bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–04–28
sixty-six papers selected by
Viktor Korolchuk, Newcastle University
  1. Molecular mechanisms of secretory autophagy and its potential role in diseases.
  2. Role of TFEB in Huntington's Disease.
  3. Missing WD40 Repeats in ATG16L1 Delays Canonical Autophagy and Inhibits Noncanonical Autophagy.
  4. Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
  5. Rottlerin Enhances the Autophagic Degradation of Phosphorylated Tau in Neuronal Cells.
  6. Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.
  7. Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.
  8. Friends and Foes: The Ambivalent Role of Autophagy in HIV-1 Infection.
  9. The interplay between autophagy and cGAS-STING signaling and its implications for cancer.
  10. Mycobacterial SapM hampers host autophagy initiation for intracellular bacillary survival via dephosphorylating Raptor.
  11. Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy.
  12. P4HA2 activates mTOR via hydroxylation and targeting P4HA2-mTOR inhibits lung adenocarcinoma cell growth.
  13. Molecular mechanism of autophagy and apoptosis in endometriosis: Current understanding and future research directions.
  14. Nano implant surface triggers autophagy through membrane curvature distortion to regulate the osteogenic differentiation.
  15. Simultaneously Monitoring Multiple Autophagic Processes and Assessing Autophagic Flux in Single Cells by In Situ Fluorescence Cross-Correlation Spectroscopy.
  16. Identification of TFG- and Autophagy-Regulated Proteins and Glycerophospholipids in B Cells.
  17. The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells.
  18. Defining the in vivo role of mTORC1 in thyrocytes by studying the TSC2 conditional knockout mouse model.
  19. Beyond the C-terminal glycine of ATG8 proteins - The story of some neglected amino acids.
  20. Vacuolar Degradation of Plant Organelles.
  21. TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22.
  22. Mitophagy and its regulatory mechanisms in the biological effects of nanomaterials.
  23. 6PPD induced cardiac dysfunction in zebrafish associated with mitochondrial damage and inhibition of autophagy processes.
  24. Critical role of miR-21/exosomal miR-21 in autophagy pathway.
  25. Targeting autophagy with natural products as a potential therapeutic approach for diabetic microangiopathy.
  26. TRIM28 Fosters Microglia Ferroptosis via Autophagy Modulation to Enhance Neuropathic Pain and Neuroinflammation.
  27. Deep Sequencing Identified miR-193b-3p as a Positive Regulator of Autophagy Targeting Akt3 in Ctenopharyngodon idella CIK Cells During GCRV Infection.
  28. The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.
  29. Bronchial thermoplasty decreases airway remodeling by inhibiting autophagy via the AMPK/mTOR signaling pathway.
  30. Sde Proteins Coordinate Ubiquitin Utilization and Phosphoribosylation to Promote Establishment and Maintenance of the Legionella Replication Vacuole.
  31. Tanshinone IIA positively regulates the Keap1-Nrf2 system to alleviate pulmonary fibrosis via the sestrin2-sqstm1 signaling axis-mediated autophagy.
  32. Inhibition of miR-146b-5p alleviates isoprenaline-induced cardiac hypertrophy via regulating DFCP1.
  33. Individual Atg8 paralogs and a bacterial metabolite sequentially promote hierarchical CASM-xenophagy induction and transition.
  34. OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.
  35. Assessment of Stiffness-Dependent Autophagosome Formation and Apoptosis in Embryonal Rhabdomyosarcoma Tumor Cells.
  36. High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast.
  37. The Role Played by Autophagy in FcεRI-Dependent Activation of Mast Cells.
  38. NUPR1 induces autophagy and promotes the progression of Esophageal squamous cell carcinoma via the MAPK-mTOR pathway.
  39. Lysosomal Peptide Self-Assembly To Control Cell Behavior.
  40. The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
  41. Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress.
  42. Acetylated pelargonidin-3-O-glucoside alleviates hepatocyte lipid deposition through activating the AMPK-mediated lysosome-autophagy pathway and redox state.
  43. Inhibitors to degraders: Changing paradigm in drug discovery.
  44. The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.
  45. Deciphering the impact of circRNA-mediated autophagy on tumor therapeutic resistance: a novel perspective.
  46. The Influence of Lysosomal Stress on Dental Pulp Stem Cell-Derived Schwann Cells.
  47. Inhibition of Usp14 ameliorates renal ischemia-reperfusion injury by reducing Tfap2a stabilization and facilitating mitophagy.
  48. Perfluoroalkyl sulfonate induces cardiomyocyte apoptosis via endoplasmic reticulum stress activation and autophagy flux inhibition.
  49. Inflammation and mitophagy are mitochondrial checkpoints to aging.
  50. Optogenetically engineered calcium oscillations promote autophagy-mediated cell death via AMPK activation.
  51. Near-infrared imaging for visualizing the synergistic relationship between autophagy and NFS1 protein during multidrug resistance using an ICT-TICT integrated platform.
  52. A Study of FoxO1, mTOR, miR-21, miR-29b, and miR-98 Expression Levels Regarding Metabolic Syndrome in Acne Vulgaris Patients.
  53. HO-1 upregulation promotes mitophagy-dependent ferroptosis in PM2.5-exposed hippocampal neurons.
  54. Cardiomyocyte-specific deletion of the mitochondrial transporter Abcb10 causes cardiac dysfunction via lysosomal-mediated ferroptosis.
  55. Mitigation of Stress-induced Structural Remodeling and Functional Deficiency in iPSC-CMs with PLN R9C Mutation by Promoting Autophagy.
  56. Role of NuMA1 in breast cancer stem cells with implications for combination therapy of PIM1 and autophagy inhibition in triple negative breast cancer.
  57. A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.
  58. Caspase-1 Deficiency Modulates Adipogenesis through Atg7-Mediated Autophagy: An Inflammatory-Independent Mechanism.
  59. Expression of ZKSCAN3 protein suppresses proliferation, migration, and invasion of pancreatic cancer through autophagy.
  60. The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology.
  61. Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice.
  62. NBR1-dependent Autophagy Activation Protects Against Environmental Cadmium-evoked Placental Trophoblast Senescence.
  63. RNA methylation patterns, immune characteristics, and autophagy-related mechanisms mediated by N6-methyladenosine (m6A) regulatory factors in venous thromboembolism.
  64. Membrane-bound O-acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury.
  65. PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.
  66. HMGB1 regulates autophagy of placental trophoblast through ERK signaling pathway.
  1. Life Sci. 2024 Apr 23. pii: S0024-3205(24)00243-1. [Epub ahead of print] 122653
    Molecular mechanisms of secretory autophagy and its potential role in diseases.
    Qin Li, Guolong Peng, Huimei Liu, Liwen Wang, Ruirui Lu, Lanfang Li.
      Autophagy is a cellular degradation system that recycles or degrades damaged organelles, viral particles, and aggregated proteins through the lysosomal pathway. Autophagy plays an indispensable role in cellular homeostasis and communication processes. An interesting aspect is that autophagy also mediates the secretion of cellular contents, a process known as secretory autophagy. Secretory autophagy differs from macroautophagy, which sequesters recruited proteins, organelles, or viral particles into autophagosomes and degrades these sequesters in lysosomes, while the secretory autophagy pathway participates in the extracellular export of cellular contents sequestered by autophagosomes through autophagy and endosomal modulators. Recent evidence reveals that secretory autophagy is pivotal in the occurrence and progression of diseases. In this review, we summarize the molecular mechanisms of secretory autophagy. Furthermore, we review the impact of secretory autophagy on diseases, including cancer, viral infectious diseases, neurodegenerative diseases, and cardiovascular diseases. Considering the pleiotropic actions of secretory autophagy on diseases, studying the mechanism of secretory autophagy may help to understand the relevant pathophysiological processes.
    Keywords:  Alzheimer's disease; Autophagy; COVID-19; Cancer; Secretory autophagy
    DOI:  https://doi.org/10.1016/j.lfs.2024.122653
  2. Biology (Basel). 2024 Apr 04. pii: 238. [Epub ahead of print]13(4):
    Role of TFEB in Huntington's Disease.
    Javier Ojalvo-Pacheco, Sokhna M S Yakhine-Diop, José M Fuentes, Marta Paredes-Barquero, Mireia Niso-Santano.
      Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. This expansion leads to a polyglutamine (polyQ) tract at the N-terminal end of HTT, which reduces the solubility of the protein and promotes its accumulation. Inefficient clearance of mutant HTT (mHTT) by the proteasome or autophagy-lysosomal system leads to accumulation of oligomers and toxic protein aggregates in neurons, resulting in impaired proteolytic systems, transcriptional dysregulation, impaired axonal transport, mitochondrial dysfunction and cellular energy imbalance. Growing evidence suggests that the accumulation of mHTT aggregates and autophagic and/or lysosomal dysfunction are the major pathogenic mechanisms underlying HD. In this context, enhancing autophagy may be an effective therapeutic strategy to remove protein aggregates and improve cell function. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, controls the expression of genes critical for autophagosome formation, lysosomal biogenesis, lysosomal function and autophagic flux. Consequently, the induction of TFEB activity to promote intracellular clearance may be a therapeutic strategy for HD. However, while some studies have shown that overexpression of TFEB facilitates the clearance of mHTT aggregates and ameliorates the disease phenotype, others indicate such overexpression may lead to mHTT co-aggregation and worsen disease progression. Further studies are necessary to confirm whether TFEB modulation could be an effective therapeutic strategy against mHTT-mediated toxicity in different disease models.
    Keywords:  Huntington’s disease; TFEB; autophagy; lysosome; mHTT
    DOI:  https://doi.org/10.3390/biology13040238
  3. Int J Mol Sci. 2024 Apr 19. pii: 4493. [Epub ahead of print]25(8):
    Missing WD40 Repeats in ATG16L1 Delays Canonical Autophagy and Inhibits Noncanonical Autophagy.
    Jiuge Tang, Dongmei Fang, Jialing Zhong, Min Li.
      Canonical autophagy is an evolutionarily conserved process that forms double-membrane structures and mediates the degradation of long-lived proteins (LLPs). Noncanonical autophagy (NCA) is an important alternative pathway involving the formation of microtubule-associated protein 1 light chain 3 (LC3)-positive structures that are independent of partial core autophagy proteins. NCA has been defined by the conjugation of ATG8s to single membranes (CASM). During canonical autophagy and NCA/CASM, LC3 undergoes a lipidation modification, and ATG16L1 is a crucial protein in this process. Previous studies have reported that the WDR domain of ATG16L1 is not necessary for canonical autophagy. However, our study found that WDR domain deficiency significantly impaired LLP degradation in basal conditions and slowed down LC3-II accumulation in canonical autophagy. We further demonstrated that the observed effect was due to a reduced interaction between ATG16L1 and FIP200/WIPI2, without affecting lysosome function or fusion. Furthermore, we also found that the WDR domain of ATG16L1 is crucial for chemical-induced NCA/CASM. The results showed that removing the WDR domain or introducing the K490A mutation in ATG16L1 significantly inhibited the NCA/CASM, which interrupted the V-ATPase-ATG16L1 axis. In conclusion, this study highlights the significance of the WDR domain of ATG16L1 for both canonical autophagy and NCA functions, improving our understanding of its role in autophagy.
    Keywords:  ATG16L1; WDR domain; canonical autophagy; noncanonical autophagy
    DOI:  https://doi.org/10.3390/ijms25084493
  4. bioRxiv. 2024 Apr 09. pii: 2024.04.09.587573. [Epub ahead of print]
    Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
    Jennifer deRiso, Malini Mukherjee, Madhusudhana Janga, Alicia Simmons, Michael Kareta, Jianning Tao, Indra Chandrasekar, Kameswaran Surendran.
      The plasticity and diversity of cell types with specialized functions likely defines the capacity of multicellular organisms to adapt to physiologic stressors. The kidney collecting ducts contribute to water, electrolyte, and pH homeostasis and are composed of mature intermingled epithelial cell types that are susceptible to transdifferentiate. The conversion of kidney collecting duct principal cells to intercalated cells is actively inhibited by Notch signaling to ensure urine concentrating capability. Here we identify Hes1, a target of Notch signaling, allows for maintenance of functionally distinct epithelial cell types within the same microenvironment by regulating mechanistic target of rapamycin complex 1 (mTORC1) activity. Hes1 directly represses the expression of insulin receptor substrate 1 ( Irs1 ), an upstream component of mTOR pathway and suppresses mTORC1 activity in principal cells. Genetic inactivation of tuberous sclerosis complex 2 ( Tsc2 ) to increase mTORC1 activity in mature principal cells is sufficient to promote acquisition of intercalated cell properties, while inhibition of mTORC1 in adult kidney epithelia suppresses intercalated cell properties. Considering that mTORC1 integrates environmental cues, the linkage of functionally distinct epithelial cell types to mTORC1 activity levels likely allows for cell plasticity to be regulated by physiologic and metabolic signals and the ability to sense/transduce these signals.
    DOI:  https://doi.org/10.1101/2024.04.09.587573
  5. Mol Neurobiol. 2024 Apr 27.
    Rottlerin Enhances the Autophagic Degradation of Phosphorylated Tau in Neuronal Cells.
    Min Kyoung Kam, Jee-Yun Park, Gwang Ho Yun, Hee-Young Sohn, Jung Hyun Park, Jiyoung Choi, Young Ho Koh, Chulman Jo.
      Intra-neuronal accumulation of hyper-phosphorylated tau as neurofibrillary tangles (NFT) is a hallmark of Alzheimer's disease (AD). To prevent the aggregation of phosphorylated tau in neurons, decreasing the phosphorylated tau protein levels is important. Here, we examined the biological effects of rottlerin, a phytochemical compound extracted from the Kamala tree, Mallotus philippinensis, on phosphorylated tau levels. Notably, rottlerin decreased the levels of intracellular phosphorylated and total tau. A marked increase in the LC3-II, a hallmark of autophagy, was observed in these cells, indicating that rottlerin strongly induced autophagy. Interestingly, rottlerin induced the phosphorylation of Raptor at S792 through the activation of adenosine-monophosphate activated-protein kinase (AMPK), which likely inhibits the mammalian target of rapamycin complex 1 (mTORC1), thus resulting in the activation of transcription factor EB (TFEB), a master regulator of autophagy. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) activity increased in the presence of rottlerin. The decrease of phosphorylated tau levels in the presence of rottlerin was ameliorated by the knockdown of TFEB and partially attenuated by the knockout of the Nrf2 gene. Taken together, rottlerin likely enhances the degradation of phosphorylated tau through autophagy activated by TFEB and Nrf2. Thus, our results suggest that a natural compound rottlerin could be used as a preventive and therapeutic drug for AD.
    Keywords:  Alzheimer’s disease; Autophagy; Nrf2; Rottlerin; TFEB; Tau
    DOI:  https://doi.org/10.1007/s12035-024-04182-9
  6. Skelet Muscle. 2024 Apr 20. 14(1): 7
    Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.
    Ashley N Oliveira, Jonathan M Memme, Jenna Wong, David A Hood.
       BACKGROUND: Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported.
    METHODS: Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux.
    RESULTS: WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner.
    CONCLUSIONS: Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.
    Keywords:  Autophagy; Lysosomal biogenesis; Mitochondrial respiration; Mitophagy; ROS emission; Sex differences
    DOI:  https://doi.org/10.1186/s13395-024-00339-1
  7. PLoS Biol. 2024 Apr 23. 22(4): e3002591
    Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.
    Wenping Zeng, Canjun Li, Ruikun Wu, Xingguo Yang, Qingyan Wang, Bingqian Lin, Yanan Wei, Hao Li, Ge Shan, Lili Qu, Chunlei Cang.
      Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases. However, methods to dynamically regulate lysosomal function in living cells or animals are still lacking. Here, we constructed lysosome-localized optogenetic actuators, named lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2, to achieve optogenetic manipulation of lysosomes. These new actuators enable light-dependent control of lysosomal membrane potential, pH, hydrolase activity, degradation, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy through the mTOR pathway, promotes Aβ clearance in an autophagy-dependent manner in cellular models, and alleviates Aβ-induced paralysis in the Caenorhabditis elegans model of Alzheimer's disease. Our lysosomal optogenetic actuators supplement the optogenetic toolbox and provide a method to dynamically regulate lysosomal physiology and function in living cells and animals.
    DOI:  https://doi.org/10.1371/journal.pbio.3002591
  8. Viruses. 2024 Mar 25. pii: 500. [Epub ahead of print]16(4):
    Friends and Foes: The Ambivalent Role of Autophagy in HIV-1 Infection.
    Susanne Klute, Konstantin M J Sparrer.
      Autophagy has emerged as an integral part of the antiviral innate immune defenses, targeting viruses or their components for lysosomal degradation. Thus, successful viruses, like pandemic human immunodeficiency virus 1 (HIV-1), evolved strategies to counteract or even exploit autophagy for efficient replication. Here, we provide an overview of the intricate interplay between autophagy and HIV-1. We discuss the impact of autophagy on HIV-1 replication and report in detail how HIV-1 manipulates autophagy in infected cells and beyond. We also highlight tissue and cell-type specifics in the interplay between autophagy and HIV-1. In addition, we weigh exogenous modulation of autophagy as a putative double-edged sword against HIV-1 and discuss potential implications for future antiretroviral therapy and curative approaches. Taken together, we consider both antiviral and proviral roles of autophagy to illustrate the ambivalent role of autophagy in HIV-1 pathogenesis and therapy.
    Keywords:  HIV; autophagy; innate immunity
    DOI:  https://doi.org/10.3390/v16040500
  9. Front Immunol. 2024 ;15 1356369
    The interplay between autophagy and cGAS-STING signaling and its implications for cancer.
    Maximilian Schmid, Patrick Fischer, Magdalena Engl, Joachim Widder, Sylvia Kerschbaum-Gruber, Dea Slade.
      Autophagy is an intracellular process that targets various cargos for degradation, including members of the cGAS-STING signaling cascade. cGAS-STING senses cytosolic double-stranded DNA and triggers an innate immune response through type I interferons. Emerging evidence suggests that autophagy plays a crucial role in regulating and fine-tuning cGAS-STING signaling. Reciprocally, cGAS-STING pathway members can actively induce canonical as well as various non-canonical forms of autophagy, establishing a regulatory network of feedback mechanisms that alter both the cGAS-STING and the autophagic pathway. The crosstalk between autophagy and the cGAS-STING pathway impacts a wide variety of cellular processes such as protection against pathogenic infections as well as signaling in neurodegenerative disease, autoinflammatory disease and cancer. Here we provide a comprehensive overview of the mechanisms involved in autophagy and cGAS-STING signaling, with a specific focus on the interactions between the two pathways and their importance for cancer.
    Keywords:  autophagy; cGAS/STING signaling; cancer; innate immunity; radiotherapy
    DOI:  https://doi.org/10.3389/fimmu.2024.1356369
  10. iScience. 2024 May 17. 27(5): 109671
    Mycobacterial SapM hampers host autophagy initiation for intracellular bacillary survival via dephosphorylating Raptor.
    Wei Zhang, Chunsheng Dong, Sidong Xiong.
      Secreted acid phosphatase (SapM) is an immunomodulator of Mycobacterium tuberculosis (Mtb) and consequently plays a crucial role in disease onset and development upon infection. Importantly, the virulence of SapM has rendered SapM an attractive target for drug development. However, the mechanism underlying the role of SapM in facilitating bacillary survival remains to be fully elucidated. In this context, the present study demonstrated that SapM hampered cellular autophagy to facilitate bacillary survival in mycobacterial-infected macrophages. Mechanically, SapM interacted with Raptor and was localized to the subcellular lysosomal organelle, causing the dephosphorylation of Raptor at the Ser792 position, resulting in mTORC1 hyperactivity and the subsequent autophagy inhibition. Consistent with this, SapM blocked the autophagy initiation and mitigated lung pathology in vivo. These findings highlighted the role of Raptor as a significant substrate of SapM for inhibiting autophagy, which is a novel clue for developing a treatment against tuberculosis.
    Keywords:  Microbiology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.109671
  11. J Cell Biol. 2024 Jun 03. pii: e202306150. [Epub ahead of print]223(6):
    Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy.
    Madison A Ward, Janakiram R Vangala, Hatem Elif Kamber Kaya, Holly A Byers, Nayyerehalsadat Hosseini, Antonio Diaz, Ana Maria Cuervo, Susmita Kaushik, Senthil K Radhakrishnan.
      Cells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor-erythroid derived-2-related factor-1 (Nrf1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates new proteasome synthesis, thus enabling the cells to mitigate the proteotoxic stress. Here, we report that under similar circumstances, multiple components of the autophagy-lysosomal pathway (ALP) were transcriptionally upregulated in an Nrf1-dependent fashion, thus providing the cells with an additional route to cope with proteasome insufficiency. In response to proteasome inhibitors, Nrf1-deficient cells displayed profound defects in invoking autophagy and clearance of aggresomes. This phenomenon was also recapitulated in NGLY1 knockout cells, where Nrf1 is known to be non-functional. Conversely, overexpression of Nrf1 induced ALP genes and endowed the cells with an increased capacity to clear aggresomes. Overall, our results significantly expand the role of Nrf1 in shaping the cellular response to proteotoxic stress.
    DOI:  https://doi.org/10.1083/jcb.202306150
  12. Oncogene. 2024 Apr 23.
    P4HA2 activates mTOR via hydroxylation and targeting P4HA2-mTOR inhibits lung adenocarcinoma cell growth.
    Ersuo Jin, Shengjie Wang, Donglai Chen, Jia-Ping Wang, Yuanyuan Zeng, Runfeng Sun, Hong-Tao Zhang.
      Mammalian target of rapamycin (mTOR) kinase functions as a central regulator of cell growth and metabolism, and its complexes mTORC1 and mTORC2 phosphorylate distinct substrates. Dysregulation of mTOR signaling is commonly implicated in human diseases, including cancer. Despite three decades of active research in mTOR, much remains to be determined. Here, we demonstrate that prolyl 4-hydroxylase alpha-2 (P4HA2) binds directly to mTOR and hydroxylates one highly conserved proline 2341 (P2341) within a kinase domain of mTOR, thereby activating mTOR kinase and downstream effector proteins (e.g. S6K and AKT). Moreover, the hydroxylation of P2341 strengthens mTOR stability and allows mTOR to accurately recognize its substrates such as S6K and AKT. The growth of lung adenocarcinoma cells overexpressing mTORP2341A is significantly reduced when compared with that of cells overexpressing mTORWT. Interestingly, in vivo cell growth assays show that targeting P4HA2-mTOR significantly suppresses lung adenocarcinoma cell growth. In summary, our study reveals an undiscovered hydroxylation-regulatory mechanism by which P4HA2 directly activates mTOR kinase, providing insights for therapeutically targeting mTOR kinase-driven cancers.
    DOI:  https://doi.org/10.1038/s41388-024-03032-1
  13. Reprod Med Biol. 2024 Jan-Dec;23(1):23(1): e12577
    Molecular mechanism of autophagy and apoptosis in endometriosis: Current understanding and future research directions.
    Hiroshi Kobayashi, Shogo Imanaka, Chiharu Yoshimoto, Sho Matsubara, Hiroshi Shigetomi.
       Background: Endometriosis is a common gynecological condition, with symptoms including pain and infertility. Regurgitated endometrial cells into the peritoneal cavity encounter hypoxia and nutrient starvation. Endometriotic cells have evolved various adaptive mechanisms to survive in this inevitable condition. These adaptations include escape from apoptosis. Autophagy, a self-degradation system, controls apoptosis during stress conditions. However, to date, the mechanisms regulating the interplay between autophagy and apoptosis are still poorly understood. In this review, we summarize the current understanding of the molecular characteristics of autophagy in endometriosis and discuss future therapeutic challenges.
    Methods: A search of PubMed and Google Scholar databases were used to identify relevant studies for this narrative literature review.
    Results: Autophagy may be dynamically regulated through various intrinsic (e.g., PI3K/AKT/mTOR signal transduction network) and extrinsic (e.g., hypoxia and iron-mediated oxidative stress) pathways, contributing to the development and progression of endometriosis. Upregulation of mTOR expression suppresses apoptosis via inhibiting the autophagy pathway, whereas hypoxia or excess iron often inhibits apoptosis via promoting autophagy.
    Conclusion: Endometriotic cells may have acquired antiapoptotic mechanisms through unique intrinsic and extrinsic autophagy pathways to survive in changing environments.
    Keywords:  apoptosis; autophagy; endometriosis; mitochondria; mitophagy
    DOI:  https://doi.org/10.1002/rmb2.12577
  14. Biomed Mater. 2024 Apr 24.
    Nano implant surface triggers autophagy through membrane curvature distortion to regulate the osteogenic differentiation.
    Guangwen Li, Bei Chang, Yuqi Zhao, Haochen Wang, Yan Zhang, Meiqi Zhao, Li Zhang, Wen Song, Yumei Zhang.
      Anodized titania nanotubes have been considered as an effective coating for bone implants due to their ability to induce osteogenesis, but the mechanism is not fully understood. Our previous study indicated the potential role of autophagy in osteogenic regulation of nanotubular surface, whereas how the autophagy is activated remains unknown. In this study, we focused on the cell membrane curvature-sensing protein Bif-1 and its effect on the regulation of autophagy. Both autophagosome formation and autophagic flux are enhanced on the nanotubular surface, as indicated by LC3-II accumulation and p62 degradation. In the meanwhile, the Bif-1 was significantly upregulated, which contributed to autophagy activation and osteogenic differentiation through Beclin-1/PIK3C3 signaling pathway. In conclusion, these findings may provide deeper insight into the signaling transition from mechanical to biological across the cell membrane.
    Keywords:  Nano; autophagy; curvatures; implant; membrane; triggers
    DOI:  https://doi.org/10.1088/1748-605X/ad42eb
  15. Anal Chem. 2024 Apr 22.
    Simultaneously Monitoring Multiple Autophagic Processes and Assessing Autophagic Flux in Single Cells by In Situ Fluorescence Cross-Correlation Spectroscopy.
    Haohan Song, Chaoqing Dong, Jicun Ren.
      Autophagy is a widely conserved and multistep cellular catabolic process and maintains cellular homeostasis and normal cellular functions via the degradation of some harmful intracellular components. It was reported that high basal autophagic activity may be closely related to tumorigenesis. So far, the fluorescence imaging technique has been widely used to study autophagic processes, but this method is only suitable for distinguishing autophagosomes and autolysosomes. Simultaneously monitoring multiple autophagic processes remains a significant challenge due to the lack of an efficient detection method. Here, we demonstrated a new method for simultaneously monitoring multiple autophagic processes and assessing autophagic flux in single cells based on in situ fluorescence cross-correlation spectroscopy (FCCS). In this study, microtubule-associated protein 1A/1B-light chain 3B (LC3B) was fused with two tandem fluorescent proteins [mCherry red fluorescent protein (mCherry) and enhanced green fluorescent protein (EGFP)] to achieve the simultaneous labeling and distinguishing of multiple autophagic structures based on the differences in characteristic diffusion time (τD). Furthermore, we proposed a new parameter "delivery efficiency of autophagosome (DEAP)" to assess autophagic flux based on the cross correlation (CC) value. Our results demonstrate that FCCS can efficiently distinguish three autophagic structures, assess the induced autophagic flux, and discriminate different autophagy regulators. Compared with the commonly used fluorescence imaging technique, the resolution of FCCS remains unaffected by Brownian motion and fluorescent monomers in the cytoplasm and is well suitable to distinguishing differently colored autophagic structures and monitoring autophagy.
    DOI:  https://doi.org/10.1021/acs.analchem.4c00725
  16. J Proteome Res. 2024 Apr 22.
    Identification of TFG- and Autophagy-Regulated Proteins and Glycerophospholipids in B Cells.
    Tobit D Steinmetz, Jana Thomas, Lena Reimann, Ann-Kathrin Himmelreich, Sebastian R Schulz, Florian Golombek, Kathrin Castiglione, Hans-Martin Jäck, Susanne Brodesser, Bettina Warscheid, Dirk Mielenz.
      Autophagy supervises the proteostasis and survival of B lymphocytic cells. Trk-fused gene (TFG) promotes autophagosome-lysosome flux in murine CH12 B cells, as well as their survival. Hence, quantitative proteomics of CH12tfgKO and WT B cells in combination with lysosomal inhibition should identify proteins that are prone to lysosomal degradation and contribute to autophagy and B cell survival. Lysosome inhibition via NH4Cl unexpectedly reduced a number of proteins but increased a large cluster of translational, ribosomal, and mitochondrial proteins, independent of TFG. Hence, we propose a role for lysosomes in ribophagy in B cells. TFG-regulated proteins include CD74, BCL10, or the immunoglobulin JCHAIN. Gene ontology (GO) analysis reveals that proteins regulated by TFG alone, or in concert with lysosomes, localize to mitochondria and membrane-bound organelles. Likewise, TFG regulates the abundance of metabolic enzymes, such as ALDOC and the fatty acid-activating enzyme ACOT9. To test consequently for a function of TFG in lipid metabolism, we performed shotgun lipidomics of glycerophospholipids. Total phosphatidylglycerol is more abundant in CH12tfgKO B cells. Several glycerophospholipid species with similar acyl side chains, such as 36:2 phosphatidylethanolamine and 36:2 phosphatidylinositol, show a dysequilibrium. We suggest a role for TFG in lipid homeostasis, mitochondrial functions, translation, and metabolism in B cells.
    Keywords:  B cell; BCL10; JCHAIN; TRK-fused gene; autophagy; autophagy flux; endoplasmic reticulum stress; immunoglobulin; lysosome; metabolism; phosphatidylglycerol; plasma cell; ribosome
    DOI:  https://doi.org/10.1021/acs.jproteome.3c00713
  17. Eur J Immunol. 2024 Apr 22. e2350825
    The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells.
    Jannis Wißfeld, Marvin Hering, Nora Ten Bosch, Guoliang Cui.
      Cyclosporin A is a well-established immunosuppressive drug used to treat or prevent graft-versus-host disease, the rejection of organ transplants, autoimmune disorders, and leukemia. It exerts its immunosuppressive effects by inhibiting calcineurin-mediated dephosphorylation of the nuclear factor of activated T cells (NFAT), thus preventing its nuclear entry and suppressing T cell activation. Here we report an unexpected immunostimulatory effect of cyclosporin A in activating the mammalian target of rapamycin complex 1 (mTORC1), a crucial metabolic hub required for T cell activation. Through screening a panel of tool compounds known to regulate mTORC1 activation, we found that cyclosporin A activated mTORC1 in CD8+ T cells in a 3-phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB/AKT)-dependent manner. Mechanistically, cyclosporin A inhibited the calcineurin-mediated AKT dephosphorylation, thereby stabilizing mTORC1 signaling. Cyclosporin A synergized with mTORC1 pathway inhibitors, leading to potent suppression of proliferation and cytokine production in CD8+ T cells and an increase in the killing of acute T cell leukemia cells. Consequently, relying solely on CsA is insufficient to achieve optimal therapeutic outcomes. It is necessary to simultaneously target both the calcineurin-NFAT pathway and the mTORC1 pathway to maximize therapeutic efficacy.
    Keywords:  AKT; CD8+; CsA; Ribosomal protein S6; T cells; mTOR
    DOI:  https://doi.org/10.1002/eji.202350825
  18. Thyroid. 2024 Apr 25.
    Defining the in vivo role of mTORC1 in thyrocytes by studying the TSC2 conditional knockout mouse model.
    Camila Ludke Rossetti, Bruna Lourenconi Alves, Flavia Leticia Martins Pecanha, Aime Franco, Vania Nosé, Everardo Magalhães Carneiro, John I Lew, Ernesto Bernal-Mizrachi, Joao Pedro Werneck de Castro.
       BACKGROUND: The thyroid gland is susceptible to abnormal epithelial cell growth, often resulting in thyroid dysfunction. The serine-threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, proliferation, and growth through two different protein complexes, mTORC1 and mTORC2. The PI3K-Akt-mTORC1 pathway's overactivity is well associated with heightened aggressiveness in thyroid cancer, but recent studies indicate the involvement of mTORC2 as well.
    METHODS: To elucidate mTORC1's role in thyrocytes, we developed a novel mouse model with mTORC1 gain of function in thyrocytes by deleting Tuberous Sclerosis Complex 2 (TSC2), an intracellular inhibitor of mTORC1.
    RESULTS: The resulting TPO-TSC2KO mice exhibited a 70-80% reduction in TSC2 levels, leading to a six-fold increase in mTORC1 activity. Thyroid glands of both male and female TPO-TSC2KO mice displayed rapid enlargement and continued growth throughout life, with larger follicles, and increased colloid and epithelium areas. We observed elevated thyrocyte proliferation as indicated by Ki67 staining and elevated Cyclin D3 expression in the TPO-TSC2KO mice. mTORC1 activation resulted in a progressive downregulation of key genes involved in thyroid hormone biosynthesis, including Thyroglobulin (Tg), Thyroid peroxidase (Tpo), and Sodium-iodide symporter (Nis), while Tff1, Pax8, and Mct8 mRNA levels remained unaffected. NIS protein expression was also diminished in TPO-TSC2KO mice. Treatment with the mTORC1 inhibitor rapamycin prevented thyroid mass expansion and restored the gene expression alterations in TPO-TSC2KO mice. Although T4, T3, and TSH plasma levels were normal at 2 months of age, a slight decrease in T4 and an increase in TSH levels were observed at 6 and 12 months of age while T3 remained similar in TPO-TSC2KO compared to littermate control mice.
    CONCLUSIONS: Our thyrocyte-specific mouse model reveals that mTORC1 activation inhibits TH biosynthesis, suppresses thyrocyte gene expression, and promotes growth and proliferation.
    DOI:  https://doi.org/10.1089/thy.2024.0053
  19. J Mol Biol. 2024 Apr 23. pii: S0022-2836(24)00183-9. [Epub ahead of print] 168588
    Beyond the C-terminal glycine of ATG8 proteins - The story of some neglected amino acids.
    Saskia Barz, Kay Hofmann, Fulvio Reggiori, Claudine Kraft.
      ATG8 proteins form a family of small ubiquitin-like modifiers, well-known for their importance in both macroautophagy and autophagy-independent processes. A unique feature of this protein family is their conjugation to membrane lipids through the covalent attachment of a glycine residue at the C-terminus of ATG8 proteins. Notably, most ATG8 proteins are expressed with additional amino acids at their C-terminus, shielding the key glycine residue. Consequently, lipidation requires the activation of the ATG8 precursors through proteolytic cleavage, known as priming. ATG4 proteases catalyze this priming process, and under physiological conditions, unprimed forms of ATG8 are not detected. This raises the question about the purpose of the C-terminal extension of ATG8 proteins. While the roles of lipidated and free, primed ATG8 proteins have been extensively studied, the potential function of their precursor form or the priming process itself remains largely unexplored. Here, we summarize information from existing literature and our own experiments to contribute to the understanding of these neglected amino acids.
    DOI:  https://doi.org/10.1016/j.jmb.2024.168588
  20. Plant Cell. 2024 Apr 24. pii: koae128. [Epub ahead of print]
    Vacuolar Degradation of Plant Organelles.
    Marisa S Otegui, Charlotte Steelheart, Wenlong Ma, Juncai Ma, Byung-Ho Kang, Victor Sanchez De Medina Hernandez, Yasin Dagdas, Caiji Gao, Shino Goto-Yamada, Kazusato Oikawa, Mikio Nishimura.
      Plants continuously remodel and degrade their organelles due to damage from their metabolic activities and environmental stressors, as well as an integral part of their cell differentiation programs. Whereas certain organelles use local hydrolytic enzymes for limited remodeling, most of pathways that control the partial or complete dismantling of organelles rely on vacuolar degradation. Specifically, selective autophagic pathways play a crucial role in recognizing and sorting plant organelle cargo for vacuolar clearance, especially under cellular stress conditions induced by factors like heat, drought, and damaging light. In these short reviews, we discuss the mechanisms that control the vacuolar degradation of chloroplasts, mitochondria, endoplasmic reticulum, Golgi, and peroxisomes, with an emphasis on autophagy, recently discovered selective autophagy receptors for plant organelles, and crosstalk with other catabolic pathways.
    DOI:  https://doi.org/10.1093/plcell/koae128
  21. Int J Mol Sci. 2024 Apr 09. pii: 4141. [Epub ahead of print]25(8):
    TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22.
    Liang Liu, Mitsuyo Matsumoto, Miki Watanabe-Matsui, Tadashi Nakagawa, Yuko Nagasawa, Jingyao Pang, Bert K K Callens, Akihiko Muto, Kyoko Ochiai, Hirotaka Takekawa, Mahabub Alam, Hironari Nishizawa, Mikako Shirouzu, Hiroki Shima, Keiko Nakayama, Kazuhiko Igarashi.
      BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species. While BACH1 is rapidly degraded when it is bound to heme, it remains unclear how BACH1 degradation is regulated under other conditions. We found that FBXO22, a ubiquitin ligase previously reported to promote BACH1 degradation, polyubiquitinated BACH1 only in the presence of heme in a highly purified reconstitution assay. In parallel to this regulatory mechanism, TANK binding kinase 1 (TBK1), a protein kinase that activates innate immune response and regulates iron metabolism via ferritinophagy, was found to promote BACH1 degradation when overexpressed in 293T cells. While TBK1 phosphorylated BACH1 at multiple serine and threonine residues, BACH1 degradation was observed with not only the wild-type TBK1 but also catalytically impaired TBK1. The BACH1 degradation in response to catalytically impaired TBK1 was not dependent on FBXO22 but involved both autophagy-lysosome and ubiquitin-proteasome pathways judging from its suppression by using inhibitors of lysosome and proteasome. Chemical inhibition of TBK1 in hepatoma Hepa1 cells showed that TBK1 was not required for the heme-induced BACH1 degradation. Its inhibition in Namalwa B lymphoma cells increased endogenous BACH1 protein. These results suggest that TBK1 promotes BACH1 degradation in parallel to the FBXO22- and heme-dependent pathway, placing BACH1 as a downstream effector of TBK1 in iron metabolism or innate immune response.
    Keywords:  BACH1; FBXO22; TBK1; autophagy; heme; phosphorylation; ubiquitination
    DOI:  https://doi.org/10.3390/ijms25084141
  22. J Appl Toxicol. 2024 Apr 20.
    Mitophagy and its regulatory mechanisms in the biological effects of nanomaterials.
    Rui Zhang, Haitao Yang, Menghao Guo, Shuyan Niu, Yuying Xue.
      Mitophagy is a selective cellular process critical for the removal of damaged mitochondria. It is essential in regulating mitochondrial number, ensuring mitochondrial functionality, and maintaining cellular equilibrium, ultimately influencing cell destiny. Numerous pathologies, such as neurodegenerative diseases, cardiovascular disorders, cancers, and various other conditions, are associated with mitochondrial dysfunctions. Thus, a detailed exploration of the regulatory mechanisms of mitophagy is pivotal for enhancing our understanding and for the discovery of novel preventive and therapeutic options for these diseases. Nanomaterials have become integral in biomedicine and various other sectors, offering advanced solutions for medical uses including biological imaging, drug delivery, and disease diagnostics and therapy. Mitophagy is vital in managing the cellular effects elicited by nanomaterials. This review provides a comprehensive analysis of the molecular mechanisms underpinning mitophagy, underscoring its significant influence on the biological responses of cells to nanomaterials. Nanoparticles can initiate mitophagy via various pathways, among which the PINK1-Parkin pathway is critical for cellular defense against nanomaterial-induced damage by promoting mitophagy. The role of mitophagy in biological effects was induced by nanomaterials, which are associated with alterations in Ca2+ levels, the production of reactive oxygen species, endoplasmic reticulum stress, and lysosomal damage.
    Keywords:  PINK1‐Parkin pathway; cellular responses; mitophagy; nanomaterials; regulatory mechanisms
    DOI:  https://doi.org/10.1002/jat.4609
  23. J Hazard Mater. 2024 Apr 20. pii: S0304-3894(24)00936-1. [Epub ahead of print]471 134357
    6PPD induced cardiac dysfunction in zebrafish associated with mitochondrial damage and inhibition of autophagy processes.
    Chanlin Fang, Shanshan Di, Yundong Yu, Peipei Qi, Xinquan Wang, Yuanxiang Jin.
      The compound 6PPD is widely acknowledged for its antioxidative properties; however, concerns regarding its impact on aquatic organisms have spurred comprehensive investigations. In our study, we advanced our comprehension by revealing that exposure to 6PPD could induce cardiac dysfunction, myocardial injury and DNA damage in adult zebrafish. Furthermore, our exploration unveiled that the exposure of cardiomyocytes to 6PPD resulted in apoptosis and mitochondrial injury, as corroborated by analyses using transmission electron microscopy and flow cytometry. Significantly, our study demonstrated the activation of the autophagy pathway in both the heart of zebrafish and cardiomyocytes, as substantiated by transmission electron microscopy and immunofluorescent techniques. Importantly, the increased the expression of P62 in the heart and cardiomyocytes suggested an inhibition of the autophagic process. The reduction in autophagy flux was also verified through in vivo experiments involving the infection of mCherry-GFP-LC3. We further identified that the fusion of autophagosomes and lysosomes was impaired in the 6PPD treatment group. In summary, our findings indicated that the impaired fusion of autophagosomes and lysosomes hampered the autophagic degradation process, leading to apoptosis and ultimately resulting in cardiac dysfunction and myocardial injury. This study discovered the crucial role of the autophagy pathway in regulating 6PPD-induced cardiotoxicity. SYNOPSIS: 6PPD exposure inhibited the autophagic degradation process and induced mitochondrial injury and apoptosis in the heart of adult zebrafish.
    Keywords:  6PPD exposure; Adult zebrafish; Autophagy; Cardiac dysfunction; Mitochondrial apoptosis
    DOI:  https://doi.org/10.1016/j.jhazmat.2024.134357
  24. Pathol Res Pract. 2024 Mar 30. pii: S0344-0338(24)00186-9. [Epub ahead of print]257 155275
    Critical role of miR-21/exosomal miR-21 in autophagy pathway.
    Mohamed J Saadh, Morug Salih Mahdi, Omer Qutaiba B Allela, Tuqa S Alazzawi, Mohammed Ubaid, Nodir M Rakhimov, Zainab H Athab, Pushpamala Ramaiah, Lathamangeswari Chinnasamy, Fahad Alsaikhan, Bagher Farhood.
      Activation of autophagy, a process of cellular stress response, leads to the breakdown of proteins, organelles, and other parts of the cell in lysosomes, and can be linked to several ailments, such as cancer, neurological diseases, and rare hereditary syndromes. Thus, its regulation is very carefully monitored. Transcriptional and post-translational mechanisms domestically or in whole organisms utilized to control the autophagic activity, have been heavily researched. In modern times, microRNAs (miRNAs) are being considered to have a part in post-translational orchestration of the autophagic activity, with miR-21 as one of the best studied miRNAs, it is often more than expressed in cancer cells. This regulatory RNA is thought to play a major role in a plethora of processes and illnesses including growth, cancer, cardiovascular disease, and inflammation. Different studies have suggested that a few autophagy-oriented genes, such as PTEN, Rab11a, Atg12, SIPA1L2, and ATG5, are all targeted by miR-21, indicating its essential role in the regulation.
    Keywords:  Autophagy; Cancer; Chemo-resistance; Exosome; MicroRNA
    DOI:  https://doi.org/10.1016/j.prp.2024.155275
  25. Front Pharmacol. 2024 ;15 1364616
    Targeting autophagy with natural products as a potential therapeutic approach for diabetic microangiopathy.
    Fengzhao Liu, Lijuan Zhao, Tao Wu, Wenfei Yu, Jixin Li, Wenru Wang, Chengcheng Huang, Zhihao Diao, Yunsheng Xu.
      As the quality of life improves, the incidence of diabetes mellitus and its microvascular complications (DMC) continues to increase, posing a threat to people's health and wellbeing. Given the limitations of existing treatment, there is an urgent need for novel approaches to prevent and treat DMC. Autophagy, a pivotal mechanism governing metabolic regulation in organisms, facilitates the removal of dysfunctional proteins and organelles, thereby sustaining cellular homeostasis and energy generation. Anomalous states in pancreatic β-cells, podocytes, Müller cells, cardiomyocytes, and Schwann cells in DMC are closely linked to autophagic dysregulation. Natural products have the property of being multi-targeted and can affect autophagy and hence DMC progression in terms of nutrient perception, oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis. This review consolidates recent advancements in understanding DMC pathogenesis via autophagy and proposes novel perspectives on treating DMC by either stimulating or inhibiting autophagy using natural products.
    Keywords:  autophagy; diabetic cardiomyopathy; diabetic kidney disease; diabetic microangiopathy; diabetic peripheral neuropathy; diabetic retinopathy; natural products
    DOI:  https://doi.org/10.3389/fphar.2024.1364616
  26. Mol Neurobiol. 2024 Apr 22.
    TRIM28 Fosters Microglia Ferroptosis via Autophagy Modulation to Enhance Neuropathic Pain and Neuroinflammation.
    Jian Tang, Qi Chen, Li Xiang, Ting Tu, Ying Zhang, Cehua Ou.
      This study explores the molecular underpinnings of neuropathic pain (NPP) and neuroinflammation, focusing on the role of TRIM28 in the regulation of autophagy and microglia ferroptosis. Leveraging transcriptomic data associated with NPP, we identified TRIM28 as a critical regulator of ferroptosis. Through comprehensive analysis, including Gene Ontology enrichment and protein-protein interaction network assessments, we unveiled GSK3B as a downstream target of TRIM28. Experimental validation confirmed the capacity of TRIM28 to suppress GSK3B expression and attenuate autophagic processes in microglia. We probed the consequences of autophagy and ferroptosis on microglia physiology, iron homeostasis, oxidative stress, and the release of proinflammatory cytokines. In a murine model, we validated the pivotal role of TRIM28 in NPP and neuroinflammation. Our analysis identified 20 ferroptosis regulatory factors associated with NPP, with TRIM28 emerging as a central orchestrator. Experimental evidence affirmed that TRIM28 governs microglial iron homeostasis and cell fate by downregulating GSK3B expression and modulating autophagy. Notably, autophagy was found to influence oxidative stress and proinflammatory cytokine release through the iron metabolism pathway, ultimately fueling neuroinflammation. In vivo experiments provided conclusive evidence of TRIM28-mediated pathways contributing to heightened pain sensitivity in neuroinflammatory states. The effect of TRIM28 on autophagy and microglia ferroptosis drives NPP and neuroinflammation. These findings offer promising avenues for identifying novel therapeutic targets to manage NPP and neuroinflammation.
    Keywords:  Autophagy; Ferroptosis; GSK3B; Microglia; Neuroinflammation; Neuropathic pain; TRIM28
    DOI:  https://doi.org/10.1007/s12035-024-04133-4
  27. Fish Shellfish Immunol. 2024 Apr 24. pii: S1050-4648(24)00231-6. [Epub ahead of print] 109586
    Deep Sequencing Identified miR-193b-3p as a Positive Regulator of Autophagy Targeting Akt3 in Ctenopharyngodon idella CIK Cells During GCRV Infection.
    Hongyan Yu, Zheyan Chen, Yuting Liu, Yubang Shen, Lang Gui, Junqiang Qiu, Xiaoyan Xu, Jiale Li.
      Recent research has highlighted complex and close interaction between miRNAs, autophagy, and viral infection. In this study, we observed the autophagy status in CIK cells infected with GCRV at various time points. We found that GCRV consistently induced cellar autophagy from 0 h to 12 h post infection. Subsequently, we performed deep sequencing on CIK cells infected with GCRV at 0 h and 12 h respectively, identifying 38 DEMs and predicting 9,581 target genes. With the functional enrichment analyses of GO and KEGG, we identified 35 autophagy-related target genes of these DEMs, among which akt3 was pinpointed as the most central hub gene using module assay of the PPI network. Then employing the miRanda and Targetscan programs for prediction, and verification through a double fluorescent enzyme system and qPCR method, we confirmed that miR-193b-3p could target the 3'-UTR of grass carp akt3, reducing its gene expression. Ultimately, we illustrated that grass carp miR-193b-3p could promote autophagy in CIK cells. Above results collectively indicated that miRNAs might play a critical role in autophagy of grass carp during GCRV infection and contributed significantly to antiviral immunity by targeting autophagy-related genes. This study may provide new insights into the intricate mechanisms involved in virus, autophagy, and miRNAs.
    Keywords:  GCRV; autophagy; grass carp; miRNAs
    DOI:  https://doi.org/10.1016/j.fsi.2024.109586
  28. Autophagy. 2024 Apr 23. 1-12
    The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.
    Simone Patergnani, Méghane S Bataillard, Alberto Danese, Stacy Alves, Chantal Cazevieille, René Valéro, Lisbeth Tranebjærg, Tangui Maurice, Paolo Pinton, Benjamin Delprat, Elodie M Richard.
      Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A1; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.
    Keywords:  Autophagy; WFS1; Wolfram-like syndrome; mitochondria-associated endoplasmic reticulum membrane; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2341588
  29. Acta Biochim Biophys Sin (Shanghai). 2024 Apr 24.
    Bronchial thermoplasty decreases airway remodeling by inhibiting autophagy via the AMPK/mTOR signaling pathway.
    Tao Wang, Peng Fu, Wenting Huang, Liang Long, Fa Long, Shengming Liu.
      Bronchial thermoplasty (BT), an effective treatment for severe asthma, requires heat to reach the airway to reduce the mass of airway smooth muscle cells (ASMCs). Autophagy is involved in the pathological process of airway remodeling in patients with asthma. However, it remains unclear whether autophagy participates in controlling airway remodeling induced by BT. In this study, we aim to elucidate the autophagy-mediated molecular mechanisms in BT. Our study reveal that the number of autophagosomes and the level of alpha-smooth muscle actin (α-SMA) fluorescence are significantly decreased in airway biopsy tissues after BT. As the temperature increased, BT causes a decrease in cell proliferation and a concomitant increase in the apoptosis of human airway smooth muscle cells (HASMCs). Furthermore, increase in temperature significantly downregulates cellular autophagy, autophagosome accumulation, the LC3II/LC3I ratio, and Beclin-1 expression, upregulates p62 expression, and inhibits the AMPK/mTOR pathway. Furthermore, cotreatment with AICAR (an AMPK agonist) or RAPA (an mTOR antagonist) abolishes the inhibition of autophagy and attenuates the increase in the apoptosis rate of HASMCs induced by the thermal effect. Therefore, we conclude that BT decreases airway remodeling by blocking autophagy induced by the AMPK/mTOR signaling pathway in HASMCs.
    Keywords:  AMPK/mTOR; airway remodeling; apoptosis; autophagy; bronchial thermoplasty
    DOI:  https://doi.org/10.3724/abbs.2024028
  30. bioRxiv. 2024 Apr 08. pii: 2023.09.07.553534. [Epub ahead of print]
    Sde Proteins Coordinate Ubiquitin Utilization and Phosphoribosylation to Promote Establishment and Maintenance of the Legionella Replication Vacuole.
    Kristin M Kotewicz, Mengyun Zhang, Seongok Kim, Meghan S Martin, Atish Roy Chowdhury, Albert Tai, Rebecca A Scheck, Ralph R Isberg.
      The Legionella pneumophila Sde family of translocated proteins promotes host tubular endoplasmic reticulum (ER) rearrangements that are tightly linked to phosphoribosyl-ubiquitin (pR-Ub) modification of Reticulon 4 (Rtn4). Sde proteins have two additional activities of unclear relevance to the infection process: K63 linkage-specific deubiquitination and phosphoribosyl modification of polyubiquitin (pR-Ub). We show here that the deubiquitination activity (DUB) stimulates ER rearrangements while pR-Ub protects the replication vacuole from cytosolic surveillance by autophagy. Loss of DUB activity was tightly linked to lowered pR-Ub modification of Rtn4, consistent with the DUB activity fueling the production of pR-Ub-Rtn4. In parallel, phosphoribosyl modification of polyUb, in a region of the protein known as the isoleucine patch, prevented binding by the autophagy adapter p62. An inability of Sde mutants to modify polyUb resulted in immediate p62 association, a critical precursor to autophagic attack. The ability of Sde WT to block p62 association decayed quickly after bacterial infection, as predicted by the presence of previously characterized L. pneumophila effectors that inactivate Sde and remove polyUb. In sum, these results show that the accessory Sde activities act to stimulate ER rearrangements and protect from host innate immune sensing in a temporal fashion.
    DOI:  https://doi.org/10.1101/2023.09.07.553534
  31. Phytomedicine. 2024 Apr 10. pii: S0944-7113(24)00279-4. [Epub ahead of print]129 155620
    Tanshinone IIA positively regulates the Keap1-Nrf2 system to alleviate pulmonary fibrosis via the sestrin2-sqstm1 signaling axis-mediated autophagy.
    Mingyu Wu, Hongxia Li, Rao Zhai, Baixi Shan, Congying Guo, Jun Chen.
       BACKGROUND: Activation of myofibroblasts, linked to oxidative stress, emerges as a pivotal role in the progression of pulmonary fibrosis (PF). Our prior research has underscored the therapeutic promise of tanshinone IIA (Tan-IIA) in mitigating PF by enhancing nuclear factor-erythroid 2-related factor 2 (Nrf2) activity. Nevertheless, the molecular basis through which Tan-IIA influences Nrf2 activity has yet to be fully elucidated.
    METHODS: The influence of Tan-IIA on PF was assessed in vivo and in vitro models. Inhibitors, overexpression plasmids, and small interfering RNA (siRNA) were utilized to probe its underlying mechanism of action in vitro.
    RESULTS: We demonstrate that Tan-IIA effectively activates the kelch-like ECH-associated protein 1 (Keap1)-Nrf2 antioxidant pathway, which in turn inhibits myofibroblast activation and ameliorates PF. Notably, the stability and nucleo-cytoplasmic shuttling of Nrf2 is shown to be dependent on augmented autophagic flux, which is in alignment with the observation that Tan-IIA induces autophagy. Inhibition of autophagy, conversely, fosters the activation of extracellular matrix (ECM)-producing myofibroblasts. Further, Tan-IIA initiates an autophagy program through the sestrin 2 (Sesn2)-sequestosome 1 (Sqstm1) signaling axis, crucial for protecting Nrf2 from Keap1-mediated degradation. Meanwhile, these findings were corroborated in a murine model of PF.
    CONCLUSION: Collectively, we observed for the first time that the Sqstm1-Sesn2 axis-mediated autophagic degradation of Keap1 effectively prevents myofibroblast activation and reduces the synthesis of ECM. This autophagy-dependent degradation of Keap1 can be initiated by the Tan-IIA treatment, which solidifies its potential as an Nrf2-modulating agent for PF treatment.
    Keywords:  Autophagy; Keap1-Nrf2 pathway; Pulmonary fibrosis; Sequestosome 1; Sestrin 2; Tanshinone IIA
    DOI:  https://doi.org/10.1016/j.phymed.2024.155620
  32. Mol Cell Endocrinol. 2024 Apr 20. pii: S0303-7207(24)00108-4. [Epub ahead of print]589 112252
    Inhibition of miR-146b-5p alleviates isoprenaline-induced cardiac hypertrophy via regulating DFCP1.
    Siling Liu, Linjie Su, Jie Li, Yuexin Zhang, Xiaopei Hu, Pengcheng Wang, Peiqing Liu, Jiantao Ye.
      Pathological cardiac hypertrophy often precedes heart failure due to various stimuli, yet effective clinical interventions remain limited. Recently, microRNAs (miRNAs) have been identified as critical regulators of cardiovascular development. In this study, we investigated the role of miR-146b-5p and its underlying mechanisms of action in cardiac hypertrophy. Isoprenaline (ISO) treatment induced significant hypertrophy and markedly enhanced the expression of miR-146b-5p in cultured neonatal rat cardiomyocytes and hearts of C57BL/6 mice. Transfection with the miR-146b-5p mimic led to cardiomyocyte hypertrophy accompanied by autophagy inhibition. Conversely, miR-146b-5p inhibition significantly alleviated ISO-induced autophagy depression, thereby mitigating cardiac hypertrophy both in vitro and in vivo. Our results showed that the autophagy-related mediator double FYVE domain-containing protein 1 (DFCP1) is a target of miR-146b-5p. MiR-146b-5p blocked autophagic flux in cardiomyocytes by suppressing DFCP1, thus contributing to hypertrophy. These findings revealed that miR-146b-5p is a potential regulator of autophagy associated with the onset of cardiac hypertrophy, suggesting a possible therapeutic strategy involving the inhibition of miR-146b-5p.
    Keywords:  Autophagy; Cardiac hypertrophy; DFCP1; Isoprenaline; MiR-146b-5p
    DOI:  https://doi.org/10.1016/j.mce.2024.112252
  33. Cell Rep. 2024 Apr 23. pii: S2211-1247(24)00459-5. [Epub ahead of print]43(5): 114131
    Individual Atg8 paralogs and a bacterial metabolite sequentially promote hierarchical CASM-xenophagy induction and transition.
    Chisato Sakuma, Sayaka Shizukuishi, Michinaga Ogawa, Yuko Honjo, Haruko Takeyama, Jun-Lin Guan, Jeffery Weiser, Miwa Sasai, Masahiro Yamamoto, Makoto Ohnishi, Yukihiro Akeda.
      Atg8 paralogs, consisting of LC3A/B/C and GBRP/GBRPL1/GATE16, function in canonical autophagy; however, their function is controversial because of functional redundancy. In innate immunity, xenophagy and non-canonical single membranous autophagy called "conjugation of Atg8s to single membranes" (CASM) eliminate bacteria in various cells. Previously, we reported that intracellular Streptococcus pneumoniae can induce unique hierarchical autophagy comprised of CASM induction, shedding, and subsequent xenophagy. However, the molecular mechanisms underlying these processes and the biological significance of transient CASM induction remain unknown. Herein, we profile the relationship between Atg8s, autophagy receptors, poly-ubiquitin, and Atg4 paralogs during pneumococcal infection to understand the driving principles of hierarchical autophagy and find that GATE16 and GBRP sequentially play a pivotal role in CASM shedding and subsequent xenophagy induction, respectively, and LC3A and GBRPL1 are involved in CASM/xenophagy induction. Moreover, we reveal ingenious bacterial tactics to gain intracellular survival niches by manipulating CASM-xenophagy progression by generating intracellular pneumococci-derived H2O2.
    Keywords:  Atg4s; Atg8s; CASM; CP: Cell biology; CP: Microbiology; Streptococcus pneumoniae; autophagy matrix profiling; hierarchical autophagy; pneumococci-derived H(2)O(2); poly-ubiquitin; xenophagy
    DOI:  https://doi.org/10.1016/j.celrep.2024.114131
  34. Int J Mol Sci. 2024 Apr 22. pii: 4566. [Epub ahead of print]25(8):
    OMA1-Mediated Mitochondrial Dynamics Balance Organellar Homeostasis Upstream of Cellular Stress Responses.
    Robert Gilkerson, Harpreet Kaur, Omar Carrillo, Isaiah Ramos.
      In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψm) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities.
    Keywords:  DRP1; OMA1; OPA1; apoptosis; autophagy; bioenergetics; cristae; fission; fusion; integrated stress response; mitochondria; transmembrane potential
    DOI:  https://doi.org/10.3390/ijms25084566
  35. Methods Mol Biol. 2024 Apr 23.
    Assessment of Stiffness-Dependent Autophagosome Formation and Apoptosis in Embryonal Rhabdomyosarcoma Tumor Cells.
    Serap Sezen, Sevin Adiguzel, Atefeh Zarepour, Arezoo Khosravi, Joseph W Gordon, Saeid Ghavami, Ali Zarrabi.
      Remodeling of the extracellular matrix (ECM) eventually causes the stiffening of tumors and changes to the microenvironment. The stiffening alters the biological processes in cancer cells due to altered signaling through cell surface receptors. Autophagy, a key catabolic process in normal and cancer cells, is thought to be involved in mechano-transduction and the level of autophagy is probably stiffness-dependent. Here, we provide a methodology to study the effect of matrix stiffness on autophagy in embryonal rhabdomyosarcoma cells. To mimic stiffness, we seeded cells on GelMA hydrogel matrices with defined stiffness and evaluated autophagy-related endpoints. We also evaluated autophagy-dependent pathways, apoptosis, and cell viability. Specifically, we utilized immunocytochemistry and confocal microscopy to track autophagosome formation through LC3 lipidation. This approach suggests that the use of GelMA hydrogels with defined stiffness represents a novel method to evaluate the role of autophagy in embryonal rhabdomyosarcoma and other cancer cells.
    Keywords:  Autophagy; Embryonal rhabdomyosarcoma; GelMA hydrogel; Immunocytochemistry; Stiffness; Tumor microenvironment
    DOI:  https://doi.org/10.1007/7651_2024_538
  36. Cell Commun Signal. 2024 Apr 20. 22(1): 234
    High glucose-induced p66Shc mitochondrial translocation regulates autophagy initiation and autophagosome formation in syncytiotrophoblast and extravillous trophoblast.
    Lulu Ji, Xiaoli Zhang, Zhiguo Chen, Yuexiao Wang, Hengxuan Zhu, Yaru Nai, Yanyi Huang, Rujie Lai, Yu Zhong, Xiting Yang, Qiongtao Wang, Hanyang Hu, Lin Wang.
       BACKGROUND: p66Shc, as a redox enzyme, regulates reactive oxygen species (ROS) production in mitochondria and autophagy. However, the mechanisms by which p66Shc affects autophagosome formation are not fully understood.
    METHODS: p66Shc expression and its location in the trophoblast cells were detected in vivo and in vitro. Small hairpin RNAs or CRISPR/Cas9, RNA sequencing, and confocal laser scanning microscope were used to clarify p66Shc's role in regulating autophagic flux and STING activation. In addition, p66Shc affects mitochondrial-associated endoplasmic reticulum membranes (MAMs) formation were observed by transmission electron microscopy (TEM). Mitochondrial function was evaluated by detected cytoplastic mitochondrial DNA (mtDNA) and mitochondrial membrane potential (MMP).
    RESULTS: High glucose induces the expression and mitochondrial translocation of p66Shc, which promotes MAMs formation and stimulates PINK1-PRKN-mediated mitophagy. Moreover, mitochondrial localized p66Shc reduces MMP and triggers cytosolic mtDNA release, thus activates cGAS/STING signaling and ultimately leads to enhanced autophagy and cellular senescence. Specially, we found p66Shc is required for the interaction between STING and LC3II, as well as between STING and ATG5, thereby regulates cGAS/STING-mediated autophagy. We also identified hundreds of genes associated several biological processes including aging are co-regulated by p66Shc and ATG5, deletion either of which results in diminished cellular senescence.
    CONCLUSION: p66Shc is not only implicated in the initiation of autophagy by promoting MAMs formation, but also helps stabilizing active autophagic flux by activating cGAS/STING pathway in trophoblast.
    Keywords:  Autophagy; High glucose; MAM; cGAS/STING; p66Shc
    DOI:  https://doi.org/10.1186/s12964-024-01621-x
  37. Cells. 2024 Apr 16. pii: 690. [Epub ahead of print]13(8):
    The Role Played by Autophagy in FcεRI-Dependent Activation of Mast Cells.
    Anastasia N Pavlyuchenkova, Maxim S Smirnov, Boris V Chernyak, Maria A Chelombitko.
      The significant role of mast cells in the development of allergic and inflammatory diseases is well-established. Among the various mechanisms of mast cell activation, the interaction of antigens/allergens with IgE and the subsequent binding of this complex to the high-affinity IgE receptor FcεRI stand out as the most studied and fundamental pathways. This activation process leads to the rapid exocytosis of granules containing preformed mediators, followed by the production of newly synthesized mediators, including a diverse array of cytokines, chemokines, arachidonic acid metabolites, and more. While conventional approaches to allergy control primarily focus on allergen avoidance and the use of antihistamines (despite their associated side effects), there is increasing interest in exploring novel methods to modulate mast cell activity in modern medicine. Recent evidence suggests a role for autophagy in mast cell activation, offering potential avenues for utilizing low-molecular-weight autophagy regulators in the treatment of allergic diseases. More specifically, mitochondria, which play an important role in the regulation of autophagy as well as mast cell activation, emerge as promising targets for drug development. This review examines the existing literature regarding the involvement of the molecular machinery associated with autophagy in FcεRI-dependent mast cell activation.
    Keywords:  FcεRI-dependent activation; autophagy; mast cells; mitochondria
    DOI:  https://doi.org/10.3390/cells13080690
  38. Pathol Res Pract. 2024 Apr 21. pii: S0344-0338(24)00234-6. [Epub ahead of print]257 155323
    NUPR1 induces autophagy and promotes the progression of Esophageal squamous cell carcinoma via the MAPK-mTOR pathway.
    Shiheng Ren, Yuxin Chen, Qiang Wang, Liang Song, Zhongwei Xin, Mo Shi, Xiangyan Liu.
       PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a dominant pathological type in China. NUPR1 is a complex molecule implicated in various physiological and biological functions whose expression is upregulated in response to stress. Furthermore, autophagy is a vital physiological mechanism in the onset and metastasis of malignancies. This study aims to uncover the influence of NUPR1 on ESCC occurrence and development by regulating autophagy while also exploring its association with the MAPK signaling pathway.
    METHODS: First, the differences in NUPR1 between ESCC and normal tissues were analyzed through online databases. Subsequently, the pathological tissues of clinical samples were stained and scored using immunohistochemistry. And NUPR1 expression in ESCC cells was investigated, as was the function of NUPR1 in the modulation of ESCC's malignant behavior. Furthermore, a nude mouse ESCC xenograft model was developed. Finally, RNA sequencing was performed on NUPR1-downregulated ESCC cells, which was verified using WB.
    RESULTS: Our findings initially uncovered differences in the expression of NUPR1 in ESCC and normal tissues. In vitro experiments demonstrated that NUPR1 downregulation significantly inhibited ESCC cell proliferation, invasion, and migration, as well as promoted their apoptosis. Our xenograft model exhibited significant inhibition of ESCC tumors upon NUPR1 downregulation. Subsequently, RNA sequencing uncovered that NUPR1 regulates its malignant biological behavior through MAPK-mTOR signaling pathway. Finally, we found that NUPR1 downregulation can inhibit autophagic flux in ESCC.
    CONCLUSION: Collectively, our findings show that NUPR1 enhances the progression of ESCC by triggering autophagy and is associated with the MAPK-mTOR signaling pathway.
    Keywords:  Autophagy; Esophageal squamous cell carcinoma; MAPK–mTOR signaling pathway; NUPR1
    DOI:  https://doi.org/10.1016/j.prp.2024.155323
  39. Chembiochem. 2024 Apr 25. e202400232
    Lysosomal Peptide Self-Assembly To Control Cell Behavior.
    Sangshuang Li, Huaimin Wang.
      Lysosomes are membrane-enclosed organelles that play key roles in degrading and recycling cellular debris, cellular signaling, and energy metabolism processes. Confinement of amphiphilic peptides in the lysosome to construct functional nanostructures through noncovalent interactions is an emerging approach to tune the homeostasis of lysosome. After briefly introducing the importance of lysosome and its functions, we discuss the advantages of lysosomal nanostructure formation for disease therapy. We next discuss the strategy for triggering the self-assembly of peptides in the lysosome, followed by a concise outlook of the future perspective about this emerging research direction.
    Keywords:  Cancer therapy; Lysosome; Peptide; nanofibers; self-assembly
    DOI:  https://doi.org/10.1002/cbic.202400232
  40. Cell Mol Biol Lett. 2024 Apr 23. 29(1): 59
    The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
    Yuhang Lei, Mailin Gan, Yanhao Qiu, Qiuyang Chen, Xingyu Wang, Tianci Liao, Mengying Zhao, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Yan Wang, Li Zhu, Linyuan Shen.
      Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.
    Keywords:  Intermodulation; Mitochondrial dynamics; Mitophagy; Molecular mechanism; Prevention and treatment; Skeletal muscle atrophy
    DOI:  https://doi.org/10.1186/s11658-024-00572-y
  41. Int J Mol Sci. 2024 Apr 15. pii: 4368. [Epub ahead of print]25(8):
    Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress.
    Orsolya Kapuy.
      Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance.
    Keywords:  apoptosis; autophagy; bistability; endoplasmic reticulum stress; systems biology; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms25084368
  42. Food Funct. 2024 Apr 25.
    Acetylated pelargonidin-3-O-glucoside alleviates hepatocyte lipid deposition through activating the AMPK-mediated lysosome-autophagy pathway and redox state.
    Lianghua Xie, Xin Hao, Jiahong Xie, Jianling Mo, Changzheng Yuan, Wei Chen.
      Nonalcoholic fatty liver disease (NAFLD) is a worldwide public health issue, but a widely accepted therapy is still lacking until now. Anthocyanins are natural flavonoid compounds that possess various bioactivities, but their applications are limited due to their low bioavailability and stability. Acylated anthocyanins are reported to show higher stability, whereas their effects on NAFLD are still unclear. Herein, pelargonidin-3-O-(6''-acetyl)-glucoside (Ace Pg3G) was found to dose-dependently reduce intracellular lipid droplets and triglycerides, and improve cellular oxidative stress that accompanied lipid deposition. Besides, Ace Pg3G was proved to activate AMPK phosphorylation, thus stimulating AMPK-mediated lysosome-autophagy pathway to eliminate overloaded lipid. Further study unveiled that Ace Pg3G regulated genes related to lipid metabolism downstream of AMPK to inhibit lipid synthesis and accelerate lipid oxidation. Overall, this study provided the first evidence, to our best knowledge, that Ace Pg3G ameliorated free fatty acid-induced lipid deposition in hepatocytes through regulating AMPK-mediated autophagy pathways and redox state.
    DOI:  https://doi.org/10.1039/d4fo00185k
  43. iScience. 2024 May 17. 27(5): 109574
    Inhibitors to degraders: Changing paradigm in drug discovery.
    V Haridas, Souvik Dutta, Akshay Munjal, Shailja Singh.
      The chemical understanding of biological processes provides not only a deeper insight but also a solution to abnormal biological functioning. Protein degradation, a natural biological process for debris removal in the cell, has been studied for years. The recent finding that natural degradation pathways can be utilized for therapeutic purposes is a paradigm shift in the drug discovery approach. Methods such as Proteolysis Targeting Chimera (PROTAC), lysosomal targeting chimera, hydrophobic tagging, AUtophagy TArgeting Chimera, AUTOphagy TArgeting Chimera and several other variants of these methods have made a considerable impact on the way of drug design. Few selected examples testify that a huge wave of change is on the way. The drug design based on the targeted protein degradation is a powerful tool in our arsenal. More molecules will be invented that will uncover the hidden secrets of biological functioning and provide enduring solutions to several unmet medical needs.
    Keywords:  Biochemistry; Biological sciences; Cell biology; Protein
    DOI:  https://doi.org/10.1016/j.isci.2024.109574
  44. Mitochondrion. 2024 Apr 21. pii: S1567-7249(24)00043-6. [Epub ahead of print]76 101885
    The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.
    Priyanka Biswal, Manas Ranjan Sahu, Mir Hilal Ahmad, Amal Chandra Mondal.
      Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.
    Keywords:  Apoptosis; Hippo signaling; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.mito.2024.101885
  45. Cell Mol Biol Lett. 2024 Apr 26. 29(1): 60
    Deciphering the impact of circRNA-mediated autophagy on tumor therapeutic resistance: a novel perspective.
    Ting Wang, Mengjie He, Xudong Zhang, Zhixun Guo, Pinghan Wang, Fangyi Long.
      Cancer therapeutic resistance remains a significant challenge in the pursuit of effective treatment strategies. Circular RNAs (circRNAs), a class of non-coding RNAs, have recently emerged as key regulators of various biological processes, including cancer progression and drug resistance. This review highlights the emerging role of circRNAs-mediated autophagy in cancer therapeutic resistance, a cellular process that plays a dual role in cancer by promoting both cell survival and death. Increasing evidence suggests that circRNAs can modulate autophagy pathways, thereby influencing the response of cancer cells to therapeutic agents. In this context, the intricate interplay between circRNAs, autophagy, and therapeutic resistance is explored. Various mechanisms are discussed through which circRNAs can impact autophagy, including direct interactions with autophagy-related genes, modulation of signaling pathways, and cross-talk with other non-coding RNAs. Furthermore, the review delves into specific examples of how circRNA-mediated autophagy regulation can contribute to resistance against chemotherapy and radiotherapy. Understanding these intricate molecular interactions provides valuable insights into potential strategies for overcoming therapeutic resistance in cancer. Exploiting circRNAs as therapeutic targets or utilizing them as diagnostic and predictive biomarkers opens new avenues for developing personalized treatment approaches. In summary, this review underscores the importance of circRNA-mediated autophagy in cancer therapeutic resistance and proposes future directions for research in this exciting and rapidly evolving field.
    Keywords:  Autophagy; Cancer; Circular RNAs (circRNAs); Therapeutic resistance
    DOI:  https://doi.org/10.1186/s11658-024-00571-z
  46. Biomolecules. 2024 Mar 27. pii: 405. [Epub ahead of print]14(4):
    The Influence of Lysosomal Stress on Dental Pulp Stem Cell-Derived Schwann Cells.
    Karen Libberecht, Nathalie Dirkx, Tim Vangansewinkel, Wendy Vandendries, Ivo Lambrichts, Esther Wolfs.
       BACKGROUND: Dysregulation of the endo-lysosomal-autophagy pathway has been identified as a critical factor in the pathology of various demyelinating neurodegenerative diseases, including peripheral neuropathies. This pathway plays a crucial role in transporting newly synthesized myelin proteins to the plasma membrane in myelinating Schwann cells, making these cells susceptible to lysosome-related dysfunctions. Nevertheless, the specific impact of lysosomal dysfunction in Schwann cells and its contribution to neurodegeneration remain poorly understood.
    METHODS: We aim to mimic lysosomal dysfunction in Schwann cells using chloroquine, a lysosomal dysfunction inducer, and to monitor lysosomal leakiness, Schwann cell viability, and apoptosis over time. Additionally, due to the ethical and experimental issues associated with cell isolation and the culturing of human Schwann cells, we use human dental pulp stem cell-derived Schwann cells (DPSC-SCs) as a model in our study.
    RESULTS: Chloroquine incubation boosts lysosomal presence as demonstrated by an increased Lysotracker signal. Further in-depth lysosomal analysis demonstrated an increased lysosomal size and permeability as illustrated by a TEM analysis and GAL3-LAMP1 staining. Moreover, an Alamar blue assay and Caspase-3 staining demonstrates a reduced viability and increased apoptosis, respectively.
    CONCLUSIONS: Our data indicate that prolonged lysosomal dysfunction leads to lysosomal permeability, reduced viability, and eventually apoptosis in human DPSC-SCs.
    Keywords:  Schwann cells; chloroquine; dental pulp stem cells; lysosomal stress
    DOI:  https://doi.org/10.3390/biom14040405
  47. Transl Res. 2024 Apr 19. pii: S1931-5244(24)00079-3. [Epub ahead of print]
    Inhibition of Usp14 ameliorates renal ischemia-reperfusion injury by reducing Tfap2a stabilization and facilitating mitophagy.
    Yang Li, Boqing Dong, Ying Wang, Huanjing Bi, Jing Zhang, Chenguang Ding, Chenge Wang, Xiaoming Ding, Wujun Xue.
      Mitochondrial dysfunction is recognized as a pivotal contributor to the pathogenesis of renal ischemia-reperfusion (IR) injury. Mitophagy, the process responsible for removing damaged protein aggregates, stands as a critical mechanism safeguarding cells against IR injury. Currently, the role of deubiquitination in regulating mitophagy still needs to be completely elucidated. This study aimed to evaluate the impact of ubiquitin-specific peptidase 14 (Usp14), a deubiquitinase, in IR injury by influencing mitophagy. Utilizing a murine model of renal IR injury, Usp14 silencing was found to ameliorate kidney injury, leading to decreased levels of serum creatinine and blood urea nitrogen, alongside diminished oxidative stress and inflammation. In renal epithelial cells subjected to hypoxia/reoxygenation (H/R), Usp14 knockdown increased cell viability and reduced apoptosis. Further mechanistic studies revealed that Usp14 interacted with and deubiquitinated transcription factor AP-2 alpha (Tfap2a), thereby suppressing its downstream target gene, TANK binding kinase 1 (Tbk1), to influence mitophagy. Tfap2a overexpression or Tbk1 inhibition reversed the protective effects of Usp14 silencing on renal tubular cell injury and its facilitation of mitophagy. In summary, our study demonstrated the renoprotective role of Usp14 knockdown in mitigating renal IR injury by promoting Tfap2a-mediated Tbk1 upregulation and mitophagy. These findings advocate for exploring Usp14 inhibition as a promising therapeutic avenue for mitigating IR injury, primarily by enhancing the clearance of damaged mitochondria through augmented mitophagy.
    Keywords:  Mitophagy; Oxidative stress; Renal ischemia/reperfusion injury; Ubiquitin-specific protease 14
    DOI:  https://doi.org/10.1016/j.trsl.2024.04.002
  48. Sci Total Environ. 2024 Apr 20. pii: S0048-9697(24)02728-1. [Epub ahead of print] 172582
    Perfluoroalkyl sulfonate induces cardiomyocyte apoptosis via endoplasmic reticulum stress activation and autophagy flux inhibition.
    Yuanhao Wang, Da Yin, Xin Sun, Wei Zhang, Huan Ma, Jingnan Huang, Chuanbin Yang, Jigang Wang, Qingshan Geng.
      Perfluoroalkyl sulfonate (PFOS) is a commonly used chemical compound that often found in materials such as waterproofing agents, food packaging, and fire retardants. Known for its stability and persistence in the environment, PFOS can enter the human body through various pathways, including water and the food chain, raising concerns about its potential harm to human health. Previous studies have suggested a cardiac toxicity of PFOS, but the specific cellular mechanisms remained unclear. Here, by using AC16 cardiomyocyte as a model to investigate the molecular mechanisms potential the cardiac toxicity of PFOS. Our findings revealed that PFOS exposure reduced cell viability and induces apoptosis in human cardiomyocyte. Proteomic analysis and molecular biological techniques showed that the Endoplasmic Reticulum (ER) stress-related pathways were activated, while the cellular autophagy flux was inhibited in PFOS-exposed cells. Subsequently, we employed strategies such as autophagy activation and ER stress inhibition to alleviate the PFOS-induced apoptosis in AC16 cells. These results collectively suggest that PFOS-induced ER stress activation and autophagy flux inhibition contribute to cardiomyocyte apoptosis, providing new insights into the mechanisms of PFOS-induced cardiomyocyte toxicity.
    Keywords:  Autophagy; Cardiomyocyte; Cardiotoxicity; ER stress; Perfluoroalkyl sulfonate
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.172582
  49. Nat Commun. 2024 Apr 20. 15(1): 3375
    Inflammation and mitophagy are mitochondrial checkpoints to aging.
    Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.
      
    DOI:  https://doi.org/10.1038/s41467-024-47840-1
  50. Open Biol. 2024 Apr;14(4): 240001
    Optogenetically engineered calcium oscillations promote autophagy-mediated cell death via AMPK activation.
    Yi-Shyun Lai, Meng-Ru Hsieh, Thi My Hang Nguyen, Ying-Chi Chen, Hsueh-Chun Wang, Wen-Tai Chiu.
      Autophagy is a double-edged sword for cells; it can lead to both cell survival and death. Calcium (Ca2+) signalling plays a crucial role in regulating various cellular behaviours, including cell migration, proliferation and death. In this study, we investigated the effects of modulating cytosolic Ca2+ levels on autophagy using chemical and optogenetic methods. Our findings revealed that ionomycin and thapsigargin induce Ca2+ influx to promote autophagy, whereas the Ca2+ chelator BAPTA-AM induces Ca2+ depletion and inhibits autophagy. Furthermore, the optogenetic platform allows the manipulation of illumination parameters, including density, frequency, duty cycle and duration, to create different patterns of Ca2+ oscillations. We used the optogenetic tool Ca2+-translocating channelrhodopsin, which is activated and opened by 470 nm blue light to induce Ca2+ influx. These results demonstrated that high-frequency Ca2+ oscillations induce autophagy. In addition, autophagy induction may involve Ca2+-activated adenosine monophosphate (AMP)-activated protein kinases. In conclusion, high-frequency optogenetic Ca2+ oscillations led to cell death mediated by AMP-activated protein kinase-induced autophagy.
    Keywords:  AMPK; autophagy; calcium; cell death; optogenetics
    DOI:  https://doi.org/10.1098/rsob.240001
  51. Chem Sci. 2024 Apr 24. 15(16): 6028-6035
    Near-infrared imaging for visualizing the synergistic relationship between autophagy and NFS1 protein during multidrug resistance using an ICT-TICT integrated platform.
    Wei Hu, Yifan He, Haixian Ren, Li Chai, Haiyan Li, Jianbin Chen, Chunya Li, Yanying Wang, Tony D James.
      Drug resistance is a major challenge for cancer treatment, and its identification is crucial for medical research. However, since drug resistance is a multi-faceted phenomenon, it is important to simultaneously evaluate multiple target fluctuations. Recently developed fluorescence-based probes that can simultaneously respond to multiple targets offer many advantages for real-time and in situ monitoring of cellular metabolism, including ease of operation, rapid reporting, and their non-invasive nature. As such we developed a dual-response platform (Vis-H2S) with integrated ICT-TICT to image H2S and viscosity in mitochondria, which could simultaneously track fluctuations in cysteine desulfurase (NFS1 protein and H2S inducer) and autophagy during chemotherapy-induced multidrug resistance. This platform could monitor multiple endogenous metabolites and the synergistic relationship between autophagy and NFS1 protein during multidrug resistance induced by chemotherapy. The results indicated that chemotherapeutic drugs simultaneously up-regulate the levels of NFS1 protein and autophagy. It was also found that the NFS1 protein was linked with autophagy, which eventually led to multidrug resistance. As such, this platform could serve as an effective tool for the in-depth exploration of drug resistance mechanisms.
    DOI:  https://doi.org/10.1039/d3sc06459j
  52. Cureus. 2024 Mar;16(3): e56562
    A Study of FoxO1, mTOR, miR-21, miR-29b, and miR-98 Expression Levels Regarding Metabolic Syndrome in Acne Vulgaris Patients.
    Nazan Akdağ, Engin Atli, Drenushe Zhuri, Hazal Sezgi Ner Güler, Yıldız Gürsel Ürün.
       BACKGROUND: Acne vulgaris (AV) is an inflammatory skin disease caused by the mechanistic target of rapamycin complex 1 (mTORC1). forkhead box protein (Fox) O1 is known to regulate the relationship between the mTORC1 signaling pathway and insulin resistance (IR). Increased mTORC1 signaling is known to predispose one to diseases such as insulin resistance (IR), obesity, and diabetes mellitus. One of the major components of mTORC1 is mTOR. FoxO1 and mTOR play key roles in the onset and progression of metabolic syndrome (MetS). In this study, we aimed to elucidate the relationship between AV and MetS through FoxO1 and mTOR signaling pathways and microRNAs (miRs) associated with these signaling pathways.
    METHODS: We examined 20 AV patients without MetS, 16 AV patients with MetS, and 20 healthy controls. The demographic characteristics of the patients, MetS parameters, clinical severity of AV (Global Acne Grading System, GAGS), and the homeostasis model assessment (HOMA) values were compared between the groups. In addition, the expression levels of FoxO1 and mTOR genes, along with the expression levels of miR-21, miR-29b, and miR-98, were assessed in skin biopsy samples from all groups using real-time polymerase chain reaction methods. FoxO1, mTOR, and miRNA expression levels were recorded as fold change.
    RESULTS: The mean age of patients with AV without MetS was statistically lower. In AV patients with MetS, those with moderate GAGS scores had statistically significantly higher HOMA values than those with mild GAGS scores. FoxO1 expression was significantly lower in AV patients compared to controls. The mTOR expression levels of AV patients with MetS were significantly higher than the other two groups. The expression levels of miR-21 and miR-29b were significantly increased in the group of AV patients with MetS compared to the group of AV patients without MetS.
    CONCLUSIONS: These results suggested that the mTOR pathway may play an important role in explaining the relationship between AV and MetS in acne pathogenesis. They also suggested that miR-21 and miR-29b play a role in the inflammatory process of AV.
    Keywords:  acne vulgaris; forkhead box protein; mechanistic target of rapamycin; metabolic syndrome; microrna (mirna)
    DOI:  https://doi.org/10.7759/cureus.56562
  53. Ecotoxicol Environ Saf. 2024 Apr 19. pii: S0147-6513(24)00390-7. [Epub ahead of print]277 116314
    HO-1 upregulation promotes mitophagy-dependent ferroptosis in PM2.5-exposed hippocampal neurons.
    Xiaolan Li, Qin Ran, Xiang He, Dan Peng, Anying Xiong, Manling Jiang, Lei Zhang, Junyi Wang, Lingling Bai, Shengbin Liu, Shiyue Li, Baoqing Sun, Guoping Li.
      Fine particulate matter (PM2.5) has been extensively implicated in the pathogenesis of neurodevelopmental disorders, but the underlying mechanism remains unclear. Recent studies have revealed that PM2.5 plays a role in regulating iron metabolism and redox homeostasis in the brain, which is closely associated with ferroptosis. In this study, the role and underlying mechanism of ferroptosis in PM2.5-induced neurotoxicity were investigated in mice, primary hippocampal neurons, and HT22 cells. Our findings demonstrated that exposure to PM2.5 could induce abnormal behaviors, neuroinflammation, and neuronal loss in the hippocampus of mice. These effects may be attributed to ferroptosis induced by PM2.5 exposure in hippocampal neurons. RNA-seq analysis revealed that the upregulation of iron metabolism-related protein Heme Oxygenase 1 (HO-1) and the activation of mitophagy might play key roles in PM2.5-induced ferroptosis in HT22 cells. Subsequent in vitro experiments showed that PM2.5 exposure significantly upregulated HO-1 in primary hippocampal neurons and HT22 cells. Moreover, PM2.5 exposure activated mitophagy in HT22 cells, leading to the loss of mitochondrial membrane potential, alterations in the expression of autophagy-related proteins LC3, P62, and mTOR, as well as an increase in mitophagy-related protein PINK1 and PARKIN. As a heme-degradation enzyme, the upregulation of HO-1 promotes the release of excess iron, genetically inhibiting the upregulation of HO-1 in HT22 cells could prevent both PM2.5-induced mitophagy and ferroptosis. Furthermore, pharmacological inhibition of mitophagy in HT22 cells reduced levels of ferrous ions and lipid peroxides, thereby preventing ferroptosis. Collectively, this study demonstrates that HO-1 mediates PM2.5-induced mitophagy-dependent ferroptosis in hippocampal neurons, and inhibiting mitophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following PM2.5 exposure.
    Keywords:  Ferroptosis; HO-1; Mitophagy; Neurotoxicity; PM2.5
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.116314
  54. Biosci Rep. 2024 Apr 24. pii: BSR20231992. [Epub ahead of print]
    Cardiomyocyte-specific deletion of the mitochondrial transporter Abcb10 causes cardiac dysfunction via lysosomal-mediated ferroptosis.
    Yura Do, Mikako Yagi, Haruka Hirai, Kenji Miki, Yukina Fikahori, Daiki Setoyama, Masatatsu Yamamoto, Tatsuhiko Furukawa, Yuya Kunishaki, Dongchon Kang, Takeshi Uchiumi.
      Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.
    Keywords:  heart failure; lysosomes; mitochondria
    DOI:  https://doi.org/10.1042/BSR20231992
  55. bioRxiv. 2024 Apr 17. pii: 2024.04.17.589921. [Epub ahead of print]
    Mitigation of Stress-induced Structural Remodeling and Functional Deficiency in iPSC-CMs with PLN R9C Mutation by Promoting Autophagy.
    Qi Yu, Robert J Barndt, Yawei Shen, Karim Sallam, Ying Tang, Stephen Y Chan, Joseph C Wu, Qing Liu, Haodi Wu.
       Background: Phospholamban (PLN) is a key regulator of cardiac function connecting adrenergic signaling and calcium homeostasis. The R9C mutation of PLN is known to cause early onset dilated cardiomyopathy (DCM) and premature death, yet the detailed mechanisms underlie the pathologic remodeling process are not well defined in human cardiomyocytes. The aim of this study is to unravel the role of PLN R9C in DCM and identify potential therapeutic targets.
    Methods: PLN R9C knock-in (KI) and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated and comprehensively examined for their expression profile, contractile function, and cellular signaling under both baseline conditions and following functional challenges.
    Results: PLN R9C KI iPSC-CMs exhibited near-normal morphology and calcium handling, slightly increased contractility, and an attenuated response to β-adrenergic activation compared to wild-type (WT) cells. However, treatment with a maturation medium (MM) has induced fundamentally different remodeling in the two groups: while it improved the structural integrity and functional performance of WT cells, the same treatment result in sarcomere disarrangement, calcium handling deficiency, and further disrupted adrenergic signaling in PLN R9C KI cells. To understand the mechanism, transcriptomic analysis showed the enrichment of protein homeostasis signaling pathways specifically in PLN R9C KI cells in response to the MM treatment and increased contractile demands. Further studies also indicated elevated ROS levels, interrupted autophagic flux, and increased pentamer PLN aggregation in functionally challenged KI cells. These results were further confirmed in patient-specific iPSC-CM models, suggesting that functional stresses exacerbate the deficiencies in PLN R9C cells through disrupting protein homeostasis. Indeed, treating stressed patient cells with autophagy-accelerating reagents, such as metformin and rapamycin, has restored autophagic flux, mitigated sarcomere disarrangement, and partially rescued β-adrenergic signaling and cardiac function.
    Conclusions: PLN R9C leads to a mild increase of calcium recycling and contractility. Functional challenges further enhanced contractile and proteostasis stress, leading to autophagic overload, structural remodeling, and functional deficiencies in PLN R9C cardiomyocytes. Activation of autophagy signaling partially rescues these effects, revealing a potential therapeutic target for DCM patients with the PLN R9C mutation.
    Graphic abstracts: A graphic abstract is available for this article.
    DOI:  https://doi.org/10.1101/2024.04.17.589921
  56. Res Sq. 2024 Apr 01. pii: rs.3.rs-3953289. [Epub ahead of print]
    Role of NuMA1 in breast cancer stem cells with implications for combination therapy of PIM1 and autophagy inhibition in triple negative breast cancer.
    Kanakaraju Manupati, Mingang Hao, Michael Haas, Syn Kok Yeo, Jun-Lin Guan.
       BACKGROUND: Nuclear mitotic apparatus protein 1 (NuMA1) is a cell cycle protein and upregulated in breast cancer. However, the role of NuMA1 in TNBC and its regulation in heterogenous populations remains elusive.
    METHODS: We performed CRISPR mediated deletion of NuMA1 in mouse TNBC cells, BF3M. FACS was utilized to isolate BCSCs, and bulk cells based on CD29 and CD61 markers. Cell viability, migration, and invasion ability of BCSCs and bulk cells was evaluated using MTT, wound healing and transwell invasion assays, respectively. In vivo mouse breast cancer and lung metastatic models were generated to evaluate the combination treatment of SMI-4a and Lys-o5 inhibitors.
    RESULTS: We identified that high expression of NuMA1 associated with poor survival of breast cancer patients. Further, human tissue microarray results depicted high expression of NuMA1 in TNBC relative to non-adjacent normal tissues. Therefore, we performed CRISPR mediated deletion of NuMA1 in a mouse mammary tumor cell line, BF3M and revealed that NuMA1 deletion reduced mammary tumorigenesis. We also showed that NuMA1 deletion reduced ALDH+ and CD29hiCD61+ breast cancer stem cells (BCSCs), indicating a role of NuMA1 in BCSCs. Further, sorted and characterized BCSCs from BF3M depicted reduced metastasis with NuMA1 KO cells. Moreover, we found that PIM1, an upstream kinase of NuMA1 plays a preferential role in maintenance of BCSCs associated phenotypes, but not in bulk cells. In contrast, PIM1 kinase inhibition in bulk cells depicted increased autophagy (FIP200). Therefore, we applied a combination treatment strategy of PIM1 and autophagy inhibition using SMI-4a and Lys05 respectively, showed higher efficacy against cell viability of both these populations and further reduced breast tumor formation and metastasis. Together, our study demonstrated NuMA1 as a potential therapeutic target and combination treatment using inhibitors for an upstream kinase PIM1 and autophagy inhibitors could be a potentially new therapeutic approach for TNBC.
    CONCLUSIONS: Our study demonstrated that combination treatment of PIM1 inhibitor and autophagy inhibitor depicted reduced mammary tumorigenesis and metastasis by targeting NuMA1 in BCSCs and bulk cells of TNBC, demonstrating this combination treatment approach could be a potentially effective therapy for TNBC patients.
    DOI:  https://doi.org/10.21203/rs.3.rs-3953289/v1
  57. J Mater Chem B. 2024 Apr 23.
    A multipurpose mitochondrial NIR probe for imaging ferroptosis and mitophagy.
    Deeksha Rajput, Nachiket Pradhan, Shabnam Mansuri, Virupakshi Soppina, Sriram Kanvah.
      This paper explores the use of a di-cationic fluorophore for visualizing mitochondria in live cells independent of membrane potential. Through the synthesized di-cationic fluorophore, we investigate the monitoring of viscosity, ferroptosis, stress-induced mitophagy, and lysosomal uptake of damaged mitochondria. The designed fluorophore is based on DQAsomes, cationic vesicles responsible for transporting drugs and DNA to mitochondria. The symmetric fluorophores possess two charge centres separated by an alkyl chain and are distinguished by a pyridinium group for mitochondrial selectivity, the C-12 alkyl substitution for membrane affinity, and an electron donor-π-acceptor fluorescent scaffold for intramolecular charge transfer. The synthesized fluorophores, PP and NP, emit wavelengths exceeding 600 nm, with a significant Stokes shift (130-211 nm), and NP demonstrates near-infrared emission (∼690 nm). Our study underscores the potential of these fluorophores for live-cell imaging, examining physiological responses such as viscosity and ferroptosis, and highlights their utility in investigating mitophagy damage and lysosomal uptake.
    DOI:  https://doi.org/10.1039/d4tb00293h
  58. Biomolecules. 2024 Apr 20. pii: 501. [Epub ahead of print]14(4):
    Caspase-1 Deficiency Modulates Adipogenesis through Atg7-Mediated Autophagy: An Inflammatory-Independent Mechanism.
    Yumeng Wang, Gaojun Chen, Min Xu, Yewei Cui, Weijiong He, Hongxiang Zeng, Ting Zeng, Rui Cheng, Xi Li.
      Obesity stands as a significant risk factor for type 2 diabetes, hyperlipidemia, and cardiovascular diseases, intertwining increased inflammation and decreased adipogenesis with metabolic disorders. Studies have highlighted the correlation between Caspase-1 and inflammation in obesity, elucidating its essential role in the biological functions of adipose tissue. However, the impact of Caspase-1 on adipogenesis and the underlying mechanisms remain largely elusive. In our study, we observed a positive correlation between Caspase-1 expression and obesity and its association with adipogenesis. In vivo experiments revealed that, under normal diet conditions, Caspase-1 deficiency improved glucose homeostasis, stimulated subcutaneous adipose tissue expansion, and enhanced adipogenesis. Furthermore, our findings indicate that Caspase-1 deficiency promotes the expression of autophagy-related proteins and inhibits autophagy with 3-MA or CQ blocked Caspase-1 deficiency-induced adipogenesis in vitro. Notably, Caspase-1 deficiency promotes adipogenesis via Atg7-mediated autophagy activation. In addition, Caspase-1 deficiency resisted against high-fat diet-induced obesity and glucose intolerance. Our study proposes the downregulation of Caspase-1 as a promising strategy for mitigating obesity and its associated metabolic disorders.
    Keywords:  Atg7; Caspase-1; adipogenesis; autophagy
    DOI:  https://doi.org/10.3390/biom14040501
  59. Cancer Sci. 2024 Apr 26.
    Expression of ZKSCAN3 protein suppresses proliferation, migration, and invasion of pancreatic cancer through autophagy.
    Keisuke Nonoyama, Yoichi Matsuo, Saburo Sugita, Yuki Eguchi, Yuki Denda, Hiromichi Murase, Tomokatsu Kato, Hiroyuki Imafuji, Kenta Saito, Mamoru Morimoto, Ryo Ogawa, Hiroki Takahashi, Akira Mitsui, Masahiro Kimura, Shuji Takiguchi.
      Elevated autophagy activity enhances the malignancy of pancreatic cancer (PaCa), and autophagy is recognized as a novel therapeutic target. Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) is a transcription factor that suppresses autophagy, but its association with PaCa is unknown. We analyzed the function of ZKSCAN3 in PaCa and investigated whether autophagy regulation through ZKSCAN3 could become a new therapeutic target for PaCa. Using reverse transcription-quantitative polymerase chain reaction and western blotting, we observed that ZKSCAN3 expression was upregulated in several PaCa cell lines compared with normal pancreatic ductal epithelial cells. Additionally, comparing ZKSCAN3 expression with the prognosis of PaCa patients using web databases, we found that higher ZKSCAN3 expression in PaCa was associated with extended overall survival. Knocking down ZKSCAN3 promoted the proliferation of PaCa cells. Moreover, following ZKSCAN3 knockdown, PaCa cells exhibited significantly enhanced migratory and invasive properties. Conversely, overexpression of ZKSCAN3 significantly suppressed the proliferation, migration and invasion of PaCa cells. Additionally, the knockdown of ZKSCAN3 increased the expression of LC3-II, a marker of autophagy, whereas ZKSCAN3 overexpression decreased LC3-II expression. In a xenograft mouse model, tumors formed by MIA PaCa-2 cells in which ZKSCAN3 was knocked down significantly increased in size compared with the control group. In conclusion, ZKSCAN3 expression was upregulated in several pancreatic cancer cells. Additionally, it was revealed that ZKSCAN3 is negatively correlated with the malignancy of PaCa through autophagy. These results suggest that autophagy regulation via ZKSCAN3 may be a new therapeutic target for PaCa.
    Keywords:  ZKSCAN3; autophagy; cancer; pancreatic cancer; zinc finger protein
    DOI:  https://doi.org/10.1111/cas.16173
  60. J Neurochem. 2024 Apr 22.
    The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology.
    Stephanie Tam, Darcy Wear, Christopher D Morrone, Wai Haung Yu.
      Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid β, tau, ɑ-synuclein, prions, and TDP-43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood-brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease.
    Keywords:  autophagy; extracellular vesicle; neurodegeneration; proteostasis; translation
    DOI:  https://doi.org/10.1111/jnc.16108
  61. Exp Lung Res. 2024 ;50(1): 106-117
    Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice.
    Jialin Li, Kexuan Liu, Wenjuan He, Wencai Zhang, Yongchao Li.
       BACKGROUND: Pulmonary emphysema is a condition that causes damage to the lung tissue over time. GBP5, as part of the guanylate-binding protein family, is dysregulated in mouse pulmonary emphysema. However, the role of GBP5 in lung inflammation in ARDS remains unveiled.
    METHODS: To investigate whether GBP5 regulates lung inflammation and autophagy regulation, the study employed a mouse ARDS model and MLE-12 cell culture. Vector transfection was performed for the genetic manipulation of GBP5. Then, RT-qPCR, WB and IHC staining were conducted to assess its transcriptional and expression levels. Histological features of the lung tissue were observed through HE staining. Moreover, ELISA was conducted to evaluate the secretion of inflammatory cytokines, autophagy was assessed by immunofluorescent staining, and MPO activity was determined using a commercial kit.
    RESULTS: Our study revealed that GBP5 expression was altered in mouse ARDS and LPS-induced MLE-12 cell models. Moreover, the suppression of GBP5 reduced lung inflammation induced by LPS in mice. Conversely, overexpression of GBP5 diminished the inhibitory impact of LPS on ARDS during autophagy, leading to increased inflammation. In the cell line of MLE-12, GBP5 exacerbates LPS-induced inflammation by blocking autophagy.
    CONCLUSION: The study suggests that GBP5 facilitates lung inflammation and autophagy regulation. Thus, GBP5 could be a potential therapeutic approach for improving ARDS treatment outcomes, but further research is required to validate these findings.
    Keywords:  ARDS; GBP5; Pulmonary emphysema; autophagy; inflammation
    DOI:  https://doi.org/10.1080/01902148.2024.2339269
  62. Chemosphere. 2024 Apr 24. pii: S0045-6535(24)01031-2. [Epub ahead of print] 142138
    NBR1-dependent Autophagy Activation Protects Against Environmental Cadmium-evoked Placental Trophoblast Senescence.
    Qing Ling, Yu-Feng Zhang, Wei Chang, Si-Ting Liu, Hua-Long Zhu, Hua Wang.
      Cadmium (Cd), a well-established developmental toxicant, accumulates in the placentae and disrupts its structure and function. Population study found adverse pregnancy outcomes caused by environmental Cd exposure associated with cell senescence. However, the role of autophagy activation in Cd-induced placental cell senescence and its reciprocal mechanisms are unknown. In this study, we employed animal experiments, cell culture, and case-control study to investigate the above mentioned. We have demonstrated that exposure to Cd during gestation induces placental senescence and activates autophagy. Pharmacological and genetic interventions further exacerbated placental senescence induced by Cd through the suppression of autophagy. Conversely, activation of autophagy ameliorated Cd-induced placental senescence. Knockdown of NBR1 exacerbated senescence in human placental trophoblast cells. Further investigations revealed that NBR1 facilitated the degradation of p21 via LC3B. Our case-control study has demonstrated a positive correlation between placental senescence and autophagy activation in all-cause fetal growth restriction (FGR). These findings offer a novel perspective for mitigating placental aging and placental-origin developmental diseases induced by environmental toxicants.
    Keywords:  Autophagy; Cadmium; NBR1; Placenta; Senescence
    DOI:  https://doi.org/10.1016/j.chemosphere.2024.142138
  63. BMC Genomics. 2024 Apr 24. 25(1): 403
    RNA methylation patterns, immune characteristics, and autophagy-related mechanisms mediated by N6-methyladenosine (m6A) regulatory factors in venous thromboembolism.
    Deshuai Zhang, Wenxia Fu, Shiwei Zhu, Yitong Pan, Ruogu Li.
      Recent studies have found a link between deep vein thrombosis and inflammatory reactions. N6-methyladenosine (m6A), a crucial element in immunological regulation, is believed to contribute to the pathophysiology of venous thromboembolism (VTE). However, how the m6A-modified immune microenvironment is involved in VTE remains unclear. In the present study, we identified a relationship between VTE and the expression of several m6A regulatory elements by analyzing peripheral blood samples from 177 patients with VTE and 88 healthy controls from public GEO databases GSE19151 and GSE48000. We used machine learning to identify essential genes and constructed a diagnostic model for VTE using multivariate logistic regression. Unsupervised cluster analysis revealed a marked difference between m6A modification patterns in terms of immune cell infiltration, inflammatory reactivity, and autophagy. We identified two m6A-related autophagy genes (i.e., CHMP2B and SIRT1) and the crucial m6A regulator YTHDF3 using bioinformatics. We also examined two potential mechanisms through which YTHDF3 may affect VTE. m6A modification, immunity, and autophagy are closely linked in VTE, offering novel mechanistic and therapeutic insights.
    Keywords:  Autophagy; Epigenetics; Immune characteristics; Machine learning; Venous thrombosis
    DOI:  https://doi.org/10.1186/s12864-024-10294-2
  64. Elife. 2024 Apr 22. pii: RP92243. [Epub ahead of print]12
    Membrane-bound O-acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury.
    Venkateshwari Varadharajan, Iyappan Ramachandiran, William J Massey, Raghav Jain, Rakhee Banerjee, Anthony J Horak, Megan R McMullen, Emily Huang, Annette Bellar, Shuhui W Lorkowski, Kailash Gulshan, Robert N Helsley, Isabella James, Vai Pathak, Jaividhya Dasarathy, Nicole Welch, Srinivasan Dasarathy, David Streem, Ofer Reizes, Daniela S Allende, Jonathan D Smith, Judith Simcox, Laura E Nagy, J Mark Brown.
      Recent genome-wide association studies (GWAS) have identified a link between single-nucleotide polymorphisms (SNPs) near the MBOAT7 gene and advanced liver diseases. Specifically, the common MBOAT7 variant (rs641738) associated with reduced MBOAT7 expression is implicated in non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis. However, the precise mechanism underlying MBOAT7-driven liver disease progression remains elusive. Previously, we identified MBOAT7-driven acylation of lysophosphatidylinositol lipids as key mechanism suppressing the progression of NAFLD (Gwag et al., 2019). Here, we show that MBOAT7 loss of function promotes ALD via reorganization of lysosomal lipid homeostasis. Circulating levels of MBOAT7 metabolic products are significantly reduced in heavy drinkers compared to healthy controls. Hepatocyte- (Mboat7-HSKO), but not myeloid-specific (Mboat7-MSKO), deletion of Mboat7 exacerbates ethanol-induced liver injury. Lipidomic profiling reveals a reorganization of the hepatic lipidome in Mboat7-HSKO mice, characterized by increased endosomal/lysosomal lipids. Ethanol-exposed Mboat7-HSKO mice exhibit dysregulated autophagic flux and lysosomal biogenesis, associated with impaired transcription factor EB-mediated lysosomal biogenesis and autophagosome accumulation. This study provides mechanistic insights into how MBOAT7 influences ALD progression through dysregulation of lysosomal biogenesis and autophagic flux, highlighting hepatocyte-specific MBOAT7 loss as a key driver of ethanol-induced liver injury.
    Keywords:  MBOAT7; alcohol-associated liver disease; autophagy; medicine; mouse
    DOI:  https://doi.org/10.7554/eLife.92243
  65. bioRxiv. 2024 Apr 17. pii: 2024.04.15.589676. [Epub ahead of print]
    PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.
    Marwah Karim, Manjari Mishra, Chieh-Wen Lo, Sirle Saul, Halise Busra Cagirici, Do Hoang Nhu Tran, Aditi Agrawal, Luca Ghita, Amrita Ojha, Michael P East, Karen Anbro Gammeltoft, Malaya Kumar Sahoo, Gary L Johnson, Soumita Das, Dirk Jochmans, Courtney A Cohen, Judith Gottwein, John Dye, Norma Neff, Benjamin A Pinsky, Tuomo Laitinen, Tatu Pantsar, Antti Poso, Fabio Zanini, Steven De Jonghe, Christopher R M Asquith, Shirit Einav.
      In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We discovered PIP4K2C's roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays revealed that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced impairment of autophagic flux. Reversing this autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual inhibition of PIP4K2C and PIKfyve as a candidate strategy to combat emerging viruses.
    DOI:  https://doi.org/10.1101/2024.04.15.589676
  66. Biol Reprod. 2024 Apr 22. pii: ioae064. [Epub ahead of print]
    HMGB1 regulates autophagy of placental trophoblast through ERK signaling pathway.
    Ming-Rui Li, En-Xiang Chen, Zhuo-Hang Li, Hong-Lan Song, Yi Zhang, Fang-Fang Li, You-Long Xie, Jing Tang, Yu-Bin Ding, Li-Juan Fu.
       OBJECTIVE: The purpose of this study is to investigate the role of high mobility group protein B1 (HMGB1) in placental development and fetal growth.
    METHODS: We employed the Cre-loxP recombination system to establish a placenta-specific HMGB1 knockout mouse model. Breeding HMGB1flox/flox mice with Elf5-Cre mice facilitated the knockout, leveraging Elf5 expression in extra-embryonic ectoderm, ectoplacental cone, and trophoblast giant cells at 12.5 days of embryonic development. The primary goal of this model was to elucidate the molecular mechanism of HMGB1 in placental development, assessing parameters such as placental weight, fetal weight, and bone development. Additionally, we utilized lentiviral interference and overexpression of HMGB1 in human trophoblast cells to further investigate HMGB1's functional role.
    RESULTS: Our findings indicate that HMGB1flox/floxElf5cre/+ mouse display fetal growth restriction (FGR), characterized by decreased placental and fetal weight and impaired bone development. And the absence of HMGB1 inhibits autophagosome formation, impairs lysosomal degradation, and disrupts autophagic flux. Depletion of HMGB1 in human trophoblast cells also suppresses cell viability, proliferation, migration, and invasion by inhibiting the ERK signaling pathway. Overexpression of HMGB1 observed the opposite phenotypes.
    CONCLUSIONS: HMGB1 participates in the regulation of autophagy through the ERK signaling pathway and affects placental development.
    Keywords:  Autophagy; Fetal growth restriction; High mobility group protein B1; Placenta; Trophoblast
    DOI:  https://doi.org/10.1093/biolre/ioae064
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