bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023–12–17
68 papers selected by
Viktor Korolchuk, Newcastle University
  1. The formation of ubiquitin rich condensates triggers recruitment of the ATG9A lipid transfer complex to initiate basal autophagy.
  2. Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology.
  3. Quantitative Analysis of Autophagy in Single Cells: Differential Response to Amino Acid and Glucose Starvation.
  4. A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis.
  5. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
  6. Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach.
  7. The role and function of autophagy through signaling and pathogenetic pathways and lncRNAs in ovarian cancer.
  8. Molecular determinants of the crosstalk between endosomal microautophagy and chaperone-mediated autophagy.
  9. The hookup model of the HOPS complex in autophagosome-lysosome fusion.
  10. Sequestration of translation initiation factors in p62 condensates.
  11. Induction mechanisms of autophagy and endoplasmic reticulum stress in intestinal ischemia-reperfusion injury, inflammatory bowel disease, and colorectal cancer.
  12. Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation.
  13. Susceptibility of Toxoplasma gondii to autophagy in human cells relies on multiple interacting parasite loci.
  14. FilGAP regulates tumor growth in Glioma through the regulation of mTORC1 and mTORC2.
  15. The Drosophila NPY-like system protects against chronic stress-induced learning deficit by preventing the disruption of autophagic flux.
  16. Discovery of a Small-Molecule Modulator of the Autophagy-Lysosome Pathway That Targets Lamin A/C and LAMP1, Induces Autophagic Flux, and Affects Lysosome Positioning in Neurons.
  17. Ectopic BH3-Only Protein Bim Associates with Hsp70 to Regulate Yeast Mitophagy.
  18. The route of autophagy regulation by osteopontin: a review on the linking mechanisms.
  19. Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.
  20. The Role of Autophagy in Type 2 Diabetic Kidney Disease Management.
  21. The Potential of Natural Compounds Regulating Autophagy in the Treatment of Osteoporosis.
  22. Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies.
  23. Autophagy and Senescence: The Molecular Mechanisms and Implications in Liver Diseases.
  24. Mammalian phagophores with finger-like shapes emerge from recycling endosomes.
  25. Investigating the prognostic value of mTORC1 signaling in bladder cancer via bioinformatics evaluation.
  26. Autophagy Analysis: A Step-by-Step Simple Practical Guide for Immunofluorescence and Western Blotting.
  27. Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis.
  28. Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.
  29. Involvement of Mitochondria in Parkinson's Disease.
  30. Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1-TFEB pathway to Huntington's disease neurodegeneration.
  31. NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease.
  32. Prolyl isomerase Pin1 promotes autophagy and cancer cell viability through activating FoxO3 signalling.
  33. Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages.
  34. The Role of TFE3 in Mediating Skeletal Muscle Mitochondrial Adaptations to Exercise Training.
  35. Autophagy-mediated NKG2D internalization impairs NK cell function and exacerbates radiation pneumonitis.
  36. Aberrant accumulation of ceramides in mitochondria trigger cell death requiring autophagy in Arabidopsis.
  37. Transport of N-acetylchitooligosaccharides and fluorescent N-acetylchitooligosaccharide analogs into rat liver lysosomes.
  38. Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.
  39. LTN1 promotes RLR degradation to inhibit immune response to RNA virus through the ESCRT pathway.
  40. Tetrabromobisphenol A induces neuronal cytotoxicity by inhibiting PINK1-Parkin-mediated mitophagy via upregulating ATF3 expression.
  41. Neurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway.
  42. Metabolism of Polyamines and Kidney Disease: A Promising Therapeutic Target.
  43. FARSB Facilitates Hepatocellular Carcinoma Progression by Activating the mTORC1 Signaling Pathway.
  44. Ferritinophagy-mediated ferroptosis facilitates methotrexate-induced hepatotoxicity by high-mobility group box 1 (HMGB1).
  45. Imaging HOCl Generation during the Mitochondria Peripheral Fission with a Tailor-Made Fluorescent Probe.
  46. PlAtg8-mediated autophagy regulates vegetative growth, sporangial cleavage, and pathogenesis in Peronophythora litchii.
  47. Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B.
  48. The Relevance of Autophagy within Inner Ear in Baseline Conditions and Tinnitus-Related Syndromes.
  49. Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells.
  50. The significance of caloric restriction mimetics as anti-aging drugs.
  51. Atg7 senses ATP levels and regulates AKT1-PDCD4 phosphorylation-ubiquitination axis to promote survival during metabolic stress.
  52. Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis.
  53. Lysosomal membrane integrity in fibroblasts derived from patients with Gaucher disease.
  54. T-2 Toxin-Mediated β-Arrestin-1 O-GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation.
  55. Lymphangioleiomyomatosis and mTOR inhibitors in real world-a narrative review.
  56. Methylated MFGE8 Promotes Early Brain Injury After Subarachnoid Hemorrhage and Inhibiting Autophagy of Nerve Cell.
  57. Effects of a N-Maleimide-derivatized Phosphatidylethanolamine on the Architecture and Properties of Lipid Bilayers.
  58. Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6.
  59. Deferoxamine Ameliorates Cypermethrin-Induced Iron Accumulation and Associated Alterations.
  60. Dibromoacetonitrile induced autophagy by mediating the PERK signalling pathway and ROS interaction in HT22 cell.
  61. PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.
  62. Small molecules as modulators of the proteostasis machinery: Implication in cardiovascular diseases.
  63. Lost in mTORC1-related translation limits healing, repair and regeneration in mammals.
  64. IGF2BP1/IMP1 deletion enhances a facultative stem cell state via regulation of MAP1LC3B.
  65. Spartin-mediated lipid transfer facilitates lipid droplet turnover.
  66. Oral Carbon Monoxide Enhances Autophagy Modulation in Prostate, Pancreatic, and Lung Cancers.
  67. Blockade of DDR1/PYK2/ERK signaling suggesting SH2 superbinder as a novel autophagy inhibitor for pancreatic cancer.
  68. Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.
  1. bioRxiv. 2023 Nov 29. pii: 2023.11.28.569058. [Epub ahead of print]
    The formation of ubiquitin rich condensates triggers recruitment of the ATG9A lipid transfer complex to initiate basal autophagy.
    D G Broadbent, C M McEwan, T M Tsang, D M Poole, B C Naylor, J C Price, J C Schmidt, J L Andersen.
      Autophagy is an essential cellular recycling process that maintains protein and organelle homeostasis. ATG9A vesicle recruitment is a critical early step in autophagy to initiate autophagosome biogenesis. The mechanisms of ATG9A vesicle recruitment are best understood in the context of starvation-induced non-selective autophagy, whereas less is known about the signals driving ATG9A vesicle recruitment to autophagy initiation sites in the absence of nutrient stress. Here we demonstrate that loss of ATG9A or the lipid transfer protein ATG2 leads to the accumulation of phosphorylated p62 aggregates in the context of basal autophagy. Furthermore, we show that p62 degradation requires the lipid scramblase activity of ATG9A. Lastly, we present evidence that poly-ubiquitin is an essential signal that recruits ATG9A and mediates autophagy foci assembly in nutrient replete cells. Together, our data support a ubiquitin-driven model of ATG9A recruitment and autophagosome formation during basal autophagy.
    DOI:  https://doi.org/10.1101/2023.11.28.569058
  2. Cells. 2023 Nov 30. pii: 2742. [Epub ahead of print]12(23):
    Unraveling the Intricacies of Autophagy and Mitophagy: Implications in Cancer Biology.
    Sunmi Lee, Ji-Yoon Son, Jinkyung Lee, Heesun Cheong.
      Autophagy is an essential lysosome-mediated degradation pathway that maintains cellular homeostasis and viability in response to various intra- and extracellular stresses. Mitophagy is a type of autophagy that is involved in the intricate removal of dysfunctional mitochondria during conditions of metabolic stress. In this review, we describe the multifaceted roles of autophagy and mitophagy in normal physiology and the field of cancer biology. Autophagy and mitophagy exhibit dual context-dependent roles in cancer development, acting as tumor suppressors and promoters. We also discuss the important role of autophagy and mitophagy within the cancer microenvironment and how autophagy and mitophagy influence tumor host-cell interactions to overcome metabolic deficiencies and sustain the activity of cancer-associated fibroblasts (CAFs) in a stromal environment. Finally, we explore the dynamic interplay between autophagy and the immune response in tumors, indicating their potential as immunomodulatory targets in cancer therapy. As the field of autophagy and mitophagy continues to evolve, this comprehensive review provides insights into their important roles in cancer and cancer microenvironment.
    Keywords:  autophagy; cancer; cancer-associated fibroblasts (CAFs); mitophagy; tumor microenvironment (TME); tumor-associated immune cells
    DOI:  https://doi.org/10.3390/cells12232742
  3. bioRxiv. 2023 Dec 03. pii: 2023.12.01.569679. [Epub ahead of print]
    Quantitative Analysis of Autophagy in Single Cells: Differential Response to Amino Acid and Glucose Starvation.
    Katie R Martin, Stephanie L Celano, Ryan D Sheldon, Russell G Jones, Jeffrey P MacKeigan.
      Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we sought to generate a quantitative catalog of autophagy across multiple stages and in single, living cells under normal growth conditions as well as in media starved specifically of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions. In addition to sharing our findings here, we provide our data as a high-quality resource for others interested in mathematical modeling or otherwise exploring autophagy in individual cells across a population.
    DOI:  https://doi.org/10.1101/2023.12.01.569679
  4. bioRxiv. 2023 Dec 01. pii: 2023.12.01.569475. [Epub ahead of print]
    A mitochondrial quality control mechanism reverses the phagosome maturation arrest caused by Mycobacterium tuberculosis.
    Surbhi Verma, Mrinmoy Das, Raman D Sharma, Vikas Yadav, Shweta Thakur, Priya Sharma, Mardiana Marzuki, Shihui Foo, Giulia M Piperno, Mehak Z Khan, Babu Mathew, Meenu Bajpai, Jaswinder Singh Maras, Shanshan Howland, Sovan Sarkar, Federica Benvenuti, Amit Singh, Vinay Nandicoori, Amit Singhal, Dhiraj Kumar.
      Phagosome maturation arrest (PMA) imposed by Mycobacterium tuberculosis ( Mtb ) is a classic tool that helps Mtb evade macrophage anti-bacterial responses. The exclusion of RAB7, a small GTPase, from Mtb -phagosomes underscores PMA. Here we report an unexpected mechanism that triggers crosstalk between the mitochondrial quality control (MQC) and the phagosome maturation pathways that reverses the PMA. CRISPR-mediated p62/SQSTM1 depletion ( p62 KD ) blocks mitophagy flux without impacting mitochondrial quality. In p62 KD cells, Mtb growth and survival are diminished, mainly through witnessing an increasingly oxidative environment and increased lysosomal targeting. The lysosomal targeting of Mtb is facilitated by enhanced TOM20 + mitochondria-derived vesicles (MDVs) biogenesis, a key MQC mechanism. In p62 KD cells, TOM20 + -MDVs biogenesis is MIRO1/MIRO2-dependent and delivered to lysosomes for degradation in a RAB7-dependent manner. Upon infection in p62 KD cells, TOM20 + -MDVs get extensively targeted to Mtb -phagosomes, inadvertently facilitating RAB7 recruitment, PMA reversal and lysosomal targeting of Mtb . Triggering MQC collapse in p62 KD cells further diminishes Mtb survival signifying cooperation between redox- and lysosome-mediated mechanisms. The MQC-anti-bacterial pathway crosstalk could be exploited for host-directed anti-tuberculosis therapies.
    DOI:  https://doi.org/10.1101/2023.12.01.569475
  5. Nat Commun. 2023 Dec 11. 14(1): 8187
    GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis.
    Qiang Zhu, Matthew E Combs, Juan Liu, Xue Bai, Wenbo B Wang, Laura E Herring, Jiandong Liu, Jason W Locasale, Dawn E Bowles, Ryan T Gross, Michelle Mendiola Pla, Christopher P Mack, Joan M Taylor.
      The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.
    DOI:  https://doi.org/10.1038/s41467-023-43889-6
  6. Mol Biol Rep. 2023 Dec 08. 51(1): 3
    Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach.
    Sougata Ghosh Chowdhury, Parimal Karmakar.
      Autophagy is a process that is characterized by the destruction of redundant components and the removal of dysfunctional ones to maintain cellular homeostasis. Autophagy dysregulation has been linked to various illnesses, such as neurodegenerative disorders and cancer. The precise transcription of the genes involved in autophagy is regulated by a network of epigenetic factors. This includes histone modifications and histone-modifying enzymes. Epigenetics is a broad category of heritable, reversible changes in gene expression that do not include changes to DNA sequences, such as chromatin remodeling, histone modifications, and DNA methylation. In addition to affecting the genes that are involved in autophagy, the epigenetic machinery can also alter the signals that control this process. In cancer, autophagy plays a dual role by preventing the development of tumors on one hand and this process may suppress tumor progression. This may be the control of an oncogene that prevents autophagy while, conversely, tumor suppression may promote it. The development of new therapeutic strategies for autophagy-related disorders could be initiated by gaining a deeper understanding of its intricate regulatory framework. There is evidence showing that certain machineries and regulators of autophagy are affected by post-translational and epigenetic modifications, which can lead to alterations in the levels of autophagy and these changes can then trigger disease or affect the therapeutic efficacy of drugs. The goal of this review is to identify the regulatory pathways associated with post-translational and epigenetic modifications of different proteins in autophagy which may be the therapeutic targets shortly.
    Keywords:  Autophagy; Cancer therapy; Epigenetic factors; Post-translational modulation
    DOI:  https://doi.org/10.1007/s11033-023-08961-w
  7. Pathol Res Pract. 2023 Oct 20. pii: S0344-0338(23)00600-3. [Epub ahead of print]253 154899
    The role and function of autophagy through signaling and pathogenetic pathways and lncRNAs in ovarian cancer.
    Seyedsaber Mirabdali, Kimia Ghafouri, Yalda Farahmand, Nasim Gholizadeh, Omid Yazdani, Romina Esbati, Bahareh Salmanian Hajiagha, Asiye Rahimi.
      Lysosomal-driven autophagy is a tightly controlled cellular catabolic process that breaks down and recycles broken or superfluous cell parts. It is involved in several illnesses, including cancer, and is essential in preserving cellular homeostasis. Autophagy prevents DNA mutation and cancer development by actively eliminating pro-oxidative mitochondria and protein aggregates from healthy cells. Oncosuppressor and oncogene gene mutations cause dysregulation of autophagy. Increased autophagy may offer cancer cells a pro-survival advantage when oxygen and nutrients are scarce and resistance to chemotherapy and radiation. This finding justifies the use of autophagy inhibitors in addition to anti-neoplastic treatments. Excessive autophagy levels can potentially kill cells. The diagnosis and treatment of ovarian cancer present many difficulties due to its complexity and heterogeneity. Understanding the role of autophagy, a cellular process involved in the breakdown and recycling of cellular components, in ovarian cancer has garnered increasing attention in recent years. Of particular note is the increasing amount of data indicating a close relationship between autophagy and ovarian cancer. Autophagy either promotes or restricts tumor growth in ovarian cancer. Dysregulation of autophagy signaling pathways in ovarian cancers can affect the development, metastasis, and response to tumor treatment. The precise mechanism underlying autophagy concerning ovarian cancer remains unclear, as does the role autophagy plays in ovarian carcinoma. In this review, we tried to encapsulate and evaluate current findings in investigating autophagy in ovarian cancer.
    Keywords:  Autophagy; Epigenetic; Long non-coding RNAs; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.prp.2023.154899
  8. Cell Rep. 2023 Dec 05. pii: S2211-1247(23)01541-3. [Epub ahead of print]42(12): 113529
    Molecular determinants of the crosstalk between endosomal microautophagy and chaperone-mediated autophagy.
    Gregory J Krause, Philipp Kirchner, Barbara Stiller, Kateryna Morozova, Antonio Diaz, Kuei-Ho Chen, Nevan J Krogan, Esperanza Agullo-Pascual, Cristina C Clement, Kristen Lindenau, Danielle L Swaney, Shilpa Dilipkumar, Jose Javier Bravo-Cordero, Laura Santambrogio, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI) are pathways for selective degradation of cytosolic proteins in lysosomes and late endosomes, respectively. These autophagic processes share as a first step the recognition of the same five-amino-acid motif in substrate proteins by the Hsc70 chaperone, raising the possibility of coordinated activity of both pathways. In this work, we show the existence of a compensatory relationship between CMA and eMI and identify a role for the chaperone protein Bag6 in triage and internalization of eMI substrates into late endosomes. Association and dynamics of Bag6 at the late endosome membrane change during starvation, a stressor that, contrary to other autophagic pathways, causes a decline in eMI activity. Collectively, these results show a coordinated function of eMI with CMA, identify the interchangeable subproteome degraded by these pathways, and start to elucidate the molecular mechanisms that facilitate the switch between them.
    Keywords:  Bag6; CP: Molecular biology; autophagy; chaperone; late endosome; lysosome; microautophagy; protein degradation; protein targeting; proteostasis; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113529
  9. Autophagy. 2023 Dec 11. 1-2
    The hookup model of the HOPS complex in autophagosome-lysosome fusion.
    Shen Zhang, Linsen Li, Xiaoxia Liu, Qing Zhong.
      Macroautophagy/autophagy is a highly conserved process that involves the degradation of proteins, damaged organelles, and other cytoplasmic macromolecules. Autophagosome-lysosome fusion is critical for successful substrate degradation and is mediated by SNARE proteins. The fusion process requires additional vesicle docking and tethering-regulating factors. Our recent work has uncovered a functional model of autophagosome-lysosome fusion. We demonstrated that the six-subunit homotypic fusion and vacuole protein sorting (HOPS) complex can be assembled by two subcomplexes, the VPS39-VPS11 subcomplex (HOPS-2) and the VPS41-VPS16-VPS18-VPS33A subcomplex (HOPS-4). VPS39 binds with RAB2 on the autophagosome and VPS41 binds with RAB39A on the lysosome, which then promotes membrane tethering and autophagic SNARE-mediated membrane fusion. Moreover, we have revealed that ALS- and FTD-related C9orf72 is a guanine exchange factor (GEF) for RAB39A. In this punctum, we discuss how the C9orf72-RAB39A-HOPS axis function regulates autophagosome-lysosome fusion.
    Keywords:  Autophagosome-lysosome fusion; C9orf72; HOPS complex; RAB39A; membrane tethering
    DOI:  https://doi.org/10.1080/15548627.2023.2291938
  10. Cell Rep. 2023 Dec 12. pii: S2211-1247(23)01595-4. [Epub ahead of print]42(12): 113583
    Sequestration of translation initiation factors in p62 condensates.
    Alberto Danieli, Georg Vucak, Manuela Baccarini, Sascha Martens.
      Selective autophagy mediates the removal of harmful material from the cytoplasm. This cargo material is selected by cargo receptors, which orchestrate its sequestration within double-membrane autophagosomes and subsequent lysosomal degradation. The cargo receptor p62/SQSTM1 is present in cytoplasmic condensates, and a fraction of them are constantly delivered into lysosomes. However, the molecular composition of the p62 condensates is incompletely understood. To obtain insights into their composition, we develop a method to isolate these condensates and find that p62 condensates are enriched in components of the translation machinery. Furthermore, p62 interacts with translation initiation factors, and eukaryotic initiation factor 2α (eIF2α) and eIF4E are degraded by autophagy in a p62-dependent manner. Thus, p62-mediated autophagy may in part be linked to down-regulation of translation initiation. The p62 condensate isolation protocol developed here may facilitate the study of their contribution to cellular quality control and their roles in health and disease.
    Keywords:  CP: Cell biology; CP: Molecular biology; SQSTM1; autophagy; cargo receptor; translation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113583
  11. Biomed Pharmacother. 2023 Dec 07. pii: S0753-3322(23)01782-1. [Epub ahead of print]170 115984
    Induction mechanisms of autophagy and endoplasmic reticulum stress in intestinal ischemia-reperfusion injury, inflammatory bowel disease, and colorectal cancer.
    Yan Shi, Bing Jiang, Jingwen Zhao.
      In recent years, the incidence of intestinal ischemia-reperfusion injury (II/RI), inflammatory bowel disease (IBD), and colorectal cancer (CRC) has been gradually increasing, posing significant threats to human health. Autophagy and endoplasmic reticulum stress (ERS) play important roles in II/RI. Damage caused by ischemia and cellular stress can activate ERS, which in turn initiates autophagy to clear damaged organelles and abnormal proteins, thereby alleviating ERS and maintaining the intestinal environment. In IBD, chronic inflammation damages intestinal tissues and activates autophagy and ERS. Autophagy is initiated by upregulating ATG genes and downregulating factors that inhibit autophagy, thereby clearing abnormal proteins, damaged organelles, and bacteria. Simultaneously, persistent inflammatory stimulation can also trigger ERS, leading to protein imbalance and abnormal folding in the ER lumen. The activation of ERS can maintain cellular homeostasis by initiating the autophagy process, thereby reducing inflammatory responses and cell apoptosis in the intestine. In CRC, excessive cell proliferation and protein synthesis lead to increased ERS. The activation of ERS, regulated by signaling pathways such as IRE1α and PERK, can initiate autophagy to clear abnormal proteins and damaged organelles, thereby reducing the negative effects of ERS. It can be seen that autophagy and ERS play a crucial regulatory role in the development of intestinal diseases. Therefore, the progress in targeted therapy for intestinal diseases based on autophagy and ERS provides novel strategies for managing intestinal diseases. In this paper, we review the advances in regulation of autophagy and ERS in intestinal diseases, emphasizing the potential molecular mechanisms for therapeutic applications.
    Keywords:  Autophagy; Colorectal cancer; Endoplasmic reticulum stress; Inflammatory bowel disease; Intestinal ischemia-reperfusion injury
    DOI:  https://doi.org/10.1016/j.biopha.2023.115984
  12. Exp Cell Res. 2023 Dec 08. pii: S0014-4827(23)00423-8. [Epub ahead of print] 113872
    Sumoylation and phosphorylation of PTEN boosts and curtails autophagy respectively by influencing cell membrane localisation.
    Debojyoti De, Ginia Ghosh, Parimal Karmakar.
      Autophagy is involved in the entirety of cellular survival, homeostasis and death which becomes more self-evident when its dysregulation is implicated in several pathological conditions. PTEN positively regulates autophagy and like other proteins undergo post-translational modifications. It is crucial to investigate the relationship between PTEN and autophagy as it is generally observed to be negligible in PTEN deficient cancer cells. Here, we have shown that such modifications of PTEN namely sumoylation and phosphorylation upregulates and downregulates autophagy respectively. Transfection of plasmid containing full length PTEN in PTEN-negative prostate cancer cell line PC3, induced autophagy on further starvation. When a sumoylation-deficient mutant of PTEN was transfected and cells were put under similar starvation, a decline in autophagy was observed. On the other hand, cells transfected with phosphorylation-deficient mutant of PTEN showed elevated expression of autophagy. Contrarily, transfection with phosphorylation-mimicking mutant caused reduced expression of autophagy. On further analysis, it was detected that PTEN's association with the plasma membrane was under positive and negative influence from its sumoylation and phosphorylation respectively. This association is integral as it is the foremost site for PTEN to oppose PI3K/AKT pathway and consequently upregulate autophagy. Thus, this study indicates that sumoylation and phosphorylation of PTEN can control autophagy via its cell membrane association.
    Keywords:  Autophagic vacuoles; Cell membrane localisation; PI3K/AKT pathway; Post-translational modifications; mTOR
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113872
  13. mBio. 2023 Dec 14. e0259523
    Susceptibility of Toxoplasma gondii to autophagy in human cells relies on multiple interacting parasite loci.
    Nicholas Rinkenberger, Alex Rosenberg, Joshua B Radke, Jaya Bhushan, Tadakimi Tomita, Louis M Weiss, L David Sibley.
       IMPORTANCE: Autophagy is a process used by cells to recycle organelles and macromolecules and to eliminate intracellular pathogens. Previous studies have shown that some stains of Toxoplasma gondii are resistant to autophagy-dependent growth restriction, while others are highly susceptible. Although it is known that autophagy-mediated control requires activation by interferon gamma, the basis for why parasite strains differ in their susceptibility is unknown. Our findings indicate that susceptibility involves at least five unlinked parasite genes on different chromosomes, including several secretory proteins targeted to the parasite-containing vacuole and exposed to the host cell cytosol. Our findings reveal that susceptibility to autophagy-mediated growth restriction relies on differential recognition of parasite proteins exposed at the host-pathogen interface, thus identifying a new mechanism for cell-autonomous control of intracellular pathogens.
    Keywords:  dense granule proteins; genetic mapping; innate immunity; interferon; intracellular parasite; linkage analysis; parasitophorous vacuole; quantitative trait locus; secretory proteins
    DOI:  https://doi.org/10.1128/mbio.02595-23
  14. Sci Rep. 2023 Dec 08. 13(1): 20956
    FilGAP regulates tumor growth in Glioma through the regulation of mTORC1 and mTORC2.
    Koji Tsutsumi, Ayumi Nohara, Taiki Tanaka, Moe Murano, Yurina Miyagaki, Yasutaka Ohta.
      The mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that forms the two different protein complexes, known as mTORC1 and mTORC2. mTOR signaling is activated in a variety of tumors, including glioma that is one of the malignant brain tumors. FilGAP (ARHGAP24) is a negative regulator of Rac, a member of Rho family small GTPases. In this study, we found that FilGAP interacts with mTORC1/2 and is involved in tumor formation in glioma. FilGAP interacted with mTORC1 via Raptor and with mTORC2 via Rictor and Sin1. Depletion of FilGAP in KINGS-1 glioma cells decreased phosphorylation of S6K and AKT. Furthermore, overexpression of FilGAP increased phosphorylation of S6K and AKT, suggesting that FilGAP activates mTORC1/2. U-87MG, glioblastoma cells, showed higher mTOR activity than KINGS-1, and phosphorylation of S6K and AKT was not affected by suppression of FilGAP expression. However, in the presence of PI3K inhibitors, phosphorylation of S6K and AKT was also decreased in U-87MG by depletion of FilGAP, suggesting that FilGAP may also regulate mTORC2 in U-87MG. Finally, we showed that depletion of FilGAP in KINGS-1 and U-87MG cells significantly reduced spheroid growth. These results suggest that FilGAP may contribute to tumor growth in glioma by regulating mTORC1/2 activities.
    DOI:  https://doi.org/10.1038/s41598-023-47892-1
  15. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2307632120
    The Drosophila NPY-like system protects against chronic stress-induced learning deficit by preventing the disruption of autophagic flux.
    Tianli Chen, Mengyu Zhang, Zhaowen Ding, Jiao Hu, Jie Yang, Lei He, Jia Jia, Jingjing Yang, Junfei Yang, Xiaoxu Song, Peng Chen, Zongzhao Zhai, Jing Huang, Yirong Wang, Hongtao Qin.
      Chronic stress may induce learning and memory deficits that are associated with a depression-like state in Drosophila melanogaster. The molecular and neural mechanisms underlying the etiology of chronic stress-induced learning deficit (CSLD) remain elusive. Here, we show that the autophagy-lysosomal pathway, a conserved cellular signaling mechanism, is associated with chronic stress in Drosophila, as indicated by time-series transcriptome profiling. Our findings demonstrate that chronic stress induces the disruption of autophagic flux, and chronic disruption of autophagic flux could lead to a learning deficit. Remarkably, preventing the disruption of autophagic flux by up-regulating the basal autophagy level is sufficient to protect against CSLD. Consistent with the essential role of the dopaminergic system in modulating susceptibility to CSLD, dopamine neuronal activity is also indispensable for chronic stress to induce the disruption of autophagic flux. By screening knockout mutants, we found that neuropeptide F, the Drosophila homolog of neuropeptide Y, is necessary for normal autophagic flux and promotes resilience to CSLD. Moreover, neuropeptide F signaling during chronic stress treatment promotes resilience to CSLD by preventing the disruption of autophagic flux. Importantly, neuropeptide F receptor activity in dopamine neurons also promotes resilience to CSLD. Together, our data elucidate a mechanism by which stress-induced excessive dopaminergic activity precipitates the disruption of autophagic flux, and chronic disruption of autophagic flux leads to CSLD, while inhibitory neuropeptide F signaling to dopamine neurons promotes resilience to CSLD by preventing the disruption of autophagic flux.
    Keywords:  Drosophila melanogaster; autophagy; chronic stress; learning and memory; neuropeptide F
    DOI:  https://doi.org/10.1073/pnas.2307632120
  16. ACS Chem Neurosci. 2023 Dec 09.
    Discovery of a Small-Molecule Modulator of the Autophagy-Lysosome Pathway That Targets Lamin A/C and LAMP1, Induces Autophagic Flux, and Affects Lysosome Positioning in Neurons.
    Ryan S Hippman, Amanda M Snead, Zoe A Petros, Melissa A Korkmaz-Vaisys, Sruchi Patel, Daniel Sotelo, Andrew Dobria, Maryna Salkovski, Thu T A Nguyen, Ricardo Linares, Stephanie M Cologna, Swetha Gowrishankar, Leslie N Aldrich.
      Autophagy is a major catabolic degradation and recycling process that maintains homeostasis in cells and is especially important in postmitotic neurons. We implemented a high-content phenotypic assay to discover small molecules that promote autophagic flux and completed target identification and validation studies to identify protein targets that modulate the autophagy pathway and promote neuronal health and survival. Efficient syntheses of the prioritized compounds were developed to readily access analogues of the initial hits, enabling initial structure-activity relationship studies to improve potency and preparation of a biotin-tagged pulldown probe that retains activity. This probe facilitated target identification and validation studies through pulldown and competition experiments using both an unbiased proteomics approach and western blotting to reveal Lamin A/C and LAMP1 as the protein targets of compound RH1115. Evaluation of RH1115 in neurons revealed that this compound induces changes to LAMP1 vesicle properties and alters lysosome positioning. Dysfunction of the autophagy-lysosome pathway has been implicated in a variety of neurodegenerative diseases, including Alzheimer's disease, highlighting the value of new strategies for therapeutic modulation and the importance of small-molecule probes to facilitate the study of autophagy regulation in cultured neurons and in vivo.
    Keywords:  autophagy; medicinal chemistry; neurodegenerative diseases; phenotypic high-throughput screen; small molecules; target identification
    DOI:  https://doi.org/10.1021/acschemneuro.3c00573
  17. Dokl Biochem Biophys. 2023 Oct;512(1): 292-299
    Ectopic BH3-Only Protein Bim Associates with Hsp70 to Regulate Yeast Mitophagy.
    Linjie Yuan, Yuying Wang, B A Margulis, Ting Song, Ziqian Wang, Zhichao Zhang.
      Mitophagy, a form of selective autophagy, plays an essential role to maintain a population of healthy and functional mitochondria for normal cellular metabolism. Acting mainly as one of the B-cell lymphoma 2 (Bcl-2) family pro-apoptotic members, Bim (also known as BCL2L11) was identified to be a co-chaperone of Hsp70 to promote mitophagy in mammalian cells. Herein, with the help of a specific Hsp70/Bim disruptor and Om45-GFP processing assay, we illustrated that ectopic BimEL is able to promote mitophagy through Hsp70/Bim interaction in yeast, where Bax/Bak is absent. The Hsp70/Bim-mediated mitophagy is conserved in eukaryotes, from yeast to humans.
    Keywords:  B-cell lymphoma 2 family; Bim; Hsp70; mitophagy; yeast
    DOI:  https://doi.org/10.1134/S1607672923700485
  18. J Recept Signal Transduct Res. 2023 Dec 11. 1-7
    The route of autophagy regulation by osteopontin: a review on the linking mechanisms.
    Zohreh Abdolvahabi, Samira Ezzati-Mobaser, Zahra Hesari.
      Autophagy is a dynamic intracellular process of protein degradation, which is mostly triggered by nutrient deprivation. This process initiates with the formation of autophagosomes, which they capture cytosolic material that is then degraded upon fusion with the lysosome. Several factors have been found to be associated with autophagy modulation, of which extracellular matrix (ECM) components has attracted the attention of recent studies. Osteopontin (OPN) is an important extracellular matrix component that has been detected in a wide range of tumor cells, and is involved in cancer cell invasion and metastasis. Recently, a number of studies have focused on the relationship of OPN with autophagy, by delineating the intracellular signaling pathways that connect OPN to the autophagy process. We will summarize signaling pathways and cell surface receptors, through which OPN regulates the process of autophagy.
    Keywords:  Autophagy; cancer; cell death; osteopontin; signaling pathways
    DOI:  https://doi.org/10.1080/10799893.2023.2291563
  19. Am J Physiol Cell Physiol. 2023 Dec 11.
    Parkin-mediated mitophagy is a potential treatment for oxaliplatin-induced peripheral neuropathy.
    Guoqing Zhao, Te Zhang, Jiannan Li, Longyun Li, Peng Chen, Chunlu Zhang, Kai Li, Cancan Cui.
      Oxaliplatin-induced peripheral nerve pain (OIPNP) is a common chemotherapy-related complication, but the mechanism is complex. Mitochondria are vital for cellular homeostasis and regulating oxidative stress. Parkin-mediated mitophagy is a cellular process that removes damaged mitochondria, exhibiting a protective effect in various diseases; however, its role in OIPNP remains unclear. In this study, we found that Parkin-mediated mitophagy was decreased, and reactive oxygen species (ROS) was upregulated in OIPNP rat dorsal root ganglion (DRG) in vivo and in PC12 cells stimulated with oxaliplatin (OXA) in vitro. Overexpression of Parkin indicated that OXA might cause mitochondrial and cell damage by inhibiting mitophagy. We also showed that salidroside (SAL) upregulated Parkin-mediated mitophagy to eliminate damaged mitochondria and promote PC12 cell survival. Knockdown of Parkin indicated that mitophagy is crucial for apoptosis and mitochondrial homeostasis in PC12 cells. In vivo study also demonstrated that SAL enhances Parkin-mediated mitophagy in the DRG and alleviates peripheral nerve injury and pain. These results suggest that Parkin-mediated mitophagy is involved in the pathogenesis of OIPNP and may be a potential therapeutic target for OIPNP.
    Keywords:  Parkin; mitophagy; oxaliplatin; peripheral nerve pain; salidroside
    DOI:  https://doi.org/10.1152/ajpcell.00276.2023
  20. Cells. 2023 Nov 23. pii: 2691. [Epub ahead of print]12(23):
    The Role of Autophagy in Type 2 Diabetic Kidney Disease Management.
    Che-Hao Tseng, Kavya M Shah, I-Jen Chiu, Li-Li Hsiao.
      Diabetic kidney disease (DKD), or diabetic nephropathy (DN), is one of the most prevalent complications of type 2 diabetes mellitus (T2DM) and causes severe burden on the general welfare of T2DM patients around the world. While several new agents have shown promise in treating this condition and potentially halting the progression of the disease, more work is needed to understand the complex regulatory network involved in the disorder. Recent studies have provided new insights into the connection between autophagy, a physiological metabolic process known to maintain cellular homeostasis, and the pathophysiological pathways of DKD. Typically, autophagic activity plays a role in DKD progression mainly by promoting an inflammatory response to tissue damage, while both overactivated and downregulated autophagy worsen disease outcomes in different stages of DKD. This correlation demonstrates the potential of autophagy as a novel therapeutic target for the disease, and also highlights new possibilities for utilizing already available DN-related medications. In this review, we summarize findings on the relationship between autophagy and DKD, and the impact of these results on clinical management strategies.
    Keywords:  autophagy; diabetic kidney disease; diabetic nephropathy
    DOI:  https://doi.org/10.3390/cells12232691
  21. J Inflamm Res. 2023 ;16 6003-6021
    The Potential of Natural Compounds Regulating Autophagy in the Treatment of Osteoporosis.
    Yiwei Zhao, Zechao Qu, Songchuan Zhao, Yong Zhang, Yining Gong, Bo Zhang, Xiangcheng Gao, Dong Wang, Liang Yan.
      The maintenance of bone homeostasis is dynamically regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Abnormal differentiation of osteoclast and insufficient osteoblast production can cause bone diseases such as osteoporosis. As one of the highly conserved catabolic pathways in eukaryotic cells, autophagy plays an important role in maintaining cell homeostasis, stress injury repair, proliferation and differentiation. Numerous studies have found that autophagy activity is essential for the survival, differentiation and function of bone cells, and that regulation of autophagy can affect the metabolism of osteoblasts and osteoclasts, thus affecting bone homeostasis. Therefore, using autophagy as a theme, this review outlines the basic process of autophagy, the relationship between autophagy and osteoblasts and osteoclasts, and summarizes the latest research progress of common autophagic signaling pathways in osteoblasts and osteoclasts. The regulatory effects of protein molecules and natural compounds on the autophagy pathway of osteoblasts and osteoclasts discovered in current research are summarized and discussed. This will help to further clarify the mechanism of osteoporosis, understand the relationship between autophagy and osteoporosis, and propose new therapeutic strategies and new ideas for anti-osteoporosis.
    Keywords:  autophagy signaling pathway; natural compounds; osteoblast; osteoclast; osteoporosis
    DOI:  https://doi.org/10.2147/JIR.S437067
  22. Mol Cancer. 2023 Dec 09. 22(1): 201
    Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies.
    Manuela Giansanti, Tobias Theinert, Sarah Katharina Boeing, Dorothee Haas, Paul-Gerhardt Schlegel, Paola Vacca, Francesca Nazio, Ignazio Caruana.
      Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.
    Keywords:  Autophagy; Effector cells; Metabolism; Mitophagy; T and NK development
    DOI:  https://doi.org/10.1186/s12943-023-01893-w
  23. Int J Mol Sci. 2023 Nov 28. pii: 16880. [Epub ahead of print]24(23):
    Autophagy and Senescence: The Molecular Mechanisms and Implications in Liver Diseases.
    Qiao Li, Yan Lin, Guangyu Liang, Nanyin Xiao, Heng Zhang, Xiao Yang, Jiankun Yang, Anding Liu.
      The liver is the primary organ accountable for complex physiological functions, including lipid metabolism, toxic chemical degradation, bile acid synthesis, and glucose metabolism. Liver function homeostasis is essential for the stability of bodily functions and is involved in the complex regulation of the balance between cell proliferation and cell death. Cell proliferation-halting mechanisms, including autophagy and senescence, are implicated in the development of several liver diseases, such as cholestasis, viral hepatitis, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Among various cell death mechanisms, autophagy is a highly conserved and self-degradative cellular process that recycles damaged organelles, cellular debris, and proteins. This process also provides the substrate for further metabolism. A defect in the autophagy machinery can lead to premature diseases, accelerated aging, inflammatory state, tumorigenesis, and cellular senescence. Senescence, another cell death type, is an active player in eliminating premalignant cells. At the same time, senescent cells can affect the function of neighboring cells by secreting the senescence-associated secretory phenotype and induce paracrine senescence. Autophagy can promote and delay cellular senescence under different contexts. This review decodes the roles of autophagy and senescence in multiple liver diseases to achieve a better understanding of the regulatory mechanisms and implications of autophagy and senescence in various liver diseases.
    Keywords:  NAFLD; SASP; autophagy; liver cancer; liver fibrosis; senescence
    DOI:  https://doi.org/10.3390/ijms242316880
  24. Autophagy. 2023 Dec 14.
    Mammalian phagophores with finger-like shapes emerge from recycling endosomes.
    Claudia Puri, David C Rubinsztein.
      Autophagosomes are double-membraned vesicles that engulf cytoplasmic contents, which are ultimately degraded after autophagosome-lysosome fusion. The prevailing view, largely inferred from EM-based studies, was that mammalian autophagosomes evolved from disc-shaped precursors that invaginated and then were closed at the single opening. Many site(s) of origin of these precursors have been proposed. Using superresolution structured illumination microscopy and electron microscopy, we find that mammalian autophagosomes derive from finger-like outgrowths from the recycling endosome. These "fingers" survey a large cell volume and then close into a "fist" and the openings are sealed in an ESCRT-dependent fashion, while the precursors are still attached to the recycling endosome. We call this transient recycling endosome-attached, closed, autophagic structure an "autophago-dome". DNM2-dependent scission of the autophago-dome from the recycling endosomes liberates free autophagosomes from this compartment. These data reveal unexpected morphologies of autophagosome precursors and raise new questions about the control of this process.
    Keywords:  ESCRT; RAB11; autophagy; phagophore; recycling endosome
    DOI:  https://doi.org/10.1080/15548627.2023.2293439
  25. Sci Rep. 2023 Dec 12. 13(1): 22066
    Investigating the prognostic value of mTORC1 signaling in bladder cancer via bioinformatics evaluation.
    Xin Yu, Wenge Li, Shengrong Sun, Juanjuan Li.
      Bladder cancer, a prevalent and heterogeneous malignancy, necessitates the discovery of pertinent biomarkers to enable personalized treatment. The mammalian target of rapamycin complex 1 (mTORC1), a pivotal regulator of cellular growth, metabolism, and immune response, exhibits activation in a subset of bladder cancer tumors. In this study, we explore the prognostic significance of mTORC1 signaling in bladder cancer through the utilization of bioinformatics analysis. Our investigation incorporates transcriptomic, somatic mutation, and clinical data, examining the mTORC1 score of each sample, as well as the enrichment of differentially expressed genes (DEGs), differentiation characteristics, immunological infiltration, and metabolic activity. Our findings reveal that elevated mTORC1 levels serve as an adverse prognostic indicator for bladder cancer patients, exhibiting a significant association with Basal-type bladder cancer. Patients with heightened mTORC1 activation display heightened levels of pro-carcinogenic metabolism. Additionally, these individuals demonstrate enhanced response to immunotherapy. Finally, we develop an mTORC1-related signature capable of predicting the prognosis of bladder cancer patients.The signature offers novel mTORC1-related biomarkers and provides fresh insights into the involvement of mTORC1 in the pathogenesis of bladder cancer.
    DOI:  https://doi.org/10.1038/s41598-023-49366-w
  26. Methods Mol Biol. 2023 Dec 15.
    Autophagy Analysis: A Step-by-Step Simple Practical Guide for Immunofluorescence and Western Blotting.
    Meesala Krishna Murthy, Pratima Khandayataray, Dibyaranjan Samal, Rojalin Pattanayak, Chandra Sekhar Mohanty.
      Autophagy is a vital cellular process responsible for breaking down faulty cellular components and organelles, ultimately routed through lysosomes for degradation. This intricate mechanism involves the translocation of LC3, a cytoplasmic protein, onto the autophagosome membranes. As a result, it becomes feasible to discern cells engaged in autophagy by employing fluorescent markers designed for LC3 or other indicative autophagy markers. Although a variety of techniques such as immunofluorescence and western blotting serve as indispensable tools for assessing autophagy, the definitive confirmation comes from the visualization of autophagosomes using transmission electron microscopy. While numerous protocols for antibody staining can be found in scientific literature and on antibody suppliers' websites, these procedures often demand significant time and financial resources for setup. This chapter endeavors to provide a user-friendly and cost-effective guide for practitioners seeking proficiency in immunofluorescence staining and western blotting techniques.
    Keywords:  Antibodies; Immunofluorescence staining; Microscope; SDS-PAGE; Western blotting
    DOI:  https://doi.org/10.1007/7651_2023_508
  27. J Nanobiotechnology. 2023 Dec 08. 21(1): 472
    Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis.
    Yuan Zhong, Ali Maruf, Kai Qu, Małgorzata Milewska, Ilona Wandzik, Nianlian Mou, Yu Cao, Wei Wu.
      Atherosclerosis, cholesterol-driven plaque formation in arteries, is a complex multicellular disease which is a leading cause of vascular diseases. During the progression of atherosclerosis, the autophagic function is impaired, resulting in lipid accumulation-mediated foam cell formation. The stimulation of autophagy is crucial for the recovery of cellular recycling process. One of the potential autophagy inducers is trehalose, a naturally occurring non-reducing disaccharide. However, trehalose has poor bioavailability due to its hydrophilic nature which results in poor penetration through cell membranes. To enhance its bioavailability, we developed trehalose-releasing nanogels (TNG) for the treatment of atherosclerosis. The nanogels were fabricated through copolymerization of 6-O-acryloyl-trehalose with the selected acrylamide-type monomers affording a high trehalose conjugation (~ 58%, w/w). TNG showed a relatively small hydrodynamic diameter (dH, 67 nm) and a uniform spherical shape and were characterized by negative ζ potential (-18 mV). Thanks to the trehalose-rich content, TNG demonstrated excellent colloidal stability in biological media containing serum and were non-hemolytic to red blood cells. In vitro study confirmed that TNG could stimulate autophagy in foam cells and enhance lipid efflux and in vivo study in ApoE-/- mice indicated a significant reduction in atherosclerotic plaques, while increasing autophagic markers. In conclusion, TNG hold great promise as a trehalose delivery system to restore impaired autophagy-mediated lipid efflux in atherosclerosis and subsequently reduce atherosclerotic plaques.
    Keywords:  Atherosclerosis; Autophagy; Drug delivery; Nanogel; Trehalose
    DOI:  https://doi.org/10.1186/s12951-023-02248-9
  28. FASEB J. 2024 Jan;38(1): e23343
    Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.
    Logan R Timmins, Milene Ortiz-Silva, Bharat Joshi, Y Lydia Li, Fiona H Dickson, Timothy H Wong, Kurt R Vandevoorde, Ivan R Nabi.
      Caveolin-1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine-14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that CRISPR/Cas9 knockout (KO) of CAV1 increases mitochondrial oxidative phosphorylation, increases mitochondrial potential, and reduces ROS in MDA-MB-231 triple-negative breast cancer cells. Supporting a role for pCAV1, these effects are reversed upon expression of CAV1 phosphomimetic CAV1 Y14D but not non-phosphorylatable CAV1 Y14F. pCAV1 is a known effector of Rho-associated kinase (ROCK) signaling and ROCK1/2 signaling mediates CAV1 promotion of increased mitochondrial potential and decreased ROS production in MDA-MB-231 cells. CAV1/ROCK control of mitochondrial potential and ROS is caveolae-independent as similar results were observed in PC3 prostate cancer cells lacking caveolae. Increased mitochondrial health and reduced ROS in CAV1 KO MDA-MB-231 cells were reversed by knockdown of the autophagy protein ATG5, mitophagy regulator PINK1 or the mitochondrial fission protein Drp1 and therefore due to mitophagy. Use of the mitoKeima mitophagy probe confirmed that CAV1 signaling through ROCK inhibited basal mitophagic flux. Activation of AMPK, a major mitochondrial homeostasis protein inhibited by ROCK, is inhibited by CAV1-ROCK signaling and mediates the increased mitochondrial potential, decreased ROS, and decreased basal mitophagy flux observed in wild-type MDA-MB-231 cells. CAV1 regulation of mitochondrial health and ROS in cancer cells therefore occurs via ROCK-dependent inhibition of AMPK. This study therefore links pCAV1 signaling activity at the plasma membrane with its regulation of mitochondrial activity and cancer cell metabolism through control of mitophagy.
    Keywords:  AMPK; caveolin-1; mitochondria; mitophagy; reactive oxygen species; rho kinase
    DOI:  https://doi.org/10.1096/fj.202201872RR
  29. Int J Mol Sci. 2023 Dec 01. pii: 17027. [Epub ahead of print]24(23):
    Involvement of Mitochondria in Parkinson's Disease.
    Chi-Jing Choong, Hideki Mochizuki.
      Mitochondrial dysregulation, such as mitochondrial complex I deficiency, increased oxidative stress, perturbation of mitochondrial dynamics and mitophagy, has long been implicated in the pathogenesis of PD. Initiating from the observation that mitochondrial toxins cause PD-like symptoms and mitochondrial DNA mutations are associated with increased risk of PD, many mutated genes linked to familial forms of PD, including PRKN, PINK1, DJ-1 and SNCA, have also been found to affect the mitochondrial features. Recent research has uncovered a much more complex involvement of mitochondria in PD. Disruption of mitochondrial quality control coupled with abnormal secretion of mitochondrial contents to dispose damaged organelles may play a role in the pathogenesis of PD. Furthermore, due to its bacterial ancestry, circulating mitochondrial DNAs can function as damage-associated molecular patterns eliciting inflammatory response. In this review, we summarize and discuss the connection between mitochondrial dysfunction and PD, highlighting the molecular triggers of the disease process, the intra- and extracellular roles of mitochondria in PD as well as the therapeutic potential of mitochondrial transplantation.
    Keywords:  PINK1; Parkin; Parkinson’s disease; extracellular mitochondria; mitochondria; mitochondria transplantation
    DOI:  https://doi.org/10.3390/ijms242317027
  30. Nat Aging. 2023 Dec 08.
    Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1-TFEB pathway to Huntington's disease neurodegeneration.
    Seong Won Lee, Young Mi Oh, Matheus B Victor, Yan Yang, Shawei Chen, Ilya Strunilin, Sonika Dahiya, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Andrew S Yoo.
      Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs) in Huntington's disease identified pathways involving RCAN1, a negative regulator of calcineurin. Notably, RCAN1 protein increased with age in reprogrammed MSNs as well as in human postmortem striatum and RCAN1 knockdown rescued patient-derived MSNs of Huntington's disease from degeneration. RCAN1 knockdown enhanced chromatin accessibility of genes involved in longevity and autophagy, mediated through enhanced calcineurin activity, leading to TFEB's nuclear localization by dephosphorylation. Furthermore, G2-115, an analog of glibenclamide with autophagy-enhancing activities, reduced the RCAN1-calcineurin interaction, phenocopying the effect of RCAN1 knockdown. Our results demonstrate that targeting RCAN1 genetically or pharmacologically can increase neuronal resilience in Huntington's disease.
    DOI:  https://doi.org/10.1038/s43587-023-00538-3
  31. Biochim Biophys Acta Mol Basis Dis. 2023 Dec 05. pii: S0925-4439(23)00346-0. [Epub ahead of print]1870(2): 166980
    NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease.
    Inês Caria, Maria João Nunes, Viviana Ciraci, Andreia Neves Carvalho, Catarina Ranito, Susana G Santos, Maria João Gama, Margarida Castro-Caldas, Cecília M P Rodrigues, Jorge L Ruas, Elsa Rodrigues.
      Disruption of brain cholesterol homeostasis has been implicated in neurodegeneration. Nevertheless, the role of cholesterol in Parkinson's Disease (PD) remains unclear. We have used N2a mouse neuroblastoma cells and primary cultures of mouse neurons and 1-methyl-4-phenylpyridinium (MPP+), a known mitochondrial complex I inhibitor and the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), known to trigger a cascade of events associated with PD neuropathological features. Simultaneously, we utilized other mitochondrial toxins, including antimycin A, oligomycin, and carbonyl cyanide chlorophenylhydrazone. MPP+ treatment resulted in elevated levels of total cholesterol and in a Niemann Pick type C1 (NPC1)-like phenotype characterized by accumulation of cholesterol in lysosomes. Interestingly, NPC1 mRNA levels were specifically reduced by MPP+. The decrease in NPC1 levels was also seen in midbrain and striatum from MPTP-treated mice and in primary cultures of neurons treated with MPP+. Together with the MPP+-dependent increase in intracellular cholesterol levels in N2a cells, we observed an increase in 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and a concomitant increase in the phosphorylated levels of mammalian target of rapamycin (mTOR). NPC1 knockout delayed cell death induced by acute mitochondrial damage, suggesting that transient cholesterol accumulation in lysosomes could be a protective mechanism against MPTP/MPP+ insult. Interestingly, we observed a negative correlation between NPC1 protein levels and disease stage, in human PD brain samples. In summary, MPP+ decreases NPC1 levels, elevates lysosomal cholesterol accumulation and alters mTOR signaling, adding to the existing notion that PD may rise from alterations in mitochondrial-lysosomal communication.
    Keywords:  Brain cholesterol metabolism; Lysosomes; Mitochondria dysfunction; NPC1; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166980
  32. Cell Signal. 2024 Jan;pii: S0898-6568(23)00355-8. [Epub ahead of print]113 110940
    Prolyl isomerase Pin1 promotes autophagy and cancer cell viability through activating FoxO3 signalling.
    Juan Long, Jiaxin Wang, Yuanyuan Dong, Jian Yang, Gang Xie, Ying Tong.
      Pin1-directed prolyl isomerization is a central common oncogenic mechanism to drive tumorigenic processes. However, the role of Pin1 in cellular autophagy is still poorly understood. Here we report that pharmacological inhibition of Pin1 decreased the formation of autophagosome/autolysosomes upon nutrient starvation. Inhibition of Pin1 reduced, whereas forced expression of Pin1 increased, the level of LC3 and viability of U2OS and PANC-1 cells. Pin1 could augment the accumulation of LC3 upon chloroquine treatment, while chloroquine also disturbed its function on cell viability. RNA-Seq and qPCR identified altered autophagic pathway upon Pin1 silencing. Mechanistically, FoxO3 was identified critical for Pin1-mediated autophagy. Knockdown of FoxO3 could rescue the changes of LC3 level and cellular viability caused by Pin1 overexpression. In xenograft mouse model, Pin1 reduced the sensitivity of PANC-1 to chloroquine while FoxO3 silencing could inhibit Pin1's function. Moreover, Pin1 could bind FoxO3 via its pS284-P motif, reduce its phosphorylation at T32, facilitate its nuclear retention, and therefore increased its transcriptional activity. S284A mutation of FoxO3 interfered with its T32 phosphorylation, reduced its nuclear localization and disrupted its function to support cell viability upon nutrient starvation. Furthermore, the protein level of Pin1 positively correlated with FoxO3 nuclear localization and LC3 level in pancreatic adenocarcinoma and osteosarcoma samples. Together, this study highlights an important role for Pin1-FoxO3 axis in regulating autophagy and cancer cell viability. Intervening in the Pin1-FoxO3 interaction would serve as an effective therapeutic strategy and the pS284-P motif of FoxO3 provides a potential target for drug design.
    Keywords:  Autophagy; FoxO3; Osteosarcoma; Pancreatic cancer; Pin1; Post-translational modification
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110940
  33. Microbes Infect. 2023 Dec 09. pii: S1286-4579(23)00184-3. [Epub ahead of print] 105274
    Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages.
    Delphine Bonhomme, Ignacio Santecchia, Pedro Escoll, Stylianos Papadopoulos, Frédérique Vernel-Pauillac, Ivo G Boneca, Catherine Werts.
      Leptospira interrogans are pathogenic bacteria responsible for leptospirosis, a worldwide zoonosis. All vertebrates can be infected, and some species like humans are susceptible to the disease whereas rodents such as mice are resistant and become asymptomatic renal carriers. Leptospires are stealth bacteria that are known to escape several immune recognition pathways and resist killing mechanisms. We recently published that leptospires may survive intracellularly in and exit macrophages, avoiding xenophagy, a pathogen-targeting form of autophagy. Interestingly, the latter is one of the antimicrobial mechanisms often highjacked by bacteria to evade the host immune response. In this study we explored whether leptospires subvert the key molecular players of autophagy to facilitate infection. We showed in macrophages that leptospires triggered a specific accumulation of autophagy-adaptor p62 in puncta-like structures, without altering autophagic flux. We demonstrated that Leptospira-induced p62 accumulation is a passive mechanism depending on the leptospiral virulence factor LPS signaling via TLR4/TLR2. p62 is a central pleiotropic protein, also mediating cell stress and death, via the translocation of transcription factors. We demonstrated that Leptospira-driven accumulation of p62 induced the translocation of transcription factor NRF2, a key player in the anti-oxidant response. However, NRF2 translocation upon Leptospira infection did not result as expected in antioxydant response, but dampened the production of inflammatory mediators such as iNOS/NO, TNF and IL6. Overall, these findings highlight a novel passive bacterial mechanism linked to LPS and p62/NRF2 signaling that decreases inflammation and contributes to the stealthiness of leptospires.
    Keywords:  Autophagy adapter p62; LPS; Leptospira; NRF2; TLRs
    DOI:  https://doi.org/10.1016/j.micinf.2023.105274
  34. J Appl Physiol (1985). 2023 Dec 14.
    The Role of TFE3 in Mediating Skeletal Muscle Mitochondrial Adaptations to Exercise Training.
    Jenna C Wong, Ashley N Oliveira, Priyanka Khemraj, David A Hood.
      TFE3 is a transcription factor that activates the expression of lysosomal genes involved in the clearance of dysfunctional mitochondria, termed mitophagy. With exercise, TFE3 is presumed to optimize the mitochondrial pool through the removal of organelles via lysosomes. However, the molecular mechanisms of the involved pathways remain unknown. Wild-type (WT) and TFE3 knockout (KO) mice were subjected to 6 weeks of voluntary wheel running as an endurance training regimen. This was followed by a 45-minute bout of in situ stimulation of the sciatic nerve innervating hindlimb muscles to evaluate muscle fatigue and contractile properties. A subset of animals was treated with colchicine to measure autophagy and mitophagy flux. Fatigability during stimulation was reduced with training in WT animals, as seen by a 13% increase in percent of maximum force at 5 minutes of stimulation, and a 30% increase at 30 minutes. Permeabilized fiber oxygen consumption was also improved with training. Concurrent with improved muscle and mitochondrial function, COX activity and COX I protein expression were increased in trained WT animals compared to untrained animals, signifying an increase in mitochondrial content. These training adaptations were abolished with the loss of TFE3. Surprisingly, the absence of TFE3 did not affect lysosomal content, nor did it blunt the induction of mitophagy flux with contractile activity compared to WT mice. Our results suggest that the loss of TFE3 compromises beneficial training adaptations that lead to improved muscle endurance and mitochondrial function.
    Keywords:  TFE3; exercise; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00484.2023
  35. Front Immunol. 2023 ;14 1250920
    Autophagy-mediated NKG2D internalization impairs NK cell function and exacerbates radiation pneumonitis.
    Ruiqing Wang, Xinyue Ma, Xinyu Zhang, Dizhi Jiang, Hongyuan Mao, Zerun Li, Yu Tian, Bo Cheng.
       Introduction: Radiation pneumonitis is a critical complication that constrains the use of radiation therapy for thoracic malignancies, leading to substantial morbidity via respiratory distress and lung function impairment. The role of Natural killer (NK) cells in inflammatory diseases is well-documented; however, their involvement in radiation pneumonitis is not fully understood.
    Methods: To explore the involvement of NK cells in radiation pneumonitis, we analyzed tissue samples for NK cell presence and function. The study utilized immunofluorescence staining, western blotting, and immunoprecipitation to investigate CXCL10 and ROS levels, autophagy activity, and NKG2D receptor dynamics in NK cells derived from patients and animal models subjected to radiation.
    Result: In this study, we observed an augmented infiltration of NK cells in tissues affected by radiation pneumonitis, although their function was markedly diminished. In animal models, enhancing NK cell activity appeared to decelerate the disease progression. Concomitant with the disease course, there was a notable upsurge in CXCL10 and ROS levels. CXCL10 was found to facilitate NK cell migration through CXCR3 receptor activation. Furthermore, evidence of excessive autophagy in patient NK cells was linked to ROS accumulation, as indicated by immunofluorescence and Western blot analyses. The association between the NKG2D receptor and its adaptor proteins (AP2 subunits AP2A1 and AP2M1), LC3, and lysosomes was intensified after radiation exposure, as demonstrated by immunoprecipitation. This interaction led to NKG2D receptor endocytosis and subsequent lysosomal degradation.
    Conclusion: Our findings delineate a mechanism by which radiation-induced lung injury may suppress NK cell function through an autophagy-dependent pathway. The dysregulation observed suggests potential therapeutic targets; hence, modulating autophagy and enhancing NK cell activity could represent novel strategies for mitigating radiation pneumonitis.
    Keywords:  CXCL10/CXCR3; NK cell; NKG2D; autophagy; radiation pneumonitis
    DOI:  https://doi.org/10.3389/fimmu.2023.1250920
  36. J Exp Bot. 2023 Dec 09. pii: erad456. [Epub ahead of print]
    Aberrant accumulation of ceramides in mitochondria trigger cell death requiring autophagy in Arabidopsis.
    He-Nan Bao, Jian Yin, Ling-Yan Wang, Rui-Hua Wang, Li-Qun Huang, Yi-Li Chen, Jian-Xin Wu, Jia-Qi Sun, Wei-Wei Liu, Nan Yao, Jian Li.
      Sphingolipids are membrane lipids and play critical roles in signal transduction. Ceramides, central components of sphingolipid metabolism, are involved in cell death. However, the mechanism of ceramides regulating cell death in plants remains unclear. Here, we found ceramides accumulated in mitochondria of accelerated cell death 5 mutant (acd5), and expression of mitochondrion-localized ceramide kinase (ACD5) suppressed mitochondrial ceramides accumulation and the acd5 cell death phenotype. We applied immuno-electron microscopy and observed ceramide-hyperaccumulation in acer acd5 double mutants which are characterized by mutations in both ACER (alkaline ceramidase) and ACD5 genes. The results confirmed that, plants with specific ceramide accumulation exhibited localization of ceramides to mitochondria, resulting in an increase of mitochondrial reactive oxygen species. Interestingly, when compared to the wild type, autophagy deficient mutants showed stronger resistance to ceramide-induced cell death. Lipid profiling analysis demonstrated that plants with ceramide accumulation exhibited a significant increase in phosphatidylethanolamine levels. Further, we found that ceramide treatment or endogenous ceramide accumulation induces autophagy. When exposed to exogenous ceramides, we found an increase in the level of ATG8e associated with mitochondria, where it bound to ceramides directly. Taken together, we proposed that the accumulation of ceramides in mitochondria can induce cell death by regulating autophagy.
    Keywords:   Arabidopsis ; Ceramide; autophagy; cell death; mitochondria; phosphatidylethanolamine
    DOI:  https://doi.org/10.1093/jxb/erad456
  37. Glycobiology. 2023 Dec 09. pii: cwad099. [Epub ahead of print]
    Transport of N-acetylchitooligosaccharides and fluorescent N-acetylchitooligosaccharide analogs into rat liver lysosomes.
    Younès Bouzidi, Michaël Bosco, Haifei Gao, Stéphanie Pradeau, Lucrèce Matheron, Isabelle Chantret, Patricia Busca, Sébastien Fort, Christine Gravier-Pelletier, Stuart E H Moore.
      Free polymannose-type oligosaccharides (fOS) are processed by cytosolic enzymes to generate Man 5GlcNAc which is transferred to lysosomes and degraded. Lysosomal fOS import was demonstrated in vitro but is poorly characterized in part due to lack of convenient substrates. As chitooligosaccharides (COS, oligomers β1,4-linked GlcNAc) block [ 3H]Man5GlcNAc transport into lysosomes, we asked if COS are themselves transported and if so, can they be chemically modified to generate fluorescent substrates. We show that COS are degraded by lysosomal hydrolases to generate GlcNAc, and robust ATP-dependent transport of [ 3H]COS2/4 di and tetrasaccharides into intact rat liver lysosomes was observed only after blocking lysosomal [ 3H]GlcNAc efflux with cytochalasin B. As oligosaccharides with unmodified reducing termini are the most efficient inhibitors of [ 3H]COS2/4 and [ 3H]Man5GlcNAc transport, the non-reducing GlcNAc residue of COS2-4 was de-N-acetylated using Sinorhizobium meliloti NodB, and the resulting amine substituted with rhodamine B (RB) to yield RB-COS2-4. The fluorescent compounds inhibit [ 3H]Man5GlcNAc transport and display temperature-sensitive, ATP-dependent transport into a sedimentable compartment that is ruptured with the lysosomotropic agent L-methyl methionine ester. Once in this compartment, RB-COS3 is converted to RB-COS2 further identifying it as the lysosomal compartment. RB-COS2/3 and [ 3H]Man5GlcNAc transports are blocked similarly by competing sugars, and are partially inhibited by the vacuolar ATPase inhibitor bafilomycin and high concentrations of the P-type ATPase inhibitor orthovanadate. These data show that Man5GlcNAc, COS2/4 and RB-COS2/3 are transported into lysosomes by the same or closely related mechanism and demonstrate the utility of COS modified at their non-reducing terminus to study lysosomal oligosaccharide transport.
    Keywords:  autophagy; lysosome; oligosaccharide; protein N-glycosylation; sugar transport
    DOI:  https://doi.org/10.1093/glycob/cwad099
  38. Ageing Res Rev. 2023 Dec 07. pii: S1568-1637(23)00321-5. [Epub ahead of print] 102162
    Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer's disease and other proteinopathies.
    Michael F Almeida, Karen L G Farizatto, Renato S Almeida, Ben A Bahr.
      Unhealthy lifestyle choices, poor diet, and aging can have negative influences on cognition, gradually increasing the risk for mild cognitive impairment (MCI) and the continuum comprising early dementia. Aging is the greatest risk factor for age-related dementias such as Alzheimer's disease, and the aging process is known to be influenced by life events that can positively or negatively affect age-related diseases. Remarkably, life experiences that make the brain vulnerable to dementia, such as seizure episodes, neurotoxin exposures, metabolic disorders, and trauma-inducing events (e.g. traumatic injuries or mild neurotrauma from a fall or blast exposure), have been associated with negative effects on proteostasis and synaptic integrity. Functional compromise of the autophagy-lysosomal pathway, a major contributor to proteostasis, has been implicated in Alzheimer's disease, Parkinson's disease, obesity-related pathology, Huntington's disease, as well as in synaptic degeneration which is the best correlate of cognitive decline. Correspondingly, pharmacological and non-pharmacological strategies that positively modulate lysosomal proteases are recognized as synaptoprotective through degradative clearance of pathogenic proteins. Here, we discuss life-associated vulnerabilities that influence key hallmarks of brain aging and the increased burden of age-related dementias. Additionally, we discuss exercise and diet among the lifestyle strategies that regulate proteostasis as well as synaptic integrity, leading to evident prevention of cognitive deficits during brain aging in pre-clinical models.
    Keywords:  brain aging; cognition; lysosomal proteases; synapses
    DOI:  https://doi.org/10.1016/j.arr.2023.102162
  39. Autophagy. 2023 Dec 07. 1-16
    LTN1 promotes RLR degradation to inhibit immune response to RNA virus through the ESCRT pathway.
    Fei Qin, Baoshan Cai, Peng Wang, Runyu Cao, Yuling Zhang, Hongling Wen, Yi Zheng, Wei Zhao, Chengjiang Gao, Bingyu Liu.
      The excessive activation of immune responses will trigger autoimmune diseases or inflammatory injury. The endosomal sorting complexes required for transport (ESCRT) system can capture and mediate ubiquitinated protein degradation, which timely terminates signaling pathway hyperactivation. However, whether the ESCRT system participates in regulating RIGI-like receptor (RLR)-mediated antiviral responses remains unknown. In this study, we show that LTN1/listerin, a major component of RQC, can recruit E3 ubiquitin ligase TRIM27 to trigger K63-linked polyubiquitination of RIGI and IFIH1/MDA5. This K63-linked polyubiquitination facilitates the sorting and degradation of RIGI and IFIH1 proteins through the ESCRT-dependent pathway. Concordantly, LTN1 deficiency enhances the innate antiviral response to infection with RNA viruses. Thus, our work uncovers a new mechanism for RIGI and IFIH1 degradation and identifies the role of LTN1 in negatively regulating RLR-mediated antiviral innate immunity, which may provide new targets for the intervention of viral infection.Abbreviation: 5'-pppRNA: 5' triphosphate double stranded RNA; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A1; ESCRT: endosomal sorting complexes required for transport; CHX: cycloheximide; IFIH1/MDA5: interferon induced with helicase C domain 1; IFN: interferon; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; RIGI: RNA sensor RIG-I; RLR: RIGI-like receptors; RQC: ribosome-associated protein quality control; SeV: Sendai virus; TRIM27: tripartite motif-containing 27; VSV: vesicular stomatitis virus; VPS4: vacuolar protein sorting 4.
    Keywords:  Antiviral innate immunity; ESCRT; LTN1; RLR; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2023.2291939
  40. Sci Total Environ. 2023 Dec 06. pii: S0048-9697(23)07805-1. [Epub ahead of print]912 169175
    Tetrabromobisphenol A induces neuronal cytotoxicity by inhibiting PINK1-Parkin-mediated mitophagy via upregulating ATF3 expression.
    Xijuan Chao, Dezhi Yao, Chuxuan Chen, Zhiguo Sheng, Benzhan Zhu.
      Tetrabromobisphenol A (TBBPA), as a widely used brominated flame retardant, has been implicated as a potential neurotoxicant. However, the mechanism of TBBPA-induced neurotoxicity has not been fully elucidated yet. In this study, using mouse hippocampal neuron cell HT22 as the in vitro model, the neuronal cytotoxicity of TBBPA and the mechanism by focusing on mitophagy have been studied. We found that neuronal cytotoxic effects were indeed induced by TBBPA exposure at concentrations of >20 μM for 24 h, including decreased cell viability (to 92.38 % at 20 μM; 18.25 % at 80 μM), enhanced ROS (enhanced 53.26 % at IC50 of 60 μM, compared with that in the control group) and mitochondrial ROS (mtROS) levels (enhanced 24.12 % at 60 μM), reduced mitochondrial membrane potential (MMP) (decreased 33.60 % at 60 μM). As a protective mechanism in cells, autophagy was initiated; however, mitophagy was inhibited, where PINK1 (PINK1-Parkin activation is critical in the depolarized MMP-induced mitophagy) expression was found to be repressed and decreased, further leading to the failure of Parkin recruitment to the damaged mitochondria. Mitophagy activator, nicotinamide mononucleotide (β-NMN) that activates the PINK1-Parkin pathway, could alleviate TBBPA-induced mitophagy deficiency and further reduce the neuronal cytotoxicity, demonstrating that TBBPA-induced PINK1-Parkin-mediated mitophagy deficiency contributed to the neuronal cytotoxicity. Furthermore, we found TBBPA caused the upregulation of Atf3 (activating transcription factor 3) gene transcription and expression levels, alongside reduced Pink1 levels; whereas enhanced Pink1 transcript levels were observed after ATF3 depletion even under TBBPA treatment, demonstrating TBBPA-induced overexpression of ATF3 should be responsible for the reduced PINK1 expression. Therefore, for the first time, here we demonstrate that TBBPA can inhibit PINK1-Parkin-mediated mitophagy via upregulating ATF3 expression, which further contributes to its neuronal cytotoxicity. This study should be able to improve our understanding of the mechanism of TBBPA-induced neuronal cytotoxicity.
    Keywords:  ATF3; Mitophagy deficiency; Neuronal cytotoxicity; PINK1/Parkin; TBBPA
    DOI:  https://doi.org/10.1016/j.scitotenv.2023.169175
  41. CNS Neurosci Ther. 2023 Dec 11.
    Neurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway.
    Yu-Jia Zhao, Kai-Fei Xu, Fu-Xing Shu, Feng Zhang.
      Neurodegenerative diseases (NDs) constitute a group of disorders characterized by the progressive deterioration of nervous system functionality. Currently, the precise etiological factors responsible for NDs remain incompletely elucidated, although it is probable that a combination of aging, genetic predisposition, and environmental stressors participate in this process. Accumulating evidence indicates that viral infections, especially neurotropic viruses, can contribute to the onset and progression of NDs. In this review, emerging evidence supporting the association between viral infection and NDs is summarized, and how the autophagy pathway mediated by viral infection can cause pathological aggregation of cellular proteins associated with various NDs is discussed. Furthermore, autophagy-related genes (ARGs) involved in Herpes simplex virus (HSV-1) infection and NDs are analyzed, and whether these genes could link HSV-1 infection to NDs is discussed. Elucidating the mechanisms underlying NDs is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of NDs.
    Keywords:  Alzheimer's disease; Parkinson's disease; autophagy; neurodegenerative diseases; neurotropic virus
    DOI:  https://doi.org/10.1111/cns.14548
  42. Kidney Dis (Basel). 2023 Dec;9(6): 469-484
    Metabolism of Polyamines and Kidney Disease: A Promising Therapeutic Target.
    Dan Luo, Xiaohui Lu, Yi Li, Yiping Xu, Yi Zhou, Haiping Mao.
       Background: More than 850 million people worldwide suffer from acute and chronic kidney diseases (CKD) which are tremendous socioeconomic burdens for society. Currently, the treatment choices for CKD are limited. There is a great need to understand the underlying mechanisms of the development of CKD in order to develop potential therapeutic strategies.
    Summary: The alteration in cellular metabolism has emerged as an important common pathological mechanism in different kidney diseases. Metabolic intervening and reprogramming will yield new insights to prevent and slow the progression of kidney disease. As one essential component of cellular metabolisms in fuel-source preferences (glucose, fatty acids, or ketones), the polyamine compound metabolism comprising the metabolites (spermine, spermidine, and putrescine) and their biosynthetic and catabolic enzymes are an endogenous pathophysiological regulator that is arising as a potential therapeutic object for many diseases.
    Key Messages: This article aimed to review current knowledge on polyamine metabolism and physiological processes, and its potential regulatory and beneficial roles in immunoregulation, mitochondrial homeostasis, autophagy, DNA damage, and kidney diseases, and thus provide a novel therapeutic opportunity for kidney diseases.
    Keywords:  Kidney disease; Polyamines; Spermidine; Spermine; Therapeutic potential
    DOI:  https://doi.org/10.1159/000533296
  43. Int J Mol Sci. 2023 Nov 24. pii: 16709. [Epub ahead of print]24(23):
    FARSB Facilitates Hepatocellular Carcinoma Progression by Activating the mTORC1 Signaling Pathway.
    Yaofeng Wang, Gengqiao Wang, Shaobo Hu, Chuanzheng Yin, Peng Zhao, Xing Zhou, Shuyu Shao, Ran Liu, Wenjun Hu, Gang Logan Liu, Wenbo Ke, Zifang Song.
      Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Human phenylalanine tRNA synthetase (PheRS) comprises two α catalytic subunits encoded by the FARSA gene and two β regulatory subunits encoded by the FARSB gene. FARSB is a potential oncogene, but no experimental data show the relationship between FARSB and HCC progression. We found that the high expression of FARSB in liver cancer is closely related to patients' low survival and poor prognosis. In liver cancer cells, the mRNA and protein expression levels of FARSB are increased and promote cell proliferation and migration. Mechanistically, FARSB activates the mTOR complex 1 (mTORC1) signaling pathway by binding to the component Raptor of the mTORC1 complex to play a role in promoting cancer. In addition, we found that FARSB can inhibit erastin-induced ferroptosis by regulating the mTOR signaling pathway, which may be another mechanism by which FARSB promotes HCC progression. In summary, FARSB promotes HCC progression and is associated with the poor prognosis of patients. FARSB is expected to be a biomarker for early screening and treatment of HCC.
    Keywords:  FARSB; Raptor; ferroptosis; hepatocellular carcinoma; mTORC1
    DOI:  https://doi.org/10.3390/ijms242316709
  44. Liver Int. 2023 Dec 11.
    Ferritinophagy-mediated ferroptosis facilitates methotrexate-induced hepatotoxicity by high-mobility group box 1 (HMGB1).
    Chengbo Wang, Maodong Leng, Cong Ding, Xiangzhan Zhu, Yaodong Zhang, Chenchen Sun, Pu Lou.
       BACKGROUND AND AIM: Hepatotoxicity is a well-defined reaction to methotrexate (MTX), a drug commonly used for the treatment of rheumatoid arthritis and various tumours. We sought to elucidate the mechanism underlying MTX-induced hepatotoxicity and establish a potentially effective intervention strategy.
    METHODS: We administered MTX to liver cells and mice and assessed hepatotoxicity by cell viability assay and hepatic pathological changes. We determined ferroptosis and ferritinophagy by detecting ferroptosis-related markers and autophagic degradation of ferritin heavy chain 1 (FTH1).
    RESULTS: We have shown that hepatocytes treated with MTX undergo ferroptosis, and this process can be attenuated by ferroptosis inhibitors. Interestingly, NCOA4-mediated ferritinophagy was found to be involved in MTX-induced ferroptosis, which was demonstrated by the relief of ferroptosis through the inhibition of autophagy or knockdown of Ncoa4. Furthermore, MTX treatment resulted in the elevation of high-mobility group box 1 (HMGB1) expression. The depletion of Hmgb1 in hepatocytes considerably alleviated MTX-induced hepatotoxicity by limiting autophagy and the subsequent autophagy-dependent ferroptosis. It is noteworthy that glycyrrhizic acid (GA), a precise inhibitor of HMGB1, effectively suppressed autophagy, ferroptosis and hepatotoxicity caused by MTX.
    CONCLUSION: Our study shows the significant roles of autophagy-dependent ferroptosis and HMGB1 in MTX-induced hepatotoxicity. It emphasizes that the inhibition of ferritinophagy and HMGB1 may have potential as a therapeutic approach for preventing and treating MTX-induced liver injury.
    Keywords:  HMGB1; autophagy; ferritinophagy; ferroptosis; methotrexate
    DOI:  https://doi.org/10.1111/liv.15811
  45. Anal Chem. 2023 Dec 12.
    Imaging HOCl Generation during the Mitochondria Peripheral Fission with a Tailor-Made Fluorescent Probe.
    Haolin Zhang, Ya Liu, Xiaofan Zhang, Huimin Ma, Wen Shi, Xiaohua Li.
      Mitochondrial fission is a highly regulated process that can affect metabolism, proliferation, and apoptosis. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, which is found preceded by increased Ca2+ and reactive oxygen species, as well as reduced membrane potential and pH. However, the variation of hypochlorous acid (HOCl) during the peripheral fission has not been well studied, and the existing fluorescent probes are unsuitable for detecting mitochondrial HOCl because of the 0.8-fold decreased pH during this process. Herein, we design a novel CCS (changeable π-conjugation system)-based probe (ON-mito) with a dibenzo[1,4]oxazepine core, which can selectively react with HOCl at pH 6.4, generating an oxazine-containing product that emits at 660 nm. The capability of ON-mito for imaging the HOCl generation in HeLa cells during mitophagy is demonstrated under weakly acidic condition. Further, with ON-mito, we find for the first time a burst increase of the mitochondrial HOCl in COS-7 cells during peripheral fission, which may serve as an important indicator of this process. Probe ON-mito may be useful for studying mitochondrial damage under diverse conditions.
    DOI:  https://doi.org/10.1021/acs.analchem.3c04215
  46. Microbiol Spectr. 2023 Dec 12. e0353123
    PlAtg8-mediated autophagy regulates vegetative growth, sporangial cleavage, and pathogenesis in Peronophythora litchii.
    Ge Yu, Wenqiang Li, Chengdong Yang, Xue Zhang, Manfei Luo, Taixu Chen, Xuejian Wang, Rongbo Wang, Qinghe Chen.
       IMPORTANCE: Peronophythora litchii is the pathogen of litchi downy blight, which is the most serious disease in litchi. Autophagy is an evolutionarily conserved catabolic process in eukaryotes. Atg8 is a core protein of the autophagic pathway, which modulates growth and pathogenicity in the oomycete P. litchii. In P. litchii, CRISPR/Cas9-mediated knockout of the PlATG8 impaired autophagosome formation. PlATG8 knockout mutants exhibited attenuated colony expansion, sporangia production, zoospore discharge, and virulence on litchi leaves and fruits. The reduction in zoospore release was likely underpinned by impaired sporangial cleavage. Thus, in addition to governing autophagic flux, PlAtg8 is indispensable for vegetative growth and infection of P. litchii.
    Keywords:  Peronophythora litchii; PlAtg8; autophagosome formation; pathogenicity; sporangial cleavage
    DOI:  https://doi.org/10.1128/spectrum.03531-23
  47. Sci Adv. 2023 Dec 15. 9(50): eadj1205
    Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B.
    Prosenjit Pal, Matthew Taylor, Pui Yiu Lam, Francesca Tonelli, Chloe A Hecht, Pawel Lis, Raja S Nirujogi, Toan K Phung, Wondwossen M Yeshaw, Ebsy Jaimon, Rotimi Fasimoye, Emily A Dickie, Melanie Wightman, Thomas Macartney, Suzanne R Pfeffer, Dario R Alessi.
      We demonstrate that the Parkinson's VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35[D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates, and knockout of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe also induced LRRK2 kinase-mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.
    DOI:  https://doi.org/10.1126/sciadv.adj1205
  48. Int J Mol Sci. 2023 Nov 23. pii: 16664. [Epub ahead of print]24(23):
    The Relevance of Autophagy within Inner Ear in Baseline Conditions and Tinnitus-Related Syndromes.
    Gloria Lazzeri, Francesca Biagioni, Michela Ferrucci, Stefano Puglisi-Allegra, Paola Lenzi, Carla Letizia Busceti, Francesco Giannessi, Francesco Fornai.
      Tinnitus is the perception of noise in the absence of acoustic stimulation (phantom noise). In most patients suffering from chronic peripheral tinnitus, an alteration of outer hair cells (OHC) starting from the stereocilia (SC) occurs. This is common following ototoxic drugs, sound-induced ototoxicity, and acoustic degeneration. In all these conditions, altered coupling between the tectorial membrane (TM) and OHC SC is described. The present review analyzes the complex interactions involving OHC and TM. These need to be clarified to understand which mechanisms may underlie the onset of tinnitus and why the neuropathology of chronic degenerative tinnitus is similar, independent of early triggers. In fact, the fine neuropathology of tinnitus features altered mechanisms of mechanic-electrical transduction (MET) at the level of OHC SC. The appropriate coupling between OHC SC and TM strongly depends on autophagy. The involvement of autophagy may encompass degenerative and genetic tinnitus, as well as ototoxic drugs and acoustic trauma. Defective autophagy explains mitochondrial alterations and altered protein handling within OHC and TM. This is relevant for developing novel treatments that stimulate autophagy without carrying the burden of severe side effects. Specific phytochemicals, such as curcumin and berberin, acting as autophagy activators, may mitigate the neuropathology of tinnitus.
    Keywords:  Hensen’s cells; basilar membrane; hypoacusia; inner hair cells; neurodegeneration; outher hair cells; radial shearing; reticular lamina; stereocilia; tectorial membrane
    DOI:  https://doi.org/10.3390/ijms242316664
  49. Int J Mol Sci. 2023 Nov 24. pii: 16720. [Epub ahead of print]24(23):
    Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells.
    Yasushi Kubota, Toshimi Hoshiko, Taishi Higashi, Keiichi Motoyama, Seiji Okada, Shinya Kimura.
      Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-β-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-β-CyD (FA-HP-β-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-β-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-β-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-β-CyD against AML cells was stronger than that of HP-β-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-β-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-β-CyD suppressed the proliferation of AML cells in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double-deficient mice with AML. These results suggest that FA-HP-β-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy.
    Keywords:  2-hydroxypropyl-β-cyclodextrin; Venetoclax; acute myeloid leukemia; autophagy; cholesterol; folate receptor; folic acid; metabolism; mitochondria; molecular targeting
    DOI:  https://doi.org/10.3390/ijms242316720
  50. Biochem Biophys Res Commun. 2023 Dec 04. pii: S0006-291X(23)01448-1. [Epub ahead of print]692 149354
    The significance of caloric restriction mimetics as anti-aging drugs.
    Khloud Nassar, Doaa El-Mekawey, Ahmed E Elmasry, Mohamed S Refaey, Mai El-Sayed Ghoneim, Yaseen A M M Elshaier.
      Aging is an intricate process characterized by the gradual deterioration of the physiological integrity of a living organism. This unfortunate phenomenon inevitably leads to a decline in functionality and a heightened susceptibility to the ultimate fate of mortality. Therefore, it is of utmost importance to implement interventions that possess the capability to reverse or preempt age-related pathology. Caloric restriction mimetics (CRMs) refer to a class of molecules that have been observed to elicit advantageous outcomes on both health and longevity in various model organisms and human subjects. Notably, these compounds offer a promising alternative to the arduous task of adhering to a caloric restriction diet and mitigate the progression of the aging process and extend the duration of life in laboratory animals and human population. A plethora of molecular signals have been linked to the practice of caloric restriction, encompassing Insulin-like Growth Factor 1 (IGF1), Mammalian Target of Rapamycin (mTOR), the Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway, and Sirtuins, with particular emphasis on SIRT1. Therefore, this review will center its focus on several compounds that act as CRMs, highlighting their molecular targets, chemical structures, and mechanisms of action. Moreover, this review serves to underscore the significant relationship between post COVID-19 syndrome, antiaging, and importance of utilizing CRMs. This particular endeavor will serve as a comprehensive guide for medicinal chemists and other esteemed researchers, enabling them to meticulously conceive and cultivate novel molecular entities with the potential to function as efficacious antiaging pharmaceutical agents.
    Keywords:  Aging; Autophagy; CRMs; Drug repurposing; Post COVID-19 syndrome
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149354
  51. Commun Biol. 2023 Dec 11. 6(1): 1252
    Atg7 senses ATP levels and regulates AKT1-PDCD4 phosphorylation-ubiquitination axis to promote survival during metabolic stress.
    Chengsi Deng, Chunlu Li, Xiang Dong, Yang Yu, Wendong Guo, Yi Guan, Xun Sun, Liu Cao.
      We report that autophagy-related gene 7 (ATG7) modulates p53 activity to regulate cell cycle and survival during metabolic stress, and that indicates Atg7 is functionally involved in cellular homeostasis in autophagy independent fashion. As a protein translation inhibitor, Programmed cell death 4 (PDCD4) expression is regulated by AKT1 phosphorylation. Here, we find that Atg7 interacts with PDCD4 and AKT1 to regulate AKT1-PDCD4 phosphorylation-ubiquitination axis during metabolic stress. We demonstrate that Atg7 senses decrease of ATP levels to suppress AKT-mediated PDCD4 phosphorylation at Ser67, which inhibits PDCD4 ubiquitinating during metabolic stress. Finally, PDCD4 accumulates and functions as a protein translation inhibitor to conserve energy, thus reducing apoptosis and allowing cells to survive stress periods. These results suggest that the ATP-Atg7-PDCD4 axis acts as a metabolic adaptation pathway which dictates cells to overcome metabolic stress.
    DOI:  https://doi.org/10.1038/s42003-023-05656-7
  52. bioRxiv. 2023 Dec 01. pii: 2023.11.29.569312. [Epub ahead of print]
    Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis.
    Yann Ehinger, Sophie Laguesse, Khanhky Phamluong, Alexandra Salvi, Zachary W Hoisington, Drishti Soneja, Yoshitaka J Sei, Ken Nakamura, Dorit Ron.
      mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme. We found that miR34a-5p in the NAc targets Aldolase A for translation repression and promotes alcohol intake. Our data further suggest that glycolysis is inhibited in the NAc manifesting in an mTORC1-dependent attenuation of L-lactate, the end product of glycolysis. Finally, we show that systemic administration of L-lactate attenuates mouse excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2023.11.29.569312
  53. Cell Struct Funct. 2023 Dec 09.
    Lysosomal membrane integrity in fibroblasts derived from patients with Gaucher disease.
    Asuka Hamamoto, Natsuki Kita, Siddabasave Gowda B Gowda, Hiroyuki Takatsu, Kazuhisa Nakayama, Makoto Arita, Shu-Ping Hui, Hye-Won Shin.
      Gaucher disease (GD) is a recessively inherited lysosomal storage disorder characterized by a deficiency of lysosomal glucocerebrosidase (GBA1). This deficiency results in the accumulation of its substrate, glucosylceramide (GlcCer), within lysosomes. Here, we investigated lysosomal abnormalities in fibroblasts derived from patients with GD. It is noteworthy that the cellular distribution of lysosomes and lysosomal proteolytic activity remained largely unaffected in GD fibroblasts. However, we found that lysosomal membranes of GD fibroblasts were susceptible to damage when exposed to a lysosomotropic agent. Moreover, the susceptibility of lysosomal membranes to a lysosomotropic agent could be partly restored by exogenous expression of wild-type GBA1. Here, we report that the lysosomal membrane integrity is altered in GD fibroblasts, but lysosomal distribution and proteolytic activity is not significantly altered.Key words: glucosylceramide, lysosome, Gaucher disease, lysosomotropic agent.
    Keywords:  Gaucher disease; glucosylceramide; lysosome; lysosomotropic agent
    DOI:  https://doi.org/10.1247/csf.23066
  54. Adv Sci (Weinh). 2023 Dec 11. e2307648
    T-2 Toxin-Mediated β-Arrestin-1 O-GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation.
    Tushuai Li, Wenxue Sun, Shenglong Zhu, Chengsheng He, Tong Chang, Jie Zhang, Yongquan Chen.
      T-2 toxin causes renal dysfunction with proteinuria and glomerular podocyte damage. This work explores the role of metabolic disorder/reprogramming-mediated epigenetic modification in the progression of T-2 toxin-stimulated podocyte injury. A metabolomics experiment is performed to assess metabolic responses to T-2 toxin infection in human podocytes. Roles of protein O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in regulating T-2 toxin-stimulated podocyte injury in mouse and podocyte models are assessed. O-GlcNAc target proteins are recognized by mass spectrometry and co-immunoprecipitation experiments. Moreover, histone acetylation and autophagy levels are measured. T-2 toxin infection upregulates glucose transporter type 1 (GLUT1) expression and enhances hexosamine biosynthetic pathway in glomerular podocytes, resulting in a significant increase in β-arrestin-1 O-GlcNAcylation. Decreasing β-arrestin-1 or O-GlcNAc transferase (OGT) effectively prevents T-2 toxin-induced renal dysfunction and podocyte injury. Mechanistically, O-GlcNAcylation of β-arrestin-1 stabilizes β-arrestin-1 to activate the mammalian target of rapamycin (mTOR) pathway as well as to inhibit autophagy during podocyte injury by promoting H4K16 acetylation. To sum up, OGT-mediated β-arrestin-1 O-GlcNAcylation is a vital regulator in the development of T-2 toxin-stimulated podocyte injury via activating the mTOR pathway to suppress autophagy. Targeting β-arrestin-1 or OGT can be a potential therapy for T-2 toxin infection-associated glomerular injury, especially podocyte injury.
    Keywords:  T-2 toxins; glomerular injury; histone acetylation; o-glcnacylation; podocyte injury; β-arrestin-1
    DOI:  https://doi.org/10.1002/advs.202307648
  55. J Thorac Dis. 2023 Nov 30. 15(11): 6333-6344
    Lymphangioleiomyomatosis and mTOR inhibitors in real world-a narrative review.
    Sanghoon Park, Eun Joo Lee.
       Background and Objective: Lymphangioleiomyomatosis (LAM) is a rare disease developing mostly on lung and leading to various pulmonary and extra-pulmonary manifestations. Management of this intractable illness has been mostly symptomatic and supplementary until the advent and application of a novel drug, i.e., the mechanistic target of rapamycin (mTOR) inhibitor, and successful disease control using mTOR inhibitors is improving LAM patients. Although mTOR inhibitors are showing remarkable results there are still many rooms for further progress, and partly solved issues on problems seen in LAM still remain. We searched multiple reports and investigational studies regarding LAM, especially the therapeutic achievement won by mTOR inhibitors. This article summarized several characteristics of LAM including pathogenesis, clinical manifestation, laboratory findings, and management. We also attempted to review the latest knowledge and efficacy of mTOR inhibitors and some new drugs.
    Methods: Online searching of literature was performed. The National Center for Biotechnology Information (NCBI), PubMed, Cochrane Library, Google Scholar, and EMBASE were searched.
    Key Content and Findings: LAM is a genetic disease with a high predilection toward female subjects. Not only lung but also other organs are involved, hence extrapulmonary symptoms and signs are also noted. Representative objective finding is a progressive deterioration of lung function, sometimes leading to respiratory failure. Supportive and symptomatic care has been the mainstay of therapy with suboptimal result, until a novel drug, the mTOR inhibitor, was developed. Successful deterrence of disease progression was achieved on management with mTOR inhibitors. Several unsolved problems using mTOR inhibitors are a pending issue, such as duration of treatment.
    Conclusions: LAM has been a rare, stubborn disease to ameliorate in health due to its complex pathogenesis and accompanied by other manifestations. Adopting various tools for relief has been usually suboptimal, but mTOR inhibitors proved to achieve significant improvement in various aspects. Further investigation is needed including refinement of currently available therapeutic applications, development of novel remedies, and so on.
    Keywords:  Lymphangioleiomyomatosis (LAM); management; mechanistic target of rapamycin inhibitor (mTOR inhibitor)
    DOI:  https://doi.org/10.21037/jtd-23-778
  56. Transl Stroke Res. 2023 Dec 14.
    Methylated MFGE8 Promotes Early Brain Injury After Subarachnoid Hemorrhage and Inhibiting Autophagy of Nerve Cell.
    Liang Zou, Shancai Xu, Chunlei Wang, Pei Wu, Chao Xu, Huaizhang Shi.
       BACKGROUND: Spontaneous subarachnoid hemorrhage (SAH) is a relatively common clinical hemorrhagic stroke crisis. The important role of early brain injury (EBI) and autophagy in SAH has been increasingly recognized in recent years. This study aims to investigate the function and the undergoing mechanism of MFGE8 in EBI after SAH.
    METHODS: SAH model was established using C57BL/6 mice, and the SAH cell model was constructed by oxy-hemoglobin (Oxy-Hb) induced BV2 and SH-SY5Y co-culture system. Various methods were used to detect EBI and autophagy after SAH in mouse/cell lines, including mouse neurological function score, wet/dry method, HE and Evans blue staining, etc. The effect on EBI was explored after knockdown or overexpression of key genes DNMT1, MFGE8, and P2X7R. MSP was used to detect the methylation of MFGE8 promoter region, and ChIP was used to detect the binding relationship between DNMT1 and MFGE8 promoter region.
    RESULTS: The results showed that the activation of autophagy attenuates EBI in SAH mice. Increased level of DNMT1 and decreased level of MFGE8 were observed in brain tissues of SAH mice. Knockdown of DNMT1 or overexpression of MFGE8 attenuates EBI in mice by promoting autophagy. At the same time, we found that DNMT1 promotes methylation of MFGE8 promoter region and suppresses its protein levels. MFGE8 downregulates P2X7R levels and subsequently activates PI3k/Akt/mTOR axis, promotes autophagy, and attenuates EBI in SAH mice.
    CONCLUSION: DNMT1 promotes the methylation of MFGE8 promoter region and downregulates MFGE8 level; restoring MFGE8 downregulates P2X7R, and promotes autophagy by limiting the activation of PI3k/Akt/mTOR, thus exerting a protective effect on brain tissue of SAH mice.
    HIGHLIGHTS: • High expression of DNMT1 and P2X7R and low expression of MFGE8 were observed in SAH mice. • Activation of autophagy reduces EBI after SAH in mice. • DNMT1/MFGE8 reduces autophagy in EBI after SAH in both mouse and cell models. • DNMT1 targets the MFGE8 promoter to upregulate its methylation level. • MFGE8 inhibits P2X7R to activate PI3k/AKT/mTOR pathway and autophagy, thus inhibiting EBI after SAH.
    Keywords:  Autophagy; DNMT1; MFGE8; Methylation; Spontaneous subarachnoid hemorrhage
    DOI:  https://doi.org/10.1007/s12975-023-01217-6
  57. Int J Mol Sci. 2023 Nov 21. pii: 16570. [Epub ahead of print]24(23):
    Effects of a N-Maleimide-derivatized Phosphatidylethanolamine on the Architecture and Properties of Lipid Bilayers.
    Uxue Ballesteros, Emilio J González-Ramirez, Igor de la Arada, Jesús Sot, Asier Etxaniz, Félix M Goñi, Alicia Alonso, Lidia Ruth Montes.
      N-maleimide-derivatized phospholipids are often used to facilitate protein anchoring to membranes. In autophagy studies, this is applied to the covalent binding of Atg8, an autophagy protein, to a phosphatidylethanolamine (PE) in the nascent autophagosome. However, the question remains on how closely the N-maleimide PE derivative (PE-mal) mimicks the native PE in the bilayer. In the present paper, spectroscopic and calorimetric techniques have been applied to vesicles containing either PE or PE-mal (together with other phospholipids) to compare the properties of the native and derivatized forms of PE. According to differential scanning calorimetry, and to infrared spectroscopy, the presence of PE-mal did not perturb the fatty acyl chains in the bilayer. Fluorescence spectroscopy and microscopy showed that PE-mal did not alter the bilayer permeability either. However, fluorescence emission polarization of the Laurdan and DPH probes indicated an increased order, or decreased fluidity, in the bilayers containing PE-mal. In addition, the infrared spectral data from the phospholipid phosphate region revealed a PE-mal-induced conformational change in the polar heads, accompanied by increased hydration. Globally considered, the results suggest that PE-mal would be a reasonable substitute for PE in model membranes containing reconstituted proteins.
    Keywords:  autophagy proteins; differential scanning calorimetry; fluorescence; infrared spectroscopy; maleimide; membrane fluidity
    DOI:  https://doi.org/10.3390/ijms242316570
  58. Elife. 2023 Dec 12. pii: RP90510. [Epub ahead of print]12
    Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6.
    Anna A Cook, Tsz Chui Sophia Leung, Max Rice, Maya Nachman, Élyse Zadigue-Dube, Alanna Jean Watt.
      Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA-sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-dihydroxyflavone, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6 and a promising therapeutic target.
    Keywords:  BDNF–TrkB signaling; cellular trafficking; early endosomes; lysosome; mouse; neuroscience; transcriptomics
    DOI:  https://doi.org/10.7554/eLife.90510
  59. Mol Neurobiol. 2023 Dec 08.
    Deferoxamine Ameliorates Cypermethrin-Induced Iron Accumulation and Associated Alterations.
    Nidhi Sachan, Saripella Srikrishna, Devendra Kumar Patel, Mahendra Pratap Singh.
      Iron is widely linked with the onset and development of Parkinson's disease (PD). Accumulation of iron induces free radical generation and promotes α-synuclein aggregation, oxidative stress, and autophagy impairment. Deferoxamine, an iron chelator, is shown to ameliorate iron dyshomeostasis in rodents and humans. However, the role of deferoxamine in cypermethrin-induced iron accumulation is not yet known. Although an iron accumulation and impaired chaperone-mediated autophagy (CMA) contribute to PD, a link between the two is not yet widely understood. Current study is undertaken to explore the possible association between an iron accumulation and CMA in cypermethrin model of PD in the presence of deferoxamine. Level of iron, iron transporter proteins, oxidative stress, and CMA proteins along with indicators of Parkinsonism were measured. Deferoxamine attenuated cypermethrin-induced iron accumulation and number of iron-positive cells and ameliorated the demise of dopaminergic cells and dopamine content. Deferoxamine significantly normalizes cypermethrin-induced changes in iron transporter proteins, α-synuclein, lysosome-associated membrane protein-2A, and oxidative stress. The results demonstrate that deferoxamine ameliorates cypermethrin-induced iron dyshomeostasis and impairment in CMA.
    Keywords:  Chaperone-mediated autophagy; Cypermethrin; Deferoxamine; Iron dyshomeostasis; Oxidative stress; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-023-03827-5
  60. Toxicology. 2023 Dec 06. pii: S0300-483X(23)00285-8. [Epub ahead of print] 153698
    Dibromoacetonitrile induced autophagy by mediating the PERK signalling pathway and ROS interaction in HT22 cell.
    Fang Li, Xueyu Zhu, Xinwei Xu, Jie Zhou, Rongzhu Lu, Suhua Wang, Guangwei Xing, Yang Ye.
      Dibromoacetonitrile (DBAN) is a high-risk haloacetonitrile (HAN) generated as a byproduct of chloramine disinfection in drinking water. DBAN-induced neurotoxicity in mouse hippocampal neuronal cells (HT22) and mammals was observed to be related to reactive oxygen species (ROS). ROS, endoplasmic reticulum stress (ERS) and autophagy play crucial roles in regulating a variety of cellular processes. However, whether ERS and autophagy are associated with HAN-responsive apoptosis remains unclear. This study indicated that DBAN (10μM, 24h) activated the ERS protein kinase like endoplasmic reticulum kinase (PERK) signaling pathway. The ERS inhibitor 4-phenylbutyric acid (4-PBA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, indicating that activation of the ERS PERK pathway mediates DBAN induced cytotoxicity. Moreover, DBAN activated autophagy. The autophagy inhibitor 3-methyladenine(3-MA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, suggesting that autophagy activation mediates DBAN-induced cell toxicity. Notably, the results showed that 4-PBA inhibited DBAN-activated autophagy, demonstrating that ERS-PERK promotes DBAN-induced cellular autophagy. Pretreatment with antioxidant N-acetylcysteine (NAC) inhibited the increase in ROS production and the activation of ERS, and protected cells from toxicity. Furthermore, 4-PBA pretreatment reduced the increase in ROS production, indicating that the ROS and PERK promote each other and form a positive feedback loop. ROS also promoted DBAN-induced autophagy. In summary, our findings indicate that DBAN induced autophagy by mediating the PERK signalling pathway and ROS interaction, leading to HT22 cell damage. Accordingly, targeting these pathogenic mechanisms may provide a potential target and theoretical basis for preventing and improving HAN-induced neurotoxicity.
    Keywords:  Autophagy; Dibromoacetonitrile; Disinfection byproduct; Neurotoxicity; Oxidative stress; PERK signaling pathway
    DOI:  https://doi.org/10.1016/j.tox.2023.153698
  61. Environ Sci Technol. 2023 Dec 12.
    PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.
    Jingjia Liang, Cheng Xu, Jin Xu, Changjie Yang, Weirui Kong, Zhihao Xiao, Xiu Chen, Qian Liu, Zhenkun Weng, Jun Wang, Guibin Jiang, Zhaoyan Jiang, Aihua Gu.
      The internal exposure dose of bisphenol S (BPS) is increasing since its use as a substitute for BPA. The relationship between BPS and nonalcoholic liver disease (NAFLD) and the underlying mechanism remain unclarified. In this study, we evaluated the correlation of BPS with NAFLD in populations from the Jiangsu Survey and the 2013-2016 National Health Nutrition Examination Survey and unraveled the molecular pathway by which BPS blocked hepatic autophagy, contributing to lipid accumulation. The study found that serum and urine BPS were associated with NAFLD risks in both the Chinese and US populations. For each additional unit of the BPS level, the NAFLD risk increased by 3.163-fold (serum) and 3.979-fold (urine) in the Chinese population. In addition, after BPS exposure at a dose equivalent to human exposure for 20 weeks, mice developed liver lipid accumulation. BPS could trigger PPARα-mediated transcriptional activation of EP300 expression. BPS promoted the translocation of EP300 from the nucleus to the cytoplasm to regulate the acetylation of Raptor and the activation of mTORC1, which in turn induced autophagy blockage and interfered with lipid degradation in hepatocytes. Conversely, knockdown of EP300 reduced Raptor acetylation and ameliorated autophagy blockage. This study demonstrated that EP300 was a key enzyme for the development of BPS-related NAFLD and provided novel evidence that BPS causes NAFLD.
    Keywords:  EP300; NAFLD; PPARα; autophagy; bisphenol S; mTORC1
    DOI:  https://doi.org/10.1021/acs.est.3c05010
  62. Eur J Med Chem. 2023 Dec 07. pii: S0223-5234(23)00997-2. [Epub ahead of print]264 116030
    Small molecules as modulators of the proteostasis machinery: Implication in cardiovascular diseases.
    Zhiheng Yang, Yu Cao, Limin Kong, Jianjun Xi, Shourong Liu, Jiankang Zhang, Weiyan Cheng.
      With the escalating prevalence of cardiovascular diseases, the substantial socioeconomic burden on healthcare systems is intensifying. Accumulating empirical evidence underscores the pivotal role of the proteostasis network in regulating cardiac homeostasis and function. Disruptions in proteostasis may contribute to the loss of protein function or the acquisition of toxic functions, which are intricately linked to the development of cardiovascular ailments such as atrial fibrillation, heart failure, atherosclerosis, and cardiac aging. It is widely acknowledged that the proteostasis network encompasses molecular chaperones, autophagy, and the ubiquitin proteasome system (UPS). Consequently, the proteostasis network emerges as an appealing target for therapeutic interventions in cardiovascular diseases. Numerous small molecules, acting as modulators of the proteostasis machinery, have exhibited therapeutic efficacy in managing cardiovascular diseases. This review centers on elucidating the role of the proteostasis network in various cardiovascular diseases and explores the potential of small molecules as therapeutic agents.
    Keywords:  Autophagy; Cardiovascular diseases; Molecular chaperones; Proteostasis; Small molecules; Ubiquitin proteasome system
    DOI:  https://doi.org/10.1016/j.ejmech.2023.116030
  63. Front Cell Dev Biol. 2023 ;11 1294934
    Lost in mTORC1-related translation limits healing, repair and regeneration in mammals.
    José M Izquierdo.
      
    Keywords:  de novo translation; mTORC1; regeneration; regenerative medicine; repair; wound healing
    DOI:  https://doi.org/10.3389/fcell.2023.1294934
  64. Cell Mol Gastroenterol Hepatol. 2023 Dec 09. pii: S2352-345X(23)00214-X. [Epub ahead of print]
    IGF2BP1/IMP1 deletion enhances a facultative stem cell state via regulation of MAP1LC3B.
    Louis R Parham, Patrick A Williams, Kay Katada, Shaneice K Nettleford, Priya Chatterji, Kofi K Acheampong, Charles H Danan, Xianghui Ma, Lauren A Simon, Kaitlyn E Naughton, Tatiana Karakasheva, Emily A McMillan, Kelly A Whelan, Donita C Brady, Sydney M Shaffer, Kathryn E Hamilton.
       BACKGROUND & AIMS: The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies demonstrate autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration.
    METHODS: We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein IMP1. The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of Atg7. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single molecule fluorescent in situ hybridization (smFISH).
    RESULTS: Epithelial Imp1 deletion reduced Lgr5+ cell frequency but enhanced both organoid formation efficiency and in vivo regeneration following irradiation. We confirmed prior studies demonstrating increased autophagy with IMP1 deletion. Deletion of Atg7 reversed the enhanced regeneration observed with Imp1 deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein Microtubule Associated Protein 1 Light Chain 3 Beta (MAP1LC3B). Furthermore, immunofluorescence imaging coupled with smFISH demonstrated IMP1 colocalization with MAP1LC3B transcripts at homeostasis. Stress induction led to decreased co-localization.
    CONCLUSIONS: Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.
    DOI:  https://doi.org/10.1016/j.jcmgh.2023.12.001
  65. bioRxiv. 2023 Nov 29. pii: 2023.11.29.569220. [Epub ahead of print]
    Spartin-mediated lipid transfer facilitates lipid droplet turnover.
    Neng Wan, Zhouping Hong, Matthew A H Parson, Justin Korfhage, John E Burke, Thomas J Melia, Karin M Reinisch.
      Lipid droplets (LDs) are organelles critical for energy storage and membrane lipid homeostasis, whose number and size are carefully regulated in response to cellular conditions. The molecular mechanisms underlying lipid droplet biogenesis and degradation, however, are not well understood. The Troyer syndrome protein spartin (SPG20) supports LD delivery to autophagosomes for turnover via lipophagy. Here, we characterize spartin as a lipid transfer protein whose transfer ability is required for LD degradation. Spartin co-purifies with phospholipids and neutral lipids from cells and transfers phospholipids in vitro via its senescence domain. A senescence domain truncation that impairs lipid transfer in vitro also impairs LD turnover in cells while not affecting spartin association with either LDs or autophagosomes, supporting that spartin's lipid transfer ability is physiologically relevant. Our data indicate a role for spartin-mediated lipid transfer in LD turnover.
    Significance: The Troyer syndrome protein spartin was proposed to function as a lipophagy receptor that delivers lipid droplets, organelles key for energy storage and membrane lipid homeostasis, to autophagosomes for degradation. We identify an additional function for spartin as a lipid transfer protein and show its transfer ability is required for lipid droplet degradation, including by lipophagy. Our data support that protein-mediated lipid transfer plays a role in lipid droplet turnover. Moreover, in spartin's senescence domain we have discovered a new lipid transport module that likely also features in still undiscovered aspects of lipid droplet biology and membrane homeostasis.
    DOI:  https://doi.org/10.1101/2023.11.29.569220
  66. Adv Sci (Weinh). 2023 Dec 12. e2308346
    Oral Carbon Monoxide Enhances Autophagy Modulation in Prostate, Pancreatic, and Lung Cancers.
    Jianling Bi, Emily Witt, Megan K McGovern, Arielle B Cafi, Lauren L Rosenstock, Anna B Pearson, Timothy J Brown, Thomas B Karasic, Lucas C Absler, Srija Machkanti, Hannah Boyce, David Gallo, Sarah L Becker, Keiko Ishida, Joshua Jenkins, Alison Hayward, Alexandra Scheiflinger, Kellie L Bodeker, Ritesh Kumar, Scott K Shaw, Salma K Jabbour, Vitor A Lira, Michael D Henry, Michael S Tift, Leo E Otterbein, Giovanni Traverso, James D Byrne.
      Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas-entrapping material containing CO in a pre-clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.
    Keywords:  CO biofoams; autophagy modulation; combination therapies; smoking
    DOI:  https://doi.org/10.1002/advs.202308346
  67. Cell Death Dis. 2023 Dec 09. 14(12): 811
    Blockade of DDR1/PYK2/ERK signaling suggesting SH2 superbinder as a novel autophagy inhibitor for pancreatic cancer.
    Hui Xu, Ming Tan, Guo-Qing Hou, Ya-Zhou Sang, Li Lin, Xiao-Cai Gan, Xuan Cao, An-Dong Liu.
      Pancreatic cancer is highly lethal, of which 90% is pancreatic ductal adenocarcinoma (PDAC), with a 5-year survival rate of less than 12%, lacking effective treatment options and late diagnosis. Furthermore, the tumors show an intense resistance to cytotoxic chemotherapies. As autophagy is elevated in PDAC, targeting the autophagic pathway is regarded as a promising strategy for cancer treatment. Immunofluorescence and transmission electron microscopy were utilized to assess the autophagic flux. Label-free quantitative phosphoproteomics was used to figure out critically altered tyrosine phosphorylation of the proteins. Tumor-bearing mice were used to validate that SH2 TrM-(Arg)9 restrained the growth of tumor cells. SH2 TrM-(Arg)9 inhibited collagen-induced autophagy via blocking the DDR1/PYK2/ERK signaling cascades. SH2 TrM-(Arg)9 improved the sensitivity of PANC-1/GEM cells to gemcitabine (GEM). Inhibition of autophagy by SH2 TrM-(Arg)9 may synergized with chemotherapy and robusted tumor suppression in pancreatic cancer xenografts. SH2 TrM-(Arg)9 could enter into PDAC cells and blockade autophagy through inhibiting DDR1/PYK2/ERK signaling and may be a new treatment strategy for targeted therapy of PDAC.
    DOI:  https://doi.org/10.1038/s41419-023-06344-4
  68. Cell Rep. 2023 Dec 12. pii: S2211-1247(23)01585-1. [Epub ahead of print]42(12): 113573
    Reduced lysosomal density in neuronal dendrites mediates deficits in synaptic plasticity in Huntington's disease.
    Jia-Hui Chen, Na Xu, Lei Qi, Hao-Hao Yan, Fang-Yan Wan, Feng Gao, Chuanhai Fu, Chunlei Cang, Boxun Lu, Guo-Qiang Bi, Ai-Hui Tang.
      Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.
    Keywords:  CAG-140 mice; CP: Cell biology; CP: Neuroscience; hippocampus; light-induced dimerization; long-term potentiation; lysosome; optogenetic
    DOI:  https://doi.org/10.1016/j.celrep.2023.113573
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