for this disease.
    Keywords:  Adipose-derived stem cells; Autophagy; Gingival epithelium; Medication-related osteonecrosis of the jaw; Mice
    DOI:  https://doi.org/10.1016/j.jds.2024.05.003
  54. Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2321378121
    Nuclear envelope budding inhibition slows down progerin-induced aging process.
    Xiangyang Wang, Lin Ma, Di Lu, Gan Zhao, He Ren, Qiaoyu Lin, Mingkang Jia, Fan Huang, Shan Wang, Zhe Xu, Zhou Yang, Yan Chu, Zigang Xu, Wei Li, Li Yu, Qing Jiang, Chuanmao Zhang.
      Progerin causes Hutchinson-Gilford progeria syndrome (HGPS), but how progerin accelerates aging is still an interesting question. Here, we provide evidence linking nuclear envelope (NE) budding and accelerated aging. Mechanistically, progerin disrupts nuclear lamina to induce NE budding in concert with lamin A/C, resulting in transport of chromatin into the cytoplasm where it is removed via autophagy, whereas emerin antagonizes this process. Primary cells from both HGPS patients and mouse models express progerin and display NE budding and chromatin loss, and ectopically expressing progerin in cells can mimic this process. More excitingly, we screen a NE budding inhibitor chaetocin by high-throughput screening, which can dramatically sequester progerin from the NE and prevent this NE budding through sustaining ERK1/2 activation. Chaetocin alleviates NE budding-induced chromatin loss and ameliorates HGPS defects in cells and mice and significantly extends lifespan of HGPS mice. Collectively, we propose that progerin-induced NE budding participates in the induction of progeria, highlight the roles of chaetocin and sustained ERK1/2 activation in anti-aging, and provide a distinct avenue for treating HGPS.
    Keywords:  ERK1/2; Hutchinson–Gilford progeria syndrome; NE budding; chromatin loss; progerin
    DOI:  https://doi.org/10.1073/pnas.2321378121
  55. Cell Death Dis. 2024 Sep 30. 15(9): 696
    Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research.
    Boram Son, Wonhwa Lee, Hyeonjeong Kim, Heungsoo Shin, Hee Ho Park.
      Cancer stem cells (CSCs) are a type of stem cell that possesses not only the intrinsic abilities of stem cells but also the properties of cancer cells. Therefore, CSCs are known to have self-renewal and outstanding proliferation capacity, along with the potential to differentiate into specific types of tumor cells. Cancers typically originate from CSCs, making them a significant target for tumor treatment. Among the related cascades of the CSCs, mammalian target of rapamycin (mTOR) pathway is regarded as one of the most important signaling pathways because of its association with significant upstream signaling: phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) pathway and mitogen‑activated protein kinase (MAPK) cascade, which influence various activities of stem cells, including CSCs. Recent studies have shown that the mTOR pathway not only affects generation of CSCs but also the maintenance of their pluripotency. Furthermore, the maintenance of pluripotency or differentiation into specific types of cancer cells depends on the regulation of the mTOR signal in CSCs. Consequently, the clinical potential and importance of mTOR in effective cancer therapy are increasing. In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug development aimed at overcoming existing drawbacks, such as drug resistance, by targeting CSCs through mTOR inhibition.
    DOI:  https://doi.org/10.1038/s41419-024-07077-8
  56. Mol Metab. 2024 Oct 01. pii: S2212-8778(24)00173-X. [Epub ahead of print] 102042
    The metabolic sensor AMPK: Twelve enzymes in one.
    William J Smiles, Ashley J Ovens, Jonathan S Oakhill, Barbara Kofler.
       BACKGROUND: AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined.
    SCOPE OF REVIEW: Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research.
    MAJOR CONCLUSIONS: Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a 'myristoyl-switch' mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially targeted by mTORC1 in response to physical exercise.
    Keywords:  AMPK; cancer; exercise; mTORC1; metabolism; signalling
    DOI:  https://doi.org/10.1016/j.molmet.2024.102042
  57. Biosci Rep. 2024 Sep 30. pii: BSR20240200. [Epub ahead of print]
    Identification of the GABARAP binding determinant in PI4K2A.
    Yan Chen, Barbara Barylko, John P Eichorst, Joachim D Mueller, Joseph P Albanesi.
      GABARAP is a member of the ATG8 family of ubiquitin-like autophagy related proteins. It was initially discovered as a facilitator of GABA-A receptor translocation to the plasma membrane and has since been shown to promote the intracellular transport of a variety of other proteins under non-autophagic conditions. We and others have shown that GABARAP interacts with the Type II phosphatidylinositol 4-kinase, PI4K2A, and that this interaction is important for autophagosome-lysosome fusion. Here we identify a 7-amino acid segment within the PI4K2A catalytic domain that contains the GABARAP interaction motif (GIM). This segment resides in an exposed loop that is not conserved in the other mammalian Type II PI 4-kinase, PI4K2B, explaining the specificity of GABARAP binding to the PI4K2A isoform. Mutation of the PI4K2A GIM inhibits GABARAP binding and PI4K2A-mediated recruitment of cytosolic GABARAP to subcellular organelles. We further show that GABARAP binds to mono-phosphorylated phosphoinositides, PI3P, PI4P, and PI5P, raising the possibility that these lipids contribute to the binding energies that drive GABARAP-protein interactions on membranes.
    Keywords:  ATG8; GABARAP; LIR motif; fluorescence fluctuation spectroscopy; phosphatidylinositol 4-kinase 2A
    DOI:  https://doi.org/10.1042/BSR20240200
  58. Autophagy. 2024 Oct 03.
    USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway.
    Ling Chen, Jieling Ning, Li Linghu, Jun Tang, Na Liu, Yao Long, Jingyue Sun, Cairui Lv, Ying Shi, Tania Tao, Desheng Xiao, Ya Cao, Xiang Wang, Shuang Liu, Guangjian Li, Bin Zhang, Yongguang Tao.
      Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that autophagy is positivelyassociated with sensitivity to ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each other remain largely unclear. Here, we screened85 deubiquitinating enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.
    Keywords:  Autophagy; LUAD; NFE2L2; SQSTM1; USP13; ferroptosis
    DOI:  https://doi.org/10.1080/15548627.2024.2410619
  59. Sci Adv. 2024 Oct 04. 10(40): eadq6223
    SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
    Richard Seager, Nitheyaa Shree Ramesh, Stephen Cross, Chun Guo, Kevin A Wilkinson, Jeremy M Henley.
      Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys151, MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.
    DOI:  https://doi.org/10.1126/sciadv.adq6223
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:11.