bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–09–29
88 papers selected by
Viktor Korolchuk, Newcastle University
  1. Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
  2. Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
  3. Locked in Structure: Sestrin and GATOR-A Billion-Year Marriage.
  4. USF2 and TFEB compete in regulating lysosomal and autophagy genes.
  5. Quality control of mitochondria involves lysosomes in multiple definitive ways.
  6. An interplay between biomolecular condensates and SNARE proteins regulates plant autophagy.
  7. SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB.
  8. Inclusion body myositis: Correcting impaired mitochondrial and lysosomal autophagy as a potential therapeutic strategy.
  9. Fast and quantitative mitophagy assessment by flow cytometry using the mito-QC reporter.
  10. Assessing Autophagy Flux in Glioblastoma Temozolomide Resistant Cells.
  11. Autophagy: the misty lands of Chlamydia trachomatis infection.
  12. The Convergence of mTOR Signaling and Ethanol Teratogenesis.
  13. Membrane remodeling via ubiquitin-mediated pathways.
  14. Biomolecular condensation of ERC1 recruits ATG8 and NBR1 to drive autophagosome formation for plant heat tolerance.
  15. Were the autophagosome-lysosome/vacuole fusion models illustrated correctly in the literature?
  16. Role of autophagy in modulating tumor cell radiosensitivity: Exploring pharmacological interventions for glioblastoma multiforme treatment.
  17. White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells.
  18. ATP6V1D drives hepatocellular carcinoma stemness and progression via both lysosome acidification-dependent and -independent mechanisms.
  19. IFN-γ induces acute graft-versus-host disease by promoting HMGB1-mediated nuclear-to-cytoplasm translocation and autophagic degradation of p53.
  20. Exploring the Potential of Herbal Compounds as Autophagy Modulators in Alzheimer's Disease: A Comprehensive Review.
  21. Polyvinylpyrrolidone capped silver nanoparticles enhance the autophagic clearance of Acinetobacter baumannii from human pulmonary cells.
  22. Med13 is required for efficient P-body recruitment and autophagic degradation of Edc3 following nitrogen starvation.
  23. Hypoxia-induced autophagy inhibits myometrial proliferation in pregnant mice via the mTOR pathway in vitro.
  24. Nanoscale ZnO doping in prosthetic polymers mitigate wear particle-induced inflammation and osteolysis through inhibiting macrophage secretory autophagy.
  25. Tau accumulation is cleared by the induced expression of VCP via autophagy.
  26. Significant Role of Autophagy in Melanosomal Degradation of Dermal Macrophages - Therapeutic Insight Regarding Hyperpigmentation with Uncertain Etiology.
  27. PLK2-mediated phosphorylation of SQSTM1 S349 promotes aggregation of polyubiquitinated proteins upon proteasomal dysfunction.
  28. TGN-020 ameliorates motor dysfunction post-spinal cord injury via enhancing astrocyte autophagy and mitigating inflammation by activating AQP4/PPAR-γ/mTOR pathway.
  29. Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy.
  30. Inhibition of Autophagy by Berbamine Hydrochloride Mitigates Tumor Immune Escape by Elevating MHC-I in Melanoma Cells.
  31. Chondrocyte Ferritinophagy as a Molecular Mechanism of Arthritis-A Narrative Review.
  32. Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
  33. Homocysteine metabolites impair the PHF8/H4K20me1/mTOR/autophagy pathway by upregulating the expression of histone demethylase PHF8-targeting microRNAs in human vascular endothelial cells and mice.
  34. Two distinct regulatory pathways govern Cct2-Atg8 binding in the process of solid aggrephagy.
  35. Complement C3 deposition restricts the proliferation of internalized Staphylococcus aureus by promoting autophagy.
  36. PHOTOPROTECTIVE MELANIN IS MAINTAINED WITHIN KERATINOCYTES IN STORAGE LYSOSOMES.
  37. Autophagic inhibitor ROC-325 ameliorates glomerulosclerosis and podocyte injury via inhibiting autophagic flux in experimental FSGS mice.
  38. Black phosphorus nanosheets induce autophagy dysfunction by a size- and surface modification-related impairment of lysosomes in macrophages.
  39. Decreased SREBP2 of the striatal cell relates to disrupted protein degradation in Huntington's disease.
  40. Desmoplakin mutations in cardiac fibroblasts cause TGFβ1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation.
  41. Icariin alleviates cellular injury induced by cardiac ischemia-reperfusion injury by inhibiting IRE1/JNK-induced ferroptosis.
  42. The role of mitochondria in cytokine and chemokine signalling during ageing.
  43. Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.
  44. Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling.
  45. Brain insulin resistance in Down syndrome: Involvement of PI3K-Akt/mTOR axis in early-onset of Alzheimer's disease and its potential as a therapeutic target.
  46. Targeting IGF1/IGF1r signaling relieve pain and autophagic dysfunction in NTG-induced chronic migraine model of mice.
  47. Biochemical Pathways Delivering Distinct Glycosphingolipid Patterns in MDA-MB-231 and MCF-7 Breast Cancer Cells.
  48. TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts.
  49. Mycobacterium manipulate glutaminase 1 mediated glutaminolysis to regulate macrophage autophagy for bacteria intracellular survival.
  50. Maintaining KEAP1 levels in retinal pigment epithelial cells preserves their viability during prolonged exposure to artificial blue light.
  51. HSP90-regulated mitophagy can alleviate heat stress damage by inhibiting pyroptosis in the hepatocytes of Wenchang chickens.
  52. EspH utilizes phosphoinositide and Rab binding domains to interact with plasma membrane infection sites and Rab GTPases.
  53. Hederagenin inhibits mitochondrial damage in Parkinson's disease via mitophagy induction.
  54. Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy.
  55. Mycobacterium tuberculosis VII secretion system effector molecule Rv2347c blocks the maturation of phagosomes and activates the STING/TBK1 signaling pathway to inhibit cell autophagy.
  56. Valosin-containing protein: A potential therapeutic target for cardiovascular diseases.
  57. Bmi-1 alleviates alveolar bone resorption through the regulation of autophagy.
  58. Arf1-dependent LRBA recruitment to Rab4 endosomes is required for endolysosome homeostasis.
  59. N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy.
  60. MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation.
  61. Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.
  62. Aβ25-35-induced autophagy and apoptosis are prevented by the CRMP2-derived peptide ST2-104 (R9-CBD3) via a CaMKKβ/AMPK/mTOR signaling hub.
  63. The role of Drp1 - Pink1 - Parkin - mediated mitophagy in perfluorobutane sulfonate- induced hepatocyte damage.
  64. Bile from the hemojuvelin-deficient mouse model of iron excess is enriched in iron and ferritin.
  65. NOD1 and NOD2: Essential Monitoring Partners in the Innate Immune System.
  66. In vivo targeted-imaging of mitochondrial acidification in an aristolochic acid I-induced nephrotoxicity mouse model by a fluorescent/photoacoustic bimodal probe.
  67. Eleutheroside B Pretreatment Attenuates Hypobaric Hypoxia-Induced High-Altitude Pulmonary Edema by Regulating Autophagic Flux via the AMPK/mTOR Pathway.
  68. Current Insights on Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and their significance in the pathophysiology of ocular disorders.
  69. Morphological multiparameter filtration and persistent homology in mitochondrial image analysis.
  70. Y9, a Gboxin analog, displays anti-tumor effect in non-small cell lung cancer by inducing lysosomal dysfunction and apoptosis.
  71. The role of ubiquitination in health and disease.
  72. Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis.
  73. TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.
  74. SIRT6 loss causes intervertebral disc degeneration in mice by promoting senescence and SASP status.
  75. The senescent marker p16INK4a enhances macrophage foam cells formation.
  76. Environmentally relevant concentrations of perfluorobutane sulfonate impair locomotion behaviors and healthspan by downregulating mitophagy in C. elegans.
  77. Deoxypodophyllotoxin Mediates Autophagy Death through Inhibition of GRP78 in Human Osteosarcoma.
  78. Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
  79. Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection.
  80. The dual role of ATG7: Regulation of autophagy and apoptosis in porcine ovarian follicular granulosa cells.
  81. Thioredoxin C of Streptococcus suis serotype 2 contributes to virulence by inducing antioxidative stress and inhibiting autophagy via the MSR1/PI3K-Akt-mTOR pathway in macrophages.
  82. Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.
  83. SAL protects endothelial cells from H2O2-induced endothelial dysfunction: Regulation of inflammation and autophagy by EZH2.
  84. Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
  85. Stress granule formation enables anchorage-independence survival in cancer cells.
  86. FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.
  87. TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M.
  88. mTOR activity paces human blastocyst stage developmental progression.
  1. FEBS J. 2024 Sep 26.
    Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.
    Phineas Smith, Bernadette Carroll.
      Ageing is defined as the progressive loss of tissue function and regenerative capacity and is caused by both intrinsic factors i.e. the natural accumulation of damage, and extrinsic factors i.e. damage from environmental stressors. Cellular senescence, in brief, is an irreversible exit from the cell cycle that occurs primarily in response to excessive cellular damage, such as from ultraviolet (UV) exposure and oxidative stress, and it has been comprehensively demonstrated to contribute to tissue and organismal ageing. In this review, we will focus on the skin, an organ which acts as an essential protective barrier against injury, insults, and infection. We will explore the evidence for the existence and contribution of cellular senescence to skin ageing. We discuss the known molecular mechanisms driving senescence in the skin, with a focus on the dysregulation of the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1). We explore the interplay of dysregulated mTORC1 with lysosomes and how they contribute to senescence phenotypes.
    Keywords:  ageing; lysosome; mTORC1; senescence; skin
    DOI:  https://doi.org/10.1111/febs.17281
  2. Free Radic Biol Med. 2024 Sep 25. pii: S0891-5849(24)00675-0. [Epub ahead of print]
    Regulation of mitochondria-lysosome interactions in skeletal muscle during exercise, disuse, and aging.
    N Moradi, V C Sanfrancesco, S Champsi, D A Hood.
      Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.028
  3. Cells. 2024 Sep 21. pii: 1587. [Epub ahead of print]13(18):
    Locked in Structure: Sestrin and GATOR-A Billion-Year Marriage.
    Alexander Haidurov, Andrei V Budanov.
      Sestrins are a conserved family of stress-responsive proteins that play a crucial role in cellular metabolism, stress response, and ageing. Vertebrates have three Sestrin genes (SESN1, SESN2, and SESN3), while invertebrates encode only one. Initially identified as antioxidant proteins that regulate cell viability, Sestrins are now recognised as crucial inhibitors of the mechanistic target of rapamycin complex 1 kinase (mTORC1), a central regulator of anabolism, cell growth, and autophagy. Sestrins suppress mTORC1 through an inhibitory interaction with the GATOR2 protein complex, which, in concert with GATOR1, signals to inhibit the lysosomal docking of mTORC1. A leucine-binding pocket (LBP) is found in most vertebrate Sestrins, and when bound with leucine, Sestrins do not bind GATOR2, prompting mTORC1 activation. This review examines the evolutionary conservation of Sestrins and their functional motifs, focusing on their origins and development. We highlight that the most conserved regions of Sestrins are those involved in GATOR2 binding, and while analogues of Sestrins exist in prokaryotes, the unique feature of eukaryotic Sestrins is their structural presentation of GATOR2-binding motifs.
    Keywords:  GATOR2; SESN2; conservation; mTORC1
    DOI:  https://doi.org/10.3390/cells13181587
  4. Nat Commun. 2024 Sep 27. 15(1): 8334
    USF2 and TFEB compete in regulating lysosomal and autophagy genes.
    Jaebeom Kim, Young Suk Yu, Yehwa Choi, Do Hui Lee, Soobin Han, Junhee Kwon, Taichi Noda, Masahito Ikawa, Dongha Kim, Hyunkyung Kim, Andrea Ballabio, Keun Il Kim, Sung Hee Baek.
      Autophagy, a highly conserved self-digestion process crucial for cellular homeostasis, is triggered by various environmental signals, including nutrient scarcity. The regulation of lysosomal and autophagy-related processes is pivotal to maintaining cellular homeostasis and basal metabolism. The consequences of disrupting or diminishing lysosomal and autophagy systems have been investigated; however, information on the implications of hyperactivating lysosomal and autophagy genes on homeostasis is limited. Here, we present a mechanism of transcriptional repression involving upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes under nutrient-rich conditions. We find that USF2, together with HDAC1, binds to the CLEAR motif within lysosomal genes, thereby diminishing histone H3K27 acetylation, restricting chromatin accessibility, and downregulating lysosomal gene expression. Under starvation, USF2 competes with transcription factor EB (TFEB), a master transcriptional activator of lysosomal and autophagy genes, to bind to target gene promoters in a phosphorylation-dependent manner. The GSK3β-mediated phosphorylation of the USF2 S155 site governs USF2 DNA-binding activity, which is involved in lysosomal gene repression. These findings have potential applications in the treatment of protein aggregation-associated diseases, including α1-antitrypsin deficiency. Notably, USF2 repression is a promising therapeutic strategy for lysosomal and autophagy-related diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52600-2
  5. Autophagy. 2024 Sep 26.
    Quality control of mitochondria involves lysosomes in multiple definitive ways.
    Xiaowen Ma, Wen-Xing Ding.
      Mitochondria are crucial organelles in maintaining cellular homeostasis. They are involved in processes such as energy production, metabolism of lipids and glucose, and cell death regulation. Mitochondrial dysfunction can lead to various health issues such as aging, cancer, neurodegenerative diseases, and chronic liver diseases. While mitophagy is the main process for getting rid of excess or damaged mitochondria, there are additional mechanisms for preserving mitochondrial quality. One such alternative mechanism we have discovered is a hybrid organelle called mitochondrial-lysosome-related-organelle (MLRO), which functions independently of the typical autophagy process. More recently, another type of vesicle called vesicle derived from the inner mitochondrial membrane (VDIM) has been identified to break down the inner mitochondrial membrane without involving the standard autophagy pathway. In this article, we will delve into the similarities and differences between MLRO and VDIM, including their structure, regulation, and relevance to human diseases.
    Keywords:  Autophagy; DNM1L/DRP1; MLRO; VDIM; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2408712
  6. Autophagy. 2024 Sep 26.
    An interplay between biomolecular condensates and SNARE proteins regulates plant autophagy.
    Ruixi Li, Lei Pang.
      A recent study in our group reports a new "condensates to VPS41-associated phagic vacuole (VAPVs) conversion pathway" that is essential for macroautophagy/autophagy degradation in plant cells. Here, we compare the autophagy process between plants and other eukaryotic systems and discuss the potential roles of biomolecular condensates and synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins in plant autophagy.
    Keywords:  Autophagy; SNARE; VPS41; biomolecular condensates; membrane remodeling
    DOI:  https://doi.org/10.1080/15548627.2024.2408188
  7. Autophagy. 2024 Sep 26.
    SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB.
    Qin Xia, Xuan Liu, Lu Zhong, Jun Qu, Lei Dong.
      The calcium-activated phosphatase PPP3/calcineurin dephosphorylates TFEB (transcription factor EB) to trigger its nuclear translocation and the activation of macroautophagic/autophagic targets. However, the detailed molecular mechanism regulating TFEB activation remains poorly understood. Here, we highlighted the importance of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) in the activation of TFEB for lysosomal homeostasis. SMURF1 deficiency prevents the calcium-triggered ubiquitination of the catalytic subunit of PPP3/calcineurin in a manner consistent with defective autophagic degradation of damaged lysosomes. Mechanically, PPP3CB/CNA2 plays a bridging role in the recruitment of SMURF1 by LGALS3 (galectin 3) upon lysosome damage. Importantly, PPP3CB increases the dissociation of the N-terminal tail (NT) and C-terminal carbohydrate-recognition domain (CRD) of LGALS3, which may promote the formation of open conformers in a PPP3CB dephosphorylation activity-dependent manner. In addition, PPP3CB is ubiquitinated at lysine 146 by the recruited SMURF1 in response to intracellular calcium stimulation. The K63-linked ubiquitination of PPP3CB enhances the recruitment of TFEB. Moreover, TFEB directly interacts with both PPP3CB and the regulatory subunit PPP3R1 which facilitate the conformational correction of TFEB for its activation for the transcription of TFEB-targeted genes. Altogether, our results highlighted a critical mechanism for the regulation of PPP3/calcineurin activity via its ubiquitin ligase SMURF1 in response to lysosomal membrane damage, which may account for a potential target for the treatment of stress-related diseases.
    Keywords:  Autophagy; PPP3/calcineurin; SMURF1; TFEB; lysosomal homeostasis
    DOI:  https://doi.org/10.1080/15548627.2024.2407709
  8. Autoimmun Rev. 2024 Sep 19. pii: S1568-9972(24)00135-6. [Epub ahead of print]23(11): 103644
    Inclusion body myositis: Correcting impaired mitochondrial and lysosomal autophagy as a potential therapeutic strategy.
    Stefen Brady, Joanna Poulton, Sylviane Muller.
      Inclusion body myositis (IBM) is a late onset sporadic myopathy with a characteristic clinical presentation, but as yet unknown aetiology or effective treatment. Typical clinical features are early predominant asymmetric weakness of finger flexor and knee extensor muscles. Muscle biopsy shows endomysial inflammatory infiltrate, mitochondrial changes, and protein aggregation. Proteostasis (protein turnover) appears to be impaired, linked to potentially dysregulated chaperone-mediated autophagy and mitophagy (a type of mitochondrial quality control). In this review, we bring together the most recent clinical and biological data describing IBM. We then address the question of diagnosing this pathology and the relevance of the current biological markers that characterize IBM. In these descriptions, we put a particular emphasis on data related to the deregulation of autophagic processes and to the mitochondrial-lysosomal crosstalk. Finally, after a short description of current treatments, an overview is provided pointing towards novel therapeutic targets and emerging regulatory molecules that are being explored for treating IBM. Special attention is paid to autophagy inhibitors that may offer innovative breakthrough therapies for patients with IBM.
    Keywords:  Autoimmunity; Autophagy; Idiopathic inflammatory myopathies; Inclusion body myositis; Mitochondrial disease; Novel treatment
    DOI:  https://doi.org/10.1016/j.autrev.2024.103644
  9. Front Cell Dev Biol. 2024 ;12 1460061
    Fast and quantitative mitophagy assessment by flow cytometry using the mito-QC reporter.
    Juan Ignacio Jiménez-Loygorri, Carlos Jiménez-García, Álvaro Viedma-Poyatos, Patricia Boya.
      Mitochondrial quality control is finely tuned by mitophagy, the selective degradation of mitochondria through autophagy, and mitochondrial biogenesis. Removal of damaged mitochondria is essential to preserve cellular bioenergetics and prevent detrimental events such as sustained mitoROS production, pro-apoptotic cytochrome c release or mtDNA leakage. The array of tools available to study mitophagy is very limited but in constant development. Almost a decade ago, we developed a method to assess mitophagy flux using MitoTracker Deep Red in combination with lysosomal inhibitors. Now, using the novel tandem-fluorescence reporter mito-QC (mCherry-GFP-FIS1101-152) that allows to differentiate between healthy mitochondria (mCherry+GFP+) and mitolysosomes (mCherry+GFP-), we have developed a robust and quantitative method to assess mitophagy by flow cytometry. This approach has been validated in ARPE-19 cells using PINK1/Parkin-dependent (CCCP) and PINK1/Parkin-independent (DFP) positive controls and complementary techniques. Furthermore, we show that the mito-QC reporter can be multiplexed, especially if using spectral flow cytometry, to simultaneously study other cellular parameters such as viability or ROS production. Using this technique, we evaluated and characterized two prospective mitophagy inducers and further dissected their mechanism of action. Finally, using mito-QC reporter mice, we developed a protocol to measure mitophagy levels in the retina ex vivo. This novel methodology will propel mitophagy research forward and accelerate the discovery of novel mitophagy modulators.
    Keywords:  FACS; Fisetin; SI; autophagy; mitochondria; phenanthroline; retina
    DOI:  https://doi.org/10.3389/fcell.2024.1460061
  10. Methods Mol Biol. 2024 Sep 28.
    Assessing Autophagy Flux in Glioblastoma Temozolomide Resistant Cells.
    Courtney Clark, Amir Barzegar Behrooz, Marco Cordani, Shahla Shojaei, Saeid Ghavami.
      Autophagy is a critical cellular process involved in the degradation and recycling of cytoplasmic components, playing a dual role in cancer by either promoting cell survival or facilitating cell death. In glioblastoma (GB), autophagy has been implicated in resistance to the chemotherapeutic agent temozolomide (TMZ). This study presents a novel method to accurately measure autophagy flux in TMZ-resistant glioblastoma cells, combining advanced imaging techniques with biochemical assays. By quantifying key autophagy markers such as LC3-II and SQSTM1, our approach provides detailed insights into the dynamic processes of autophagosome formation and clearance under therapeutic stress. This method advances our understanding of autophagy in GB chemoresistance and has significant implications for the development of autophagy-targeted therapies. The ability to monitor and manipulate autophagy flux in real time offers a promising avenue for monitoring and understanding TMZ resistance and improving patient outcomes in glioblastoma treatment.
    Keywords:  Autophagy flux; Glioblastoma; LC3-II; SQSTM1 degradation; Temozolomide resistance
    DOI:  https://doi.org/10.1007/7651_2024_571
  11. Front Cell Infect Microbiol. 2024 ;14 1442995
    Autophagy: the misty lands of Chlamydia trachomatis infection.
    Shan Zhang, Yufei Jiang, Yonghui Yu, Xuan Ouyang, Dongsheng Zhou, Yajun Song, Jun Jiao.
      Chlamydia are Gram-negative, obligate intracellular bacterial pathogens that infect eukaryotic cells and reside within a host-derived vacuole known as the inclusion. To facilitate intracellular replication, these bacteria must engage in host-pathogen interactions to obtain nutrients and membranes required for the growth of the inclusion, thereby sustaining prolonged bacterial colonization. Autophagy is a highly conserved process that delivers cytoplasmic substrates to the lysosome for degradation. Pathogens have developed strategies to manipulate and/or exploit autophagy to promote their replication and persistence. This review delineates recent advances in elucidating the interplay between Chlamydia trachomatis infection and autophagy in recent years, emphasizing the intricate strategies employed by both the Chlamydia pathogens and host cells. Gaining a deeper understanding of these interactions could unveil novel strategies for the prevention and treatment of Chlamydia infection.
    Keywords:  Chlamydia trachomatis; LC3; autophagy; inclusion; mitophagy
    DOI:  https://doi.org/10.3389/fcimb.2024.1442995
  12. Reprod Toxicol. 2024 Sep 19. pii: S0890-6238(24)00187-4. [Epub ahead of print] 108720
    The Convergence of mTOR Signaling and Ethanol Teratogenesis.
    Scott K Tucker, Johann K Eberhart.
      Ethanol is one of the most common teratogens and causes of human developmental disabilities. Fetal alcohol spectrum disorders (FASD), which describes the wide range of deficits due to prenatal ethanol exposure, are estimated to affect between 1.1% to 5.0% of births in the United States. Ethanol dysregulates numerous cellular mechanisms such as programmed cell death (apoptosis), protein synthesis, autophagy, and various aspects of cell signaling, all of which contribute to FASD. The mechanistic target of rapamycin (mTOR) regulates these cellular mechanisms via sensing of nutrients like amino acids and glucose, DNA damage, and growth factor signaling. Despite an extensive literature on ethanol teratogenesis and mTOR signaling, there has been less attention paid to their interaction. Here, we discuss the impact of ethanol teratogenesis on mTORC1's ability to coordinate growth factor and amino acid sensing with protein synthesis, autophagy, and apoptosis. Notably, the effect of ethanol exposure on mTOR signaling depends on the timing and dose of ethanol as well as the system studied. Overall, the overlap between the functions of mTORC1 and the phenotypes observed in FASD suggest a mechanistic interaction. However, more work is required to fully understand the impact of ethanol teratogenesis on mTOR signaling.
    Keywords:  Alcohol; FASD; apoptosis; autophagy; growth factor signaling; mTOR; metabolism; protein synthesis
    DOI:  https://doi.org/10.1016/j.reprotox.2024.108720
  13. Cell Chem Biol. 2024 Sep 19. pii: S2451-9456(24)00356-8. [Epub ahead of print]31(9): 1627-1635
    Membrane remodeling via ubiquitin-mediated pathways.
    Anne-Claire Jacomin, Ivan Dikic.
      The dynamic process of membrane shaping and remodeling plays a vital role in cellular functions, with proteins and cellular membranes interacting intricately to adapt to various cellular needs and environmental cues. Ubiquitination-a posttranslational modification-was shown to be essential in regulating membrane structure and shape. It influences virtually all pathways relying on cellular membranes, such as endocytosis and autophagy by directing protein degradation, sorting, and oligomerization. Ubiquitin is mostly known as a protein modifier; however, it was reported that ubiquitin and ubiquitin-like proteins can associate directly with lipids, affecting membrane curvature and dynamics. In this review, we summarize some of the current knowledge on ubiquitin-mediated membrane remodeling in the context of endocytosis, autophagy, and ER-phagy.
    Keywords:  ER remodeling; ER-phagy; ESCRT; autophagy; membrane remodeling; ubiquitin
    DOI:  https://doi.org/10.1016/j.chembiol.2024.08.007
  14. bioRxiv. 2024 Sep 10. pii: 2024.09.09.611939. [Epub ahead of print]
    Biomolecular condensation of ERC1 recruits ATG8 and NBR1 to drive autophagosome formation for plant heat tolerance.
    Ka Kit Chung, Ziwei Zhao, Kai Ching Law, Juncai Ma, Cheuk Him Chiang, Kwan Ho Leung, Ruben Shrestha, Yixin Wu, Chaorui Li, Ka Ming Lee, Lei Feng, Xibao Li, Kam Bo Wong, Shou-Ling Xu, Caiji Gao, Xiaohong Zhuang.
      Macroautophagy (hereafter autophagy) is essential for cells to respond to nutrient stress by delivering cytosolic contents to vacuoles for degradation via the formation of a multi-layer vesicle named autophagosome. A set of autophagy-related (ATG) regulators are recruited to the phagophore assembly site for the initiation of phagophore, as well as its expansion and closure and subsequent delivery into the vacuole. However, it remains elusive that how the phagophore assembly is regulated under different stress conditions. Here, we described an unknown Arabidopsis (Arabidopsis thaliana) cytosolic ATG8-interaction protein family (ERC1/2), that binds ATG8 and NBR1 to promote autophagy. ERC1 proteins translocate to the phagophore membrane and develop into classical ring-like autophagosomes upon autophagic induction. However, ERC1 proteins form large droplets together with ATG8e proteins when in the absence of ATG8 lipidation activity. We described the property of these structures as phase-separated membraneless condensates by solving the in vivo organization with spatial and temporal resolution. Moreover, ERC1 condensates elicits a strong recruitment of the autophagic receptor NBR1. Loss of ERC1 suppressed NBR1 turnover and attenuated plant tolerance to heat stress condition. This work provides novel insights into the mechanical principle of phagophore initiation via an unreported ERC1-mediated biomolecular condensation for heat tolerance in Arabidopsis .
    DOI:  https://doi.org/10.1101/2024.09.09.611939
  15. Autophagy. 2024 Sep 24.
    Were the autophagosome-lysosome/vacuole fusion models illustrated correctly in the literature?
    Yongheng Liang.
      Exploration of autophagy in different species has become a hotspot in cell biology in the past decades. Macroautophagy (hereafter, autophagy) is the most widely studied type. One of the hallmarks of autophagy is the fusion of the outer membrane (OM) of a closed double-membrane mature autophagosome (AP) with the lysosomal/vacuolar single membrane. Most researchers in the autophagy field agree upon this description. However, AP-lysosome/vacuole fusion models that do not follow this description frequently appear in the literature, even published in some prestigious journals until now. Some of the misrepresented models are from autophagy laboratories with brilliant publication records. These flaws should be addressed as a public announcement in the autophagy field to avoid spreading misinformation. The editors and reviewers are the guardians to ensure correct models.
    Keywords:  Autophagosome-lysosome/vacuole fusion; double membrane; inner membrane; lysosomal/vacuolar membrane; outer membrane; single membrane
    DOI:  https://doi.org/10.1080/15548627.2024.2405954
  16. Cancer Radiother. 2024 Sep 25. pii: S1278-3218(24)00120-3. [Epub ahead of print]
    Role of autophagy in modulating tumor cell radiosensitivity: Exploring pharmacological interventions for glioblastoma multiforme treatment.
    Pierre Bischoff, Jolie Bou-Gharios, Georges Noël, Hélène Burckel.
      Autophagy is an innate cellular process characterized by self-digestion, wherein cells degrade or recycle aged proteins, misfolded proteins, and damaged organelles via lysosomal pathways. Its crucial role in maintaining cellular homeostasis, ensuring development and survival is well established. In the context of cancer therapy, autophagy's importance is firmly recognized, given its critical impact on treatment efficacy. Following radiotherapy, several factors can modulate autophagy including parameters related to radiation type and delivery methods. The concomitant use of chemotherapy with radiotherapy further influences autophagy, potentially either enhancing radiosensitivity or promoting radioresistance. This review article discusses some pharmacological agents and drugs capable of modulating autophagy levels in conjunction with radiation in tumor cells, with a focus on those identified as potential radiosensitizers in glioblastoma multiforme treatment.
    Keywords:  Autophagie; Autophagy; Glioblastoma; Glioblastome; Ionizing radiation; Radiosensibilisation; Radiosensitization; Rayonnement ionisant
    DOI:  https://doi.org/10.1016/j.canrad.2024.06.001
  17. FASEB J. 2024 Oct 15. 38(19): e70059
    White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells.
    Sunny Hoi-Sang Yeung, Ralph Hon-Sun Lee, Gerald Wai-Yeung Cheng, Iris Wai-Ting Ma, Julia Kofler, Candice Kent, Fulin Ma, Karl Herrup, Myriam Fornage, Ken Arai, Kai-Hei Tse.
      White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. Genome-wide association studies identified TRIM47 at the 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found highly expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we predicted a highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription, and vacuole formation. Together, we demonstrate that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.
    Keywords:   TRIM47 ; TRIM family; autophagy; brain endothelial cells; white matter hyperintensity
    DOI:  https://doi.org/10.1096/fj.202400689RR
  18. Autophagy. 2024 Sep 24.
    ATP6V1D drives hepatocellular carcinoma stemness and progression via both lysosome acidification-dependent and -independent mechanisms.
    Zhijie Xu, Ruiyang Liu, Haoying Ke, Fuyuan Xu, Pengfei Yang, Weiyu Zhang, Yi Zhan, Zhiju Zhao, Fei Xiao.
      Metabolic reprogramming is pivotal in cancer stem cell (CSC) self-renewal. However, the intricate regulatory mechanisms governing the crosstalk between metabolic reprogramming and liver CSCs remain elusive. Here, using a metabolic CRISPR-Cas9 knockout screen, we identify ATP6V1D, a subunit of the vacuolar-type H+-translocating ATPase (V-ATPase), as a key metabolic regulator of hepatocellular carcinoma (HCC) stemness. Elevated ATP6V1D expression correlates with poor clinical outcomes in HCC patients. ATP6V1D knockdown inhibits HCC stemness and malignant progression both in vitro and in vivo. Mechanistically, ATP6V1D enhances HCC stemness and progression by maintaining macroautophagic/autophagic flux. Specifically, ATP6V1D not only promotes lysosomal acidification, but also enhances the interaction between CHMP4B and IST1 to foster ESCRT-III complex assembly, thereby facilitating autophagosome-lysosome fusion to maintain autophagic flux. Moreover, silencing CHMP4B or IST1 attenuates HCC stemness and progression. Notably, low-dose bafilomycin A1 targeting the V-ATPase complex shows promise as a potential therapeutic strategy for HCC. In conclusion, our study highlights the critical role of ATP6V1D in driving HCC stemness and progression via the autophagy-lysosomal pathway, providing novel therapeutic targets and approaches for HCC treatment.
    Keywords:  ATP6V1D; CRISPR-Cas9 knockout screen; V-ATPase; autophagy; cancer stem cell; hepatocellular carcinoma
    DOI:  https://doi.org/10.1080/15548627.2024.2406186
  19. Clin Sci (Lond). 2024 Sep 23. pii: CS20241144. [Epub ahead of print]
    IFN-γ induces acute graft-versus-host disease by promoting HMGB1-mediated nuclear-to-cytoplasm translocation and autophagic degradation of p53.
    Shiyu Wang, Tingting Cheng, Xu Chen, Cong Zeng, Wei Qin, Yajing Xu.
      Acute graft-versus-host disease (aGVHD) poses a significant impediment to achieving a more favourable therapeutic outcome in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our prior investigations disclosed a correlation between p53 downregulation in CD4+ T cells and the occurrence of aGVHD. Notably, the insufficiency of the CCCTC-binding factor (CTCF) emerged as a pivotal factor in repressing p53 expression. However, the existence of additional mechanisms contributing to the reduction in p53 expression remains unclear. Interferon (IFN)-γ, a pivotal proinflammatory cytokine, assumes a crucial role in regulating alloreactive T cell responses and plays a complex part in aGVHD development. IFN-γ has the capacity to induce autophagy, a vital catabolic process facilitating protein degradation, in various cell types. Presently, whether IFN-γ participates in the development of aGVHD by instigating the autophagic degradation of p53 in CD4+ T cells remains an unresolved question. In this study, we demonstrated that heightened levels of IFN-γ in the plasma during aGVHD promoted the activation, proliferation, and autophagic activity of CD4+ T cells. Furthermore, IFN-γ induced the nuclear-to-cytoplasm translocation and autophagy-dependent degradation of p53 in CD4+ T cells. The translocation and autophagic degradation of p53 were contingent upon HMGB1, which underwent upregulation and translocation from the nucleus to the cytoplasm following IFN-γ stimulation. In conclusion, our data unveil a novel mechanism underlying p53 deficiency in CD4+ T cells among aGVHD patients. This deficiency is induced by IFN-γ and relies on autophagy, establishing a link between IFN-γ, HMGB1-mediated translocation, and the autophagic degradation of p53.
    Keywords:  CD4+ T cells; HMGB1; IFN-γ; aGVHD; autophagy; p53
    DOI:  https://doi.org/10.1042/CS20241144
  20. CNS Neurol Disord Drug Targets. 2024 Sep 18.
    Exploring the Potential of Herbal Compounds as Autophagy Modulators in Alzheimer's Disease: A Comprehensive Review.
    Ekta Yadav, Ashok Kumar Mandal, Ajay Kumar Sah, Sandesh Poudel, Prateek Pathak, Habibullah Khalilullah, Mariusz Jaremko, Abdul-Hamid Emwas, Pankajkumar Yadav, Amita Verma.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder that causes atrophy of brain cells, leading to their death, and has become a leading cause of death in aging populations worldwide. AD is characterized by β-amyloid (Aβ) deposition and tau phosphorylation in neural tissues, but the precise pathophysiology of the disease is still obscure. Autophagy is an evolutionarily targeted mechanism that is necessary for the elimination of neuronal and glial misfolded proteins as well as proteins. It also plays an essential role in synaptic plasticity. The aberrant autophagy primarily influences the process of aging and neurodegeneration. Autophagy significantly influences how Aβ and tau function physiologically, therefore, atypical autophagy is expected to perform an important role in Aβ deposition and tau phosphorylation characteristic in the development of AD. Bioactive phytoconstituents could majorly contribute as a natural yet effective alternative approach to slow down the progression of neurodegeneration and promote the active aging process in elderly patients. Over the recent years, it is well evidenced that different secondary metabolites including polyphenols, alkaloids, terpenes, and phenols exhibited neuroprotective effects, and attenuated brain damage, and cognitive impairment in vitro as well as in vivo. Additionally, the underlying mechanism of action shared by them is the regulation of competent autophagy via the removal of aggregated protein and mitochondrial dysfunction. The present article is structured as a reference for researchers keen to investigate and assess the new natural compound-mediated therapeutic approach for AD treatment through the modulation of autophagy.
    Keywords:  Alzheimer’s autophagy; TFEB.; mTOR; natural compounds; neurodegenerative diseases
    DOI:  https://doi.org/10.2174/0118715273298025240905130205
  21. Discov Nano. 2024 Sep 23. 19(1): 154
    Polyvinylpyrrolidone capped silver nanoparticles enhance the autophagic clearance of Acinetobacter baumannii from human pulmonary cells.
    Saroj Sharma, Vishvanath Tiwari.
      Acinetobacter baumannii, an opportunistic pathogen has shown an upsurge in its multi-drug resistant isolates. OmpA of A. baumannii induces incomplete autophagy and apoptosis in host cells. Various therapeutic alternatives are under investigation against A. baumannii. Here, the major emphasis has been laid on comparing the efficacy of AgNP with different capping agents. OmpA targeted lead, Ivermectin capped AgNP (IVM-AgNP) has been compared with the antibacterial polyvinylpyrrolidone capped AgNP (PVP-AgNP) for their role in the modulations of host autophagy. Upregulation of p62 and LC3B confirmed by real-time PCR analysis indicated an increased autophagic flux upon the treatment with AgNPs. The elongation and closure of autophagic vacuoles was also supported by upregulated Atg genes (Atg4, Atg3, Atg5) in A. baumannii infected cells after treatment with AgNP. Autophagic flux increased on treatment with PVP-AgNP as suggested by the rise in mcherryLC3B fluorescence in A549 cells treated with PVP-AgNP as compared to the GFP-LC3B of IVM-AgNP. This suggests that PVP-AgNP treatment more effectively promotes the elongation and maturation stages of autophagy by increasing autophagic flux. These results indicate that capped AgNPs have the efficiency to revert the incomplete autophagy induced by A. baumannii back to normal autophagic levels.
    Keywords:   Acinetobacter baumannii ; Autophagosome; Autophagy; ESKAPE pathogens; Extreme drug resistance; Fluorescence microscopy; Multi-drug resistance; Outer membrane protein A; Real-time PCR; Silver nanoparticles
    DOI:  https://doi.org/10.1186/s11671-024-04107-4
  22. Mol Biol Cell. 2024 Sep 25. mbcE23120470
    Med13 is required for efficient P-body recruitment and autophagic degradation of Edc3 following nitrogen starvation.
    Sara E Hanley, Stephen D Willis, Brittany Friedson, Katrina F Cooper.
      The Cdk8 kinase module (CKM), a conserved, detachable unit of the Mediator complex, plays a vital role in regulating transcription and communicating stress signals from the nucleus to other organelles. Here, we describe a new transcription-independent role for Med13, a CKM scaffold protein, following nitrogen starvation. In S. cerevisiae, nitrogen starvation triggers Med13 to translocate to the cytoplasm. This stress also induces the assembly of conserved membraneless condensates called processing bodies (P-bodies) that dynamically sequester translationally inactive messenger ribonucleoprotein particles (mRNPs). Cytosolic Med13 co-localizes with P-bodies, where it helps recruit Edc3, a highly conserved decapping activator and P-body assembly factor, into these conserved ribonucleoprotein granules. Moreover, Med13 orchestrates the autophagic degradation of Edc3 through a selective cargo-hitchhiking autophagy pathway that utilizes Ksp1 as its autophagic receptor protein. In contrast, the autophagic degradation of Xrn1, another conserved P-body assembly factor, is Med13 independent. These results place Med13 as a new player in P-body assembly and regulation following nitrogen starvation. They support a model in which Med13 acts as a conduit between P-bodies and phagophores, two condensates that use liquid-liquid phase separation in their assembly.
    DOI:  https://doi.org/10.1091/mbc.E23-12-0470
  23. Reproduction. 2024 Sep 01. pii: REP-24-0219. [Epub ahead of print]
    Hypoxia-induced autophagy inhibits myometrial proliferation in pregnant mice via the mTOR pathway in vitro.
    Xingxing Wang, Huihui Yu, Xuan Li, Ruixian Tian, Chenyi Xu, Tengteng Li, Jiajia Fei, Xue Du, Zongzhi Yin.
      Hypoxia is closely associated with physiological and pathological conditions in the human body, and the myometrium is affected by hypoxic stress during pregnancy and delivery. Autophagy is a catabolic pathway involved in the regulation of apoptosis, proliferation and migration of a variety of cells, which can be activated under hypoxia. However, the mechanism and function of autophagy in uterine smooth muscle cells remained unclear. The aim of this study was to investigate the changes of autophagy in pregnant uterine smooth muscle cells (pUSMCs) under hypoxia and the effect of autophagy on myometrial cells proliferation during pregnancy. In this study, primary uterine smooth muscle cells were isolated from mice in late pregnancy and cultured under normoxic and hypoxic conditions respectively. Western blotting and immunofluorescence were used to detect the expression levels of autophagy-related proteins LC3B, P62, mTOR and p-mTOR under different culture conditions. Cell proliferation was assessed by CCK-8 assay. In addition, 3-Methyladenine (3-MA) was used to inhibit autophagy in hypoxia-treated pUSMCs and MHY1485 was used to activate mTOR. Studies have confirmed that under hypoxic conditions, autophagy is enhanced and cell proliferative viability is reduced in pUSMCs. Autophagy inhibitor 3-MA restored cell proliferation inhibited by hypoxia. Furthermore, hypoxia in pUSMCs led to a downregulation of p-mTOR/mTOR levels. The mTOR activator MHY1485 inhibited autophagy by preventing the binding of autophagosomes to lysosomes and reversed the hypoxia-induced inhibition of cell proliferation. Collectively, our results indicate that hypoxia upregulates autophagy through the mTOR pathway in pUSMCs, thereby inhibiting cell proliferation during pregnancy.
    DOI:  https://doi.org/10.1530/REP-24-0219
  24. Mater Today Bio. 2024 Oct;28 101225
    Nanoscale ZnO doping in prosthetic polymers mitigate wear particle-induced inflammation and osteolysis through inhibiting macrophage secretory autophagy.
    Zhuocheng Lyu, Xiangchao Meng, Fei Hu, Yuezhou Wu, Yurun Ding, Teng Long, Xinhua Qu, You Wang.
      Wear particles produced by joint replacements induce inflammatory responses that lead to periprosthetic osteolysis and aseptic loosening. However, the precise mechanisms driving wear particle-induced osteolysis are not fully understood. Recent evidence suggests that autophagy, a cellular degradation process, plays a significant role in this pathology. This study aimed to clarify the role of autophagy in mediating inflammation and osteolysis triggered by wear particles and to evaluate the therapeutic potential of zinc oxide nanoparticles (ZnO NPs). We incorporated ZnO into the prosthetic material itself, ensuring that the wear particles inherently carried ZnO, providing a targeted and sustained intervention. Our findings reveal that polymer wear particles induce excessive autophagic activity, which is closely associated with increased inflammation and osteolysis. We identified secretory autophagy as a key mechanism for IL-1β secretion, exacerbating osteolysis. Both in vitro and in vivo experiments demonstrated that ZnO-doped particles significantly inhibit autophagic overactivation, thereby reducing inflammation and osteolysis. In summary, this study establishes secretory autophagy as a critical mechanism in wear particle-induced osteolysis and highlights the potential of ZnO-doped prosthetic polymers for targeted, sustained mitigation of periprosthetic osteolysis.
    Keywords:  Aseptic loosening; Macrophages; Osteoclastogenesis; Periprosthetic osteolysis; Secretory autophagy; Wear particle-induced inflammation
    DOI:  https://doi.org/10.1016/j.mtbio.2024.101225
  25. Acta Neuropathol. 2024 Sep 24. 148(1): 46
    Tau accumulation is cleared by the induced expression of VCP via autophagy.
    Hoi-Khoanh Giong, Seung Jae Hyeon, Jae-Geun Lee, Hyun-Ju Cho, Uiyeol Park, Thor D Stein, Junghee Lee, Kweon Yu, Hoon Ryu, Jeong-Soo Lee.
      Tauopathy, including frontotemporal lobar dementia and Alzheimer's disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human TAUP301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where VCP overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer's disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.
    Keywords:  Autophagy; Tau clearance; Tau-overexpressing animal models; VCP/p97
    DOI:  https://doi.org/10.1007/s00401-024-02804-z
  26. J Invest Dermatol. 2024 Sep 25. pii: S0022-202X(24)02151-1. [Epub ahead of print]
    Significant Role of Autophagy in Melanosomal Degradation of Dermal Macrophages - Therapeutic Insight Regarding Hyperpigmentation with Uncertain Etiology.
    Kisumi Takiguchi, Kazunori Yokoi, Daiki Murase, Masafumi Yokota, Keigo Kawabata, Yoshito Takahashi, Satoshi Minami, Shuhei Nakamura, Tamotsu Yoshimori, Rei Watanabe, Manabu Fujimoto, Atsushi Tanemura.
      
    Keywords:  Autophagy; Hyperpigmentation; Macrophage; Melanosome; Rapamycin
    DOI:  https://doi.org/10.1016/j.jid.2024.09.007
  27. Autophagy. 2024 Oct;20(10): 2221-2237
    PLK2-mediated phosphorylation of SQSTM1 S349 promotes aggregation of polyubiquitinated proteins upon proteasomal dysfunction.
    Yun-Da Chen, Xiu-Ping Lin, Zi-Lun Ruan, Mi Li, Xue-Mei Yi, Xu Zhang, Shu Li, Hong-Bing Shu.
      Dysregulation in protein homeostasis results in accumulation of protein aggregates, which are sequestered into dedicated insoluble compartments so-called inclusion bodies or aggresomes, where they are scavenged through different mechanisms to reduce proteotoxicity. The protein aggregates can be selectively scavenged by macroautophagy/autophagy called aggrephagy, which is mediated by the autophagic receptor SQSTM1. In this study, we have identified PLK2 as an important regulator of SQSTM1-mediated aggregation of polyubiquitinated proteins. PLK2 is upregulated following proteasome inhibition, and then associates with and phosphorylates SQSTM1 at S349. The phosphorylation of SQSTM1 S349 strengthens its binding to KEAP1, which is required for formation of large SQSTM1 aggregates/bodies upon proteasome inhibition. Our findings suggest that PLK2-mediated phosphorylation of SQSTM1 S349 represents a critical regulatory mechanism in SQSTM1-mediated aggregation of polyubiquitinated proteins.
    Keywords:  PLK2; Phosphorylation; SQSTM1/p62; polyubiquitination; proteasome; protein aggregation
    DOI:  https://doi.org/10.1080/15548627.2024.2361574
  28. Exp Neurol. 2024 Sep 24. pii: S0014-4886(24)00301-7. [Epub ahead of print] 114975
    TGN-020 ameliorates motor dysfunction post-spinal cord injury via enhancing astrocyte autophagy and mitigating inflammation by activating AQP4/PPAR-γ/mTOR pathway.
    Jundong Kong, Qiangqiang Zhang, Haohong Zheng, Diandong Tang, Li Fang, Shuaihao An, Jian Li, Zhongkai Fan.
      Spinal Cord Injury (SCI) is a severe condition that often leads to substantial neurological impairments. This study aimed to explore the role of Aquaporin-4 (AQP4) in regulating astrocyte autophagy and neuroinflammation post-SCI, as well as to evaluate the therapeutic potential of AQP4 inhibition using the specific inhibitor TGN-020. Using Western blot, CCK8 assays, immunofluorescence staining, histopathological assessments, and behavioral analyses, we investigated the effects of TGN-020 on SCI-induced alterations in autophagy, neuroinflammation, astrocyte proliferation, neuronal damage, and motor function recovery in both rat and astrocyte models. Our findings indicate that TGN-020 significantly enhances astrocyte autophagy, reduces neuroinflammation, thereby leading to mitigated astrocyte activation by suppressing AQP4 expression. These beneficial effects are associated with the activation of the peroxisome proliferator-activated receptor-γ/mammalian target of rapamycin (PPAR-γ/mTOR) signaling pathway. Notably, the introduction of the PPAR-γ specific inhibitor GW9662 abrogated the positive regulatory effects of TGN-020 on SCI-induced autophagy and neuroinflammation. Collectively, our in vivo and in vitro experiments demonstrate that TGN-020, by down-regulating AQP4, activates the PPAR-γ/mTOR pathway, ameliorates astrocyte autophagy, diminishes neuroinflammation, and ultimately enhances motor function recovery.
    Keywords:  Aquaporin-4; Autophagy; Inflammation; PPAR-γ/mTOR; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114975
  29. Front Immunol. 2024 ;15 1450487
    Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy.
    Beibei Liu, Ling Liu, Yang Liu.
      Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.
    Keywords:  autophagy; cancer progression; cell death; drug resistance; ferroptosis; tumor
    DOI:  https://doi.org/10.3389/fimmu.2024.1450487
  30. Cells. 2024 Sep 13. pii: 1537. [Epub ahead of print]13(18):
    Inhibition of Autophagy by Berbamine Hydrochloride Mitigates Tumor Immune Escape by Elevating MHC-I in Melanoma Cells.
    Jinhuan Xian, Leilei Gao, Zhenyang Ren, Yanjun Jiang, Junjun Pan, Zheng Ying, Zhenyuan Guo, Qingsong Du, Xu Zhao, He Jin, Hua Yi, Jieying Guan, Shan Hu.
      Impaired tumor cell antigen presentation contributes significantly to immune evasion. This study identifies Berbamine hydrochloride (Ber), a compound derived from traditional Chinese medicine, as an effective inhibitor of autophagy that enhances antigen presentation in tumor cells. Ber increases MHC-I-mediated antigen presentation in melanoma cells, improving recognition and elimination by CD8+ T cells. Mutation of Atg4b, which blocks autophagy, also raises MHC-I levels on the cell surface, and further treatment with Ber under these conditions does not increase MHC-I, indicating Ber's role in blocking autophagy to enhance MHC-I expression. Additionally, Ber treatment leads to the accumulation of autophagosomes, with elevated levels of LC3-II and p62, suggesting a disrupted autophagic flux. Fluorescence staining and co-localization analyses reveal that Ber likely inhibits lysosomal acidification without hindering autophagosome-lysosome fusion. Importantly, Ber treatment suppresses melanoma growth in mice and enhances CD8+ T cell infiltration, supporting its therapeutic potential. Our findings demonstrate that Ber disturbs late-stage autophagic flux through abnormal lysosomal acidification, enhancing MHC-I-mediated antigen presentation and curtailing tumor immune escape.
    Keywords:  Berbamine hydrochloride; MHC-I; antigen presentation; autophagy; tumor immune escape
    DOI:  https://doi.org/10.3390/cells13181537
  31. Cell Biochem Biophys. 2024 Sep 22.
    Chondrocyte Ferritinophagy as a Molecular Mechanism of Arthritis-A Narrative Review.
    Yong Liu, Chao Song, Silong Gao, Daqian Zhou, Jiale Lv, Yang Zhou, Liquan Wang, Houyin Shi, Fei Liu, Zhongwei Xiong, Yunqing Hou, Zongchao Liu.
      Osteoarthritis (OA) is a prevalent joint disease affecting orthopedic patients. Its incidence is steadily increasing, causing great economic hardship for individuals and society as a whole. OA is connected with risk factors such as genetics, obesity, and joint diseases; yet, its pathophysiology is still largely understood. At present, several cell death pathways govern the initiation and advancement of OA. It has been discovered that the onset and progression of OA are strongly associated with pyroptosis, senescence, apoptosis, ferroptosis, and autophagy. Ferroptosis and autophagy have not been well studied in OA, and elucidating their molecular mechanisms in chondrocytes is important for the diagnosis of OA. For this reason, we aim was reviewed recent national and international developments and provided an initial understanding of the molecular pathways underlying autophagy and ferroptosis in OA. We determined the reference period to be the last five years by searching for the keywords "osteoarthritis, mechanical stress, Pizeo1, ferroptosis, autophagy, ferritin autophagy" in the three databases of PUBMED, Web of Science, Google Scholar. We then screened irrelevant literature by reading the abstracts. Ferroptosis is a type of programmed cell death that is dependent on reactive oxygen species and Fe2+. It is primarily caused by processes linked to amino acid metabolism, lipid peroxidation, and iron metabolism. Furthermore, Piezoelectric mechanically sensitive ion channel assembly 1 (PIEZO1), which is triggered by mechanical stress, has been revealed to be intimately associated with ferroptosis events. It was found that mechanical injury triggers changes in the intracellular environment of articular chondrocytes (e.g., elevated levels of oxidative stress and increased inflammation) through PIEZO1, ultimately leading to iron death in chondrocytes. Therefore, we believe that PIEZO1 is a key initiator protein of iron death in chondrocytes. Widely present in eukaryotic cells, autophagy is a lysosome-dependent, evolutionarily conserved catabolic process that carries misfolded proteins, damaged organelles, and other macromolecules to lysosomes for breakdown and recycling. Throughout OA, autophagy is activated to differing degrees, indicating that autophagy may play a role in the development of OA. According to recent research, autophagy is a major factor in the process that leads cells to ferroptosis. Despite the notion of ferritinophagy being put forth, not much research has been done to clarify the connection between ferroptosis and autophagy in OA.
    Keywords:  Autophagy; Chondrocytes/Cartilage; Ferritinophagy; Ferroptosis; Mechanical stress; Osteoarthritis
    DOI:  https://doi.org/10.1007/s12013-024-01534-z
  32. Autophagy. 2024 Oct;20(10): 2164-2185
    Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.
    Hortense de Calbiac, Solène Renault, Grégoire Haouy, Vincent Jung, Kevin Roger, Qihui Zhou, Maria-Letizia Campanari, Loïc Chentout, Doris Lou Demy, Anca Marian, Nicolas Goudin, Dieter Edbauer, Chiara Guerrera, Sorana Ciura, Edor Kabashi.
      The GGGGCC hexanucleotide repeat expansion (HRE) of the C9orf72 gene is the most frequent cause of amyotrophic lateral sclerosis (ALS), a devastative neurodegenerative disease characterized by motor neuron degeneration. C9orf72 HRE is associated with lowered levels of C9orf72 expression and its translation results in the production of dipeptide-repeats (DPRs). To recapitulate C9orf72-related ALS disease in vivo, we developed a zebrafish model where we expressed glycine-proline (GP) DPR in a c9orf72 knockdown context. We report that C9orf72 gain- and loss-of-function properties act synergistically to induce motor neuron degeneration and paralysis with poly(GP) accumulating preferentially within motor neurons along with Sqstm1/p62 aggregation indicating macroautophagy/autophagy deficits. Poly(GP) levels were shown to accumulate upon c9orf72 downregulation and were comparable to levels assessed in autopsy samples of patients carrying C9orf72 HRE. Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Proteomics analysis of zebrafish-purified motor neurons unravels mitochondria dysfunction confirmed through a comparative analysis of previously published C9orf72 iPSC-derived motor neurons. Consistently, 3D-reconstructions of motor neuron demonstrate that poly(GP) aggregates colocalize to mitochondria, thus inducing their elongation and swelling and the failure of their processing by mitophagy, with mitophagy activation through urolithin A preventing locomotor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients.
    Keywords:  Amyotrophic lateral sclerosis; apoptosis; mitochondria; motor neuron; neurodegeneration; poly-GP
    DOI:  https://doi.org/10.1080/15548627.2024.2358736
  33. FASEB J. 2024 Sep 30. 38(18): e70072
    Homocysteine metabolites impair the PHF8/H4K20me1/mTOR/autophagy pathway by upregulating the expression of histone demethylase PHF8-targeting microRNAs in human vascular endothelial cells and mice.
    Łukasz Witucki, Hieronim Jakubowski.
      The inability to efficiently metabolize homocysteine (Hcy) due to nutritional and genetic deficiencies, leads to hyperhomocysteinemia (HHcy) and endothelial dysfunction, a hallmark of atherosclerosis which underpins cardiovascular disease (CVD). PHF8 is a histone demethylase that demethylates H4K20me1, which affects the mammalian target of rapamycin (mTOR) signaling and autophagy, processes that play important roles in CVD. PHF8 is regulated by microRNA (miR) such as miR-22-3p and miR-1229-3p. Biochemically, HHcy is characterized by elevated levels of Hcy, Hcy-thiolactone and N-Hcy-protein. Here, we examined the effects of these metabolites on miR-22-3p, miR-1229-3p, and their target PHF8, as well as on the downstream consequences of these effects on H4K20me1, mTOR-, and autophagy-related proteins and mRNAs expression in human umbilical vein endothelial cells (HUVEC). We found that treatments with N-Hcy-protein, Hcy-thiolactone, or Hcy upregulated miR-22-3p and miR-1229-3p, attenuated PHF8 expression, upregulated H4K20me1, mTOR, and phospho-mTOR. Autophagy-related proteins (BECN1, ATG5, ATG7, lipidated LC3-II, and LC3-II/LC3-I ratio) were significantly downregulated by at least one of these metabolites. We also found similar changes in the expression of miR-22-3p, Phf8, mTOR- and autophagy-related proteins/mRNAs in vivo in hearts of Cbs-/- mice, which show severe HHcy and endothelial dysfunction. Treatments with inhibitors of miR-22-3p or miR-1229-3p abrogated the effects of Hcy-thiolactone, N-Hcy-protein, and Hcy on miR expression and on PHF8, H4K20me1, mTOR-, and autophagy-related proteins/mRNAs in HUVEC. Taken together, these findings show that Hcy metabolites upregulate miR-22-3p and miR-1229-3p expression, which then dysregulate the PHF8/H4K20me1/mTOR/autophagy pathway, important for vascular homeostasis.
    DOI:  https://doi.org/10.1096/fj.202302116R
  34. EMBO Rep. 2024 Sep 25.
    Two distinct regulatory pathways govern Cct2-Atg8 binding in the process of solid aggrephagy.
    Yuting Chen, Zhaojie Liu, Yi Zhang, Miao Ye, Yingcong Chen, Jianhua Gao, Juan Song, Huan Yang, Choufei Wu, Weijing Yao, Xue Bai, Mingzhu Fan, Shan Feng, Yigang Wang, Liqin Zhang, Liang Ge, Du Feng, Cong Yi.
      CCT2 serves as an aggrephagy receptor that plays a crucial role in the clearance of solid aggregates, yet the underlying molecular mechanisms by which CCT2 regulates solid aggrephagy are not fully understood. Here we report that the binding of Cct2 to Atg8 is governed by two distinct regulatory mechanisms: Atg1-mediated Cct2 phosphorylation and the interaction between Cct2 and Atg11. Atg1 phosphorylates Cct2 at Ser412 and Ser470, and disruption of these phosphorylation sites impairs solid aggrephagy by hindering Cct2-Atg8 binding. Additionally, we observe that Atg11, an adaptor protein involved in selective autophagy, directly associates with Cct2 through its CC4 domain. Deficiency in this interaction significantly weakens the association of Cct2 with Atg8. The requirement of Atg1-mediated Cct2 phosphorylation and of Atg11 for CCT2-LC3C binding and subsequent aggrephagy is conserved in mammalian cells. These findings provide insights into the crucial roles of Atg1-mediated Cct2 phosphorylation and Atg11-Cct2 binding as key mediators governing the interaction between Cct2 and Atg8 during the process of solid aggrephagy.
    Keywords:  Atg1; Atg11; Cct2-Atg8 Binding; Phosphorylation; Solid Aggrephagy
    DOI:  https://doi.org/10.1038/s44319-024-00275-7
  35. Front Cell Infect Microbiol. 2024 ;14 1400068
    Complement C3 deposition restricts the proliferation of internalized Staphylococcus aureus by promoting autophagy.
    Yining Deng, Yunke Zhang, Tong Wu, Kang Niu, Xiaoyu Jiao, Wenge Ma, Chen Peng, Wenxue Wu.
      Complement C3 (C3) is usually deposited spontaneously on the surfaces of invading bacteria prior to internalization, but the impact of C3 coating on cellular responses is largely unknown. Staphylococcus aureus (S. aureus) is a facultative intracellular pathogen that subverts autophagy and replicates in both phagocytic and nonphagocytic cells. In the present study, we deposited C3 components on the surface of S. aureus by complement opsonization before cell infection and confirmed that C3-coatings remained on the surface of the bacteria after they have invaded the cells, suggesting S. aureus cannot escape or degrade C3 labeling. We found that the C3 deposition on S. aureus notably enhanced cellular autophagic responses, and distinguished these responses as xenophagy, in contrast to LC3-associated phagocytosis (LAP). Furthermore, this upregulation was due to the recruitment of and direct interaction with autophagy-related 16-like 1 (ATG16L1), thereby resulting in autophagy-dependent resistance to bacterial growth within cells. Interestingly, this autophagic effect occurred only after C3 activation by enzymatic cleavage because full-length C3 without cleavage of the complement cascade reaction, although capable of binding to ATG16L1, failed to promote autophagy. These findings demonstrate the biological function of intracellular C3 upon bacterial infection in enhancing autophagy against internalized S. aureus.
    Keywords:  ATG16L1; Staphylococcus aureus; autophagy; complement C3; intracellular proliferation
    DOI:  https://doi.org/10.3389/fcimb.2024.1400068
  36. J Invest Dermatol. 2024 Sep 18. pii: S0022-202X(24)02100-6. [Epub ahead of print]
    PHOTOPROTECTIVE MELANIN IS MAINTAINED WITHIN KERATINOCYTES IN STORAGE LYSOSOMES.
    Matilde V Neto, Michael J Hall, João Charneca, Cristina Escrevente, Miguel C Seabra, Duarte C Barral.
      In the skin, melanin is synthesized by melanocytes within melanosomes, and transferred to keratinocytes. After being phagocytosed by keratinocytes, melanin polarizes to supranuclear caps that protect against the genotoxic effects of ultraviolet radiation. We provide evidence that melanin-containing phagosomes undergo a canonical maturation process, with the sequential acquisition of early and late endosomal markers. Subsequently, these phagosomes fuse with active lysosomes, leading to the formation of a melanin-containing phagolysosome that we named melanokerasome. Melanokerasomes achieve juxtanuclear positioning via lysosomal trafficking regulators Rab7 and RILP. Mature melanokerasomes exhibit lysosomal markers, elude connections with the endo/phagocytic pathway, are weakly degradative, retain undigested cargo and are likely tethered to the nuclear membrane. We propose that they represent a lysosomal-derived storage compartment that has exited the lysosome cycle, akin to the formation of lipofuscin in aged cells and dysfunctional lysosomes in lysosomal storage and age-related diseases. This storage lysosome allows melanin to persist for long periods, where it can exert its photoprotective effect efficiently.
    Keywords:  Melanin; keratinocyte; lysosome; melanocore; melanokerasome
    DOI:  https://doi.org/10.1016/j.jid.2024.08.023
  37. Eur J Pharmacol. 2024 Sep 20. pii: S0014-2999(24)00697-6. [Epub ahead of print] 177007
    Autophagic inhibitor ROC-325 ameliorates glomerulosclerosis and podocyte injury via inhibiting autophagic flux in experimental FSGS mice.
    Jiaying Li, Yan Yang, Luan Li, Siqi Zheng, Hong Zhang, Cuili Li, Yating Cai, Yingwen Chen, Qingying Shi, Weiteng Wang, Jieyi Luo, Xingchen Zhao, Rui Zhao Li, Huaban Liang, Yuanhan Chen, Li Zhang, Xinling Liang.
       BACKGROUND: Autophagy plays an important role in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Podocyte-specific Yes-associated protein (YAP) deletion mice, referred to as YAP-KO mice, is considered a new animal model to study the underlying mechanism of FSGS. ROC-325 is a novel small-molecule lysosomal autophagy inhibitor that is more effective than chloroquine (CQ) and hydroxychloroquine (HCQ) in suppressing autophagy. In this study, we sought to determine the therapeutic benefit and mechanism of action of ROC-325 in YAP-KO mice, an experimental FSGS model.
    METHODS AND RESULTS: YAP-KO mice were treated with ROC-325 (50 mg/kg, p.o.) daily for one month. Our results revealed that albuminuria, mesangial matrix expension, and focal segmental glomerulosclerosis in YAP-KO mice were significantly attenuated by ROC-325 administration. Transmission electron microscopy and immunofluorescence staining showed that ROC-325 treatment significantly inhibited YAP-KO-induced autophagy activation by decreasing autophagosome-lysosome fusion and increasing LC3A/B and p62/SQSTM. Meanwhile, Immunofluorescence staining revealed that preapplication of ROC-325 in podocyte with YAP-targeted siRNA and mRFP-GFP-LC3 adenovirus markedly suppressed autophagic flux in vitro, suggesting that autophagy intervention may serve as a target for FSGS.
    CONCLUSIONS: These results showed that the role of autophagic activity in FSGS mice model and ROC-325 could be a novel and promising agent for the treatment of FSGS.
    Keywords:  ROC-325; Yes-associated protein (YAP); autophagy; focal segmental glomerulosclerosis; podocyte
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177007
  38. Ecotoxicol Environ Saf. 2024 Sep 26. pii: S0147-6513(24)01149-7. [Epub ahead of print]285 117073
    Black phosphorus nanosheets induce autophagy dysfunction by a size- and surface modification-related impairment of lysosomes in macrophages.
    Shuo Deng, Qing Zhao, Daxu Liu, Zhiqiang Xiong, Siyu Zhang, Xuejiao Zhang, Fengchang Wu, Baoshan Xing.
      The widespread application of black phosphorus nanosheets (BPNSs) raises concerns about their potential impact on human health. Although that the autophagy-inducing properties of BPNSs in cancer cells are documented, their effects on macrophages-key components of the immune system and the mechanisms involved remain obscure, especially in terms of the influences of BPNS the size and surface modifications on the autophagic process. This study investigated the effects of bare BPNSs and PEGylated BPNSs (BP-PEG) on macrophage autophagy and its underlying mechanisms by comprehensive biochemical analyses. The results indicated that both BPNSs and BP-PEG are internalized by RAW264.7 cells through phagocytosis and caveolin-dependent endocytosis, leading to lysosomal accumulation. The internalized BPNSs induced mitochondrial dysfunction, which subsequently elevated the NAD+/NADH ratio and activated the SIRT-1 pathway, initiating autophagy. However, BPNSs disrupted the autophagic flux by impairing autolysosome formation, leading to apoptosis in a size-dependent manner. In contrast, BP-PEG preserved lysosomal integrity, maintaining autophagic activity and cell viability. These findings deepen our understanding of the influence of nanosheet size and surface modifications on macrophage autophagy, contributing to the formulation of regulatory guidelines to minimize the potential adverse effects and health risks associated with BPNS utilization in various applications.
    Keywords:  Apoptosis; Black phosphorus; Blockage of autophagic flux; Macrophage autophagy; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117073
  39. Brain Res. 2024 Sep 21. pii: S0006-8993(24)00504-3. [Epub ahead of print]1846 149250
    Decreased SREBP2 of the striatal cell relates to disrupted protein degradation in Huntington's disease.
    Kyoungjoo Cho, Gyung Whan Kim.
      This study delineated the intricate relation between cholesterol metabolism, protein degradation mechanisms, and the pathogenesis of Huntington's disease (HD). Through investigations using both animal models and cellular systems, we have observed significant alterations in cholesterol levels, particularly in the striatum, which is the primary lesion site in HD. Our findings indicate the dysregulation of cholesterol metabolism-related factors, such as LDLR and SREBP2, in HD, which may contribute to disease progression. Additionally, we uncovered disruptions in protein degradation pathways, including decreased neddylated proteins and dysregulated autophagy, which further exacerbated HD pathology. Moreover, our study highlighted the potential therapeutic implications of targeting these pathways. By restoring cholesterol levels and modulating protein degradation mechanisms, particularly through interventions, such as MLN4924, we observed potential improvements in cellular function, as indicated by the increased BDNF levels. These insights underscore the importance of simultaneously addressing cholesterol metabolism and protein degradation to alleviate HD pathology. Collectively, this study provides a basic understanding of the interplay between the decrease of SREBP2 and the dysfunctional protein degradation system derived from disrupted cholesterol metabolism in HD and HD cells.
    Keywords:  Cholesterol; Huntington’s disease; Neddylation; Protein degradation; SREBP2
    DOI:  https://doi.org/10.1016/j.brainres.2024.149250
  40. bioRxiv. 2024 Sep 09. pii: 2024.09.09.612149. [Epub ahead of print]
    Desmoplakin mutations in cardiac fibroblasts cause TGFβ1-mediated pathological fibrogenesis in desmoplakin cardiomyopathy via beclin-1 regulation.
    Chuanyu Wei, Shing-Fai Chan, Ardan M Saguner, Corinna Brunckhorst, Firat Duru, Joseph E Marine, Cynthia A James, Hugh Calkins, Daniel P Judge, Weinian Shou, Huei-Sheng Vincent Chen.
       Background: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( DSP ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remain unknown.
    Methods: Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including hearts. We first used unbiased genome-wide analyses to generate cardiac fibroblasts-like, induced pluripotent stem cell-derived MSCs from normal donors and ACM patients with DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to transforming growth factor beta-1 (TGF-β1) using Western/Co-IP, autophagy assay, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR.
    Results: TGFβ1 induced excessive accumulations of vimentin (VIM)/fibrillar collagens, and over-activated fibrotic genes in DSP- mutant MSCs when compared to normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP- mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered beclin-1 (BECN1) from activating autophagy and caveolin-1 (CAV1)-mediated endocytosis. Decreased autophagy caused collagen accumulations and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes [ COL1A1, COL3A1, and fibronectin ( FN )] via heightened p38 activities after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expressions.
    Conclusions: Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.
    DOI:  https://doi.org/10.1101/2024.09.09.612149
  41. Biochem Biophys Res Commun. 2024 Sep 19. pii: S0006-291X(24)01252-X. [Epub ahead of print]733 150716
    Icariin alleviates cellular injury induced by cardiac ischemia-reperfusion injury by inhibiting IRE1/JNK-induced ferroptosis.
    Zanrui Zhong, Kun Yang, Shilin Tang, Tianyi Ma.
       BACKGROUND: Ischemia-induced cellular damage and stress responses significantly impact cellular viability and function. Icariin (ICA), known for its protective effects, has been studied to understand its role in mitigating oxygen-glucose deprivation/reperfusion (OGD/R)-induced endoplasmic reticulum (ER) stress and ferroptosis in H9C2 cardiomyoblast cells.
    METHODS: We employed an in vitro OGD/R model using H9C2 cells. ICA's effects were analyzed across multiple concentrations. Key indicators of ER stress, autophagy, and ferroptosis-including markers like Bip, PERK, IRE1, ATF6, P62, FTH1, LC3II/LC3I, and NCOA4-were assessed using Western blotting, electron microscopy, and biochemical assays. Additionally, the role of the IRE1/JNK pathway in mitochondrial dynamics and its influence on mitochondrial dynamics protein was explored through specific inhibition and activation experiments.
    RESULTS: ICA significantly reduced the activation of UPR pathways, decreased autophagic vacuole formation, and maintained cell viability in response to OGD/R and Erastin-induced ferroptosis. These protective effects were associated with modulated autophagic processes, reduced lipid peroxidation, and decreased ferrous ion accumulation. Inhibition of the IRE1/JNK pathway and subsequent Drp1 activity demonstrated reduced mitochondrial recruitment and mitophagy, correlating with decreased ferroptosis markers and improved cell survival.
    CONCLUSION: Our findings highlight ICA's potential in modulating IRE1/JNK pathway, autophagy, providing a therapeutic avenue for mitigating ferroptosis in myocardial ischemia-reperfusion injury (MIRI).
    Keywords:  Autophagy; ER stress; Ferroptosis; Mitophagy; Oxygen-glucose deprivation/reperfusion; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150716
  42. Mech Ageing Dev. 2024 Sep 20. pii: S0047-6374(24)00093-9. [Epub ahead of print]222 111993
    The role of mitochondria in cytokine and chemokine signalling during ageing.
    Maria Kalykaki, Teresa Rubio-Tomás, Nektarios Tavernarakis.
      Ageing is accompanied by a persistent, low-level inflammation, termed "inflammageing", which contributes to the pathogenesis of age-related diseases. Mitochondria fulfil multiple roles in host immune responses, while mitochondrial dysfunction, a hallmark of ageing, has been shown to promote chronic inflammatory states by regulating the production of cytokines and chemokines. In this review, we aim to disentangle the molecular mechanisms underlying this process. We describe the role of mitochondrial signalling components such as mitochondrial DNA, mitochondrial RNA, N-formylated peptides, ROS, cardiolipin, cytochrome c, mitochondrial metabolites, potassium efflux and mitochondrial calcium in the age-related immune system activation. Furthermore, we discuss the effect of age-related decline in mitochondrial quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy and UPRmt, in inflammatory states upon ageing. In addition, we focus on the dynamic relationship between mitochondrial dysfunction and cellular senescence and its role in regulating the secretion of pro-inflammatory molecules by senescent cells. Finally, we review the existing literature regarding mitochondrial dysfunction and inflammation in specific age-related pathological conditions, including neurodegenerative diseases (Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis), osteoarthritis and sarcopenia.
    Keywords:  Age-related disease; Chemokine; Cytokine; Inflammageing; Mitochondrial dysfunction; Senescence
    DOI:  https://doi.org/10.1016/j.mad.2024.111993
  43. J Zhejiang Univ Sci B. 2024 Sep 26. 1-5
    Autophagy receptor-inspired chimeras: a novel approach to facilitate the removal of protein aggregates and organelle by autophagy degradation.
    Liwen Wang, Huimei Liu, Lanfang Li.
      Neurodegenerative diseases (NDDs), mainly including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), are sporadic and rare genetic disorders of the central nervous system. A key feature of these conditions is the slow accumulation of misfolded protein deposits in brain neurons, the excessive aggregation of which leads to neurotoxicity and further disorders of the nervous system.
    DOI:  https://doi.org/10.1631/jzus.B2300853
  44. Biochem Pharmacol. 2024 Sep 20. pii: S0006-2952(24)00552-5. [Epub ahead of print]229 116552
    Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling.
    Warisara Parichatikanond, Sudhir Pandey, Supachoke Mangmool.
      Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9-39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9-39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.
    Keywords:  Cardioprotection; Exendin-4; GLP-1 receptor; High glucose; Mitochondrial dysfunction; mTOR
    DOI:  https://doi.org/10.1016/j.bcp.2024.116552
  45. Biochem Biophys Res Commun. 2024 Sep 17. pii: S0006-291X(24)01249-X. [Epub ahead of print]733 150713
    Brain insulin resistance in Down syndrome: Involvement of PI3K-Akt/mTOR axis in early-onset of Alzheimer's disease and its potential as a therapeutic target.
    Mansour Azimzadeh, Pike-See Cheah, King-Hwa Ling.
      Down syndrome (DS) is the most common genetic cause of intellectual impairment, characterised by an extra copy of chromosome 21. After the age of 40, DS individuals are highly susceptible to accelerated ageing and the development of early-onset Alzheimer-like neuropathology. In the context of DS, the brain presents a spectrum of neuropathological mechanisms and metabolic anomalies. These include heightened desensitisation of brain insulin and insulin-like growth factor-1 (IGF-1) reactions, compromised mitochondrial functionality, escalated oxidative stress, reduced autophagy, and the accumulation of amyloid beta and tau phosphorylation. These multifaceted factors intertwine to shape the intricate landscape of DS-related brain pathology. Altered brain insulin signalling is linked to Alzheimer's disease (AD). This disruption may stem from anomalies in the extracellular aspect (insulin receptor) or the intracellular facet, involving the inhibition of insulin receptor substrate 1 (IRS1). Both domains contribute to the intricate mechanism underlying this dysregulation. The PI3K-Akt/mammalian target of the rapamycin (mTOR) axis is a crucial intracellular element of the insulin signalling pathway that connects numerous physiological processes in the cell cycle. In age-related neurodegenerative disorders like AD, aberrant modulation of the PI3K-Akt signalling cascade is a key factor contributing to their onset. Aberrant and sustained hyperactivation of the PI3K/Akt-mTOR axis in the DS brain is implicated in early symptoms of AD development. Targeting the PI3K-Akt/mTOR pathway may help delay the onset of early-onset AD in individuals with DS, offering a potential way to slow disease progression and enhance their quality of life.
    Keywords:  Akt; Alzheimer's disease; Aβ; Down syndrome; Insulin resistance; PI3K
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150713
  46. J Headache Pain. 2024 Sep 20. 25(1): 156
    Targeting IGF1/IGF1r signaling relieve pain and autophagic dysfunction in NTG-induced chronic migraine model of mice.
    Tianxiao Wang, Chenlu Zhu, Kaibo Zhang, Jinggui Gao, Yunhao Xu, Chenyang Duan, Shouyi Wu, Cheng Peng, Jisong Guan, Yonggang Wang.
       BACKGROUND: Chronic migraine is a severe and common neurological disorder, yet its precise physiological mechanisms remain unclear. The IGF1/IGF1r signaling pathway plays a crucial role in pain modulation. Studies have shown that IGF1, by binding to its receptor IGF1r, activates a series of downstream signaling cascades involved in neuronal survival, proliferation, autophagy and functional regulation. The activation of these pathways can influence nociceptive transmission. Furthermore, alterations in IGF1/IGF1r signaling are closely associated with the development of various chronic pain conditions. Therefore, understanding the specific mechanisms by which this pathway contributes to pain is of significant importance for the development of novel pain treatment strategies. In this study, we investigated the role of IGF1/IGF1r and its potential mechanisms in a mouse model of chronic migraine.
    METHODS: Chronic migraine was induced in mice by repeated intraperitoneal injections of nitroglycerin. Mechanical and thermal hypersensitivity responses were assessed using Von Frey filaments and radiant heat, respectively. To determine the role of IGF1/IGF1r in chronic migraine (CM), we examined the effects of the IGF1 receptor antagonist ppp (Picropodophyllin) on pain behaviors and the expression of calcitonin gene-related peptide (CGRP) and c-Fos.
    RESULT: In the nitroglycerin-induced chronic migraine model in mice, neuronal secretion of IGF1 is elevated within the trigeminal nucleus caudalis (TNC). Increased phosphorylation of the IGF1 receptor occurs, predominantly co-localizing with neurons. Treatment with ppp alleviated basal mechanical hypersensitivity and acute mechanical allodynia. Furthermore, ppp ameliorated autophagic dysfunction and reduced the expression of CGRP and c-Fos.
    CONCLUSION: Our findings demonstrate that in the chronic migraine (CM) model in mice, there is a significant increase in IGF1 expression in the TNC region. This upregulation of IGF1 leads to enhanced phosphorylation of IGF1 receptors on neurons. Targeting and inhibiting this signaling pathway may offer potential preventive strategies for mitigating the progression of chronic migraine.
    Keywords:  Autophagy; Chronic migraine; IGF1; IGF1r; mTOR
    DOI:  https://doi.org/10.1186/s10194-024-01864-6
  47. Curr Issues Mol Biol. 2024 Sep 15. 46(9): 10200-10217
    Biochemical Pathways Delivering Distinct Glycosphingolipid Patterns in MDA-MB-231 and MCF-7 Breast Cancer Cells.
    Anita Markotić, Jasminka Omerović, Sandra Marijan, Nikolina Režić-Mužinić, Vedrana Čikeš Čulić.
      The complex structure of glycosphingolipids (GSLs) supports their important role in cell function as modulators of growth factor receptors and glutamine transporters in plasma membranes. The aberrant composition of clustered GSLs within signaling platforms, so-called lipid rafts, inevitably leads to tumorigenesis due to disturbed growth factor signal transduction and excessive uptake of glutamine and other molecules needed for increased energy and structural molecule cell supply. GSLs are also involved in plasma membrane processes such as cell adhesion, and their transition converts cells from epithelial to mesenchymal with features required for cell migration and metastasis. Glutamine activates the mechanistic target of rapamycin complex 1 (mTORC1), resulting in nucleotide synthesis and proliferation. In addition, glutamine contributes to the cancer stem cell GD2 ganglioside-positive phenotype in the triple-negative breast cancer cell line MDA-MB-231. Thieno[2,3-b]pyridine derivative possesses higher cytotoxicity against MDA-MB-231 than against MCF-7 cells and induces a shift to aerobic metabolism and a decrease in S(6)nLc4Cer GSL-positive cancer stem cells in the MDA-MB-231 cell line. In this review, we discuss findings in MDA-MB-231, MCF-7, and other breast cancer cell lines concerning their differences in growth factor receptors and recent knowledge of the main biochemical pathways delivering distinct glycosphingolipid patterns during tumorigenesis and therapy.
    Keywords:  breast cancer; glycosphingolipids; growth factor receptors; membrane lipid remodeling; structure
    DOI:  https://doi.org/10.3390/cimb46090608
  48. Cell Commun Signal. 2024 Sep 20. 22(1): 444
    TRIM35 triggers cardiac remodeling by regulating SLC7A5-mediated amino acid transport and mTORC1 activation in fibroblasts.
    Boshen Yang, Zhixiang Wang, Kaifan Niu, Taixi Li, Tingting Tong, Suiji Li, Liuhang Su, Yan Wang, Chengxing Shen, Xian Jin, Juan Song, Xia Lu.
       BACKGROUND: Cardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive.
    METHODS: Heart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35cKO) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin.
    RESULTS: TRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-β1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35.
    CONCLUSION: Our findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling.
    Keywords:  Amino acid transport; Cardiac remodeling; Fibroblast activation; SLC7A5; TRIM35; mTORC1
    DOI:  https://doi.org/10.1186/s12964-024-01826-0
  49. Cell Signal. 2024 Sep 20. pii: S0898-6568(24)00390-5. [Epub ahead of print]124 111422
    Mycobacterium manipulate glutaminase 1 mediated glutaminolysis to regulate macrophage autophagy for bacteria intracellular survival.
    Jialin Yu, Na Yan, Zhaoqian Gong, Qinmei Ma, Jing Liu, Xiaoling Wu, Guangcun Deng.
      Autophagy plays a vital role in eliminating intracellular mycobacterium. It is regulated by multiple metabolic processes including glutaminolysis. Glutaminase 1 (GLS1) is the rate-limiting enzyme of glutaminolysis and has been reported to control intracellular Gln content. However, its function on regulating autophagy in mycobacterium infected macrophage is still obscure. Hence, the current study hired mycobacterium virulent strain H37Rv or attenuated strain BCG to infect macrophage and detected the changes in cell glutaminolysis. The function of GLS1 on regulating autophagy in mycobacterium infected macrophages was further investigated. The results showed that BCG infection promoted macrophage autophagy, enhanced glutaminolysis, reduced intracellular Gln content, accompanied with the up-regulation of GLS1. Conversely, H37Rv infection resulted in completely opposite effects. Meanwhile, knockdown of GLS1 increased Gln content and attenuated autophagy in BCG infected macrophages. In addition, the deprivation of Gln not only promoted the autophagy of H37Rv infected macrophages, but also abolished the effect of knockdown GLS1 on regulating BCG infection-induced mTOR activation or autophagy. To sum up, our study suggested that different virulent strains of mycobacterium infection have totally opposite effects on glutaminolysis and the expression of GLS1. Specifically, mycobacterium virulent strain reduced GLS1 expression and decreased Gln content but mycobacterium attenuated strain promoted GLS1 expression and enhanced Gln content. Furthermore, GLS1 inhibits the activation of the mTOR signaling pathway and promotes autophagy by decreasing Gln content.
    Keywords:  Autophagy; GLS1;; Glutaminolysis; Macrophage; mycobacterium
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111422
  50. J Photochem Photobiol B. 2024 Sep 24. pii: S1011-1344(24)00197-0. [Epub ahead of print]260 113037
    Maintaining KEAP1 levels in retinal pigment epithelial cells preserves their viability during prolonged exposure to artificial blue light.
    Ching-Hao Li, Tsung-Min Yang, Ida Fitriana, Te-Chao Fang, Liang-Huan Wu, George Hsiao, Yu-Wen Cheng.
      Exposure to artificial blue light, one of the most energetic forms of visible light, can increase oxidative stress in retinal cells, potentially enhancing the risk of macular degeneration. Retinal pigment epithelial (RPE) cells play a crucial role in this process; the loss of RPE cells is the primary pathway through which retinal degeneration occurs. In RPE cells, Kelch-like ECH-associated protein 1 (KEAP1) is located in both the nucleus and cytosol, where it binds to nuclear factor erythroid 2-related factor 2 (NRF2) and p62 (sequestosome-1), respectively. Blue light exposure activates the NRF2-heme oxygenase 1 (HMOX1) axis through both canonical and noncanonical p62 pathways thereby reducing oxidative damage, and initiates autophagy, which helps remove damaged proteins. These protective responses may support the survival of RPE cells. However, extended exposure to blue light drastically decreases the viability of RPE cells. This exposure diminishes the ability of KEAP1 to bind to p62 and reduces the level of KEAP1. Inhibition of autophagy does not prevent KEAP1 degradation, the NRF2-HMOX1 axis, or blue-light-induced cytotoxicity. However, proteasome inhibitor along with a transient increase in the amount of KEAP1 in RPE cells, partially restores the p62-KEAP1 complex and reduces blue-light-induced cytotoxicity. In vivo studies confirmed the downregulation of KEAP1 in damaged RPE cells. Mice subjected to periodic blue light exposure exhibited significant atrophy in the outer retina, particularly in the peripheral areas. Additionally, there was a significant decrease in c-wave electroretinography and pupillary light reflex, indicating functional impairments in both visual and nonvisual physiological processes. These data underscore the essential role of KEAP1 in managing oxidative defense and autophagy pathways triggered by blue light exposure in RPE cells.
    Keywords:  Autophagy; Blue light; KEAP1; Retinal pigment epithelial cell; p62/sequestosome-1
    DOI:  https://doi.org/10.1016/j.jphotobiol.2024.113037
  51. Int J Biol Macromol. 2024 Sep 25. pii: S0141-8130(24)06788-6. [Epub ahead of print] 135979
    HSP90-regulated mitophagy can alleviate heat stress damage by inhibiting pyroptosis in the hepatocytes of Wenchang chickens.
    Jiachen Shi, Chengyun Li, Qijun Liang, Yujie Yao, Zeping Ji, Menglin Zhou, Jiawei Cai, Xu Yao, Xiaohui Zhang.
      Heat shock protein 90 (HSP90) has a recognized anti-heat stress injury effect, but its function and corresponding molecular mechanism in heat-stressed hepatocytes are not fully understood, especially in tropical animals. In the present study, we identified several key factors affecting resistance to injury liver tissues from heat-stressed Wenchang chickens (a typical tropical species), such as HSP90, cellular pyroptosis and mitophagy. Heat stress upregulated the NLRP3/Caspase-1/GSDMD-N-mediated cellular pyroptosis pathway and the Pink1/Parkin-mediated mitophagy pathway in chicken hepatocytes, accompanied by the upregulation of HSP90. We also found that HSP90 overexpression significantly reduced heat stress-induced hepatocyte pyroptosis and enhanced mitophagy in primary hepatocytes from Wenchang chickens (PHWCs). HSP90 knockdown significantly increased heat stress-induced hepatocyte pyroptosis and decreased mitophagy in PHWCs. Interestingly, we performed immunoprecipitation and immunofluorescence colocalization and found that HSP90 and Pink1 can interact and directly regulate the level of mitophagy in PHWCs. Our results suggest that HSP90, which regulates Pink1, is an important factor in mitophagy that attenuates heat stress injury by inhibiting cellular pyroptosis.
    Keywords:  Cellular pyroptosis; HSP90; Mitophagy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135979
  52. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2400575
    EspH utilizes phosphoinositide and Rab binding domains to interact with plasma membrane infection sites and Rab GTPases.
    Ipsita Nandi, Rachana Pattani Ramachandran, Deborah E Shalev, Dina Schneidman-Duhovny, Raisa Shtuhin-Rahav, Naomi Melamed-Book, Efrat Zlotkin-Rivkin, Alexander Rouvinski, Ilan Rosenshine, Benjamin Aroeti.
      Enteropathogenic E. coli (EPEC) is a Gram-negative bacterial pathogen that causes persistent diarrhea. Upon attachment to the apical plasma membrane of the intestinal epithelium, the pathogen translocates virulence proteins called effectors into the infected cells. These effectors hijack numerous host processes for the pathogen's benefit. Therefore, studying the mechanisms underlying their action is crucial for a better understanding of the disease. We show that translocated EspH interacts with multiple host Rab GTPases. AlphaFold predictions and site-directed mutagenesis identified glutamic acid and lysine at positions 37 and 41 as Rab interacting residues in EspH. Mutating these sites abolished the ability of EspH to inhibit Akt and mTORC1 signaling, lysosomal exocytosis, and bacterial invasion. Knocking out the endogenous Rab8a gene expression highlighted the involvement of Rab8a in Akt/mTORC1 signaling and lysosomal exocytosis. A phosphoinositide binding domain with a critical tyrosine was identified in EspH. Mutating the tyrosine abolished the localization of EspH at infection sites and its capacity to interact with the Rabs. Our data suggest novel EspH-dependent mechanisms that elicit immune signaling and membrane trafficking during EPEC infection.
    Keywords:  Enteropathogenic e. coli; EspH; Rab GTPases; Rho GTPases; bacterial invasion; host-pathogen interactions; lysosomal exocytosis; phosphoinositide binding domain (PBD) PI3K/Akt/mTORC1 signaling; phosphoinositides (PIs); type III secreted effectors
    DOI:  https://doi.org/10.1080/19490976.2024.2400575
  53. Free Radic Biol Med. 2024 Sep 21. pii: S0891-5849(24)00677-4. [Epub ahead of print]224 740-756
    Hederagenin inhibits mitochondrial damage in Parkinson's disease via mitophagy induction.
    Xiaoqian Li, Mengling Hu, Xiaogang Zhou, Lu Yu, Dalian Qin, Jianming Wu, Lan Deng, Lufeng Huang, Fang Ren, Bin Liao, Anguo Wu, Dongsheng Fan.
       BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons and the formation of α-synuclein aggregates. Mitochondrial dysfunction and oxidative stress are pivotal in PD pathogenesis, with impaired mitophagy contributing to the accumulation of mitochondrial damage. Hederagenin (Hed), a natural triterpenoid, has shown potential neuroprotective effects; however, its mechanisms of action in PD models are not fully understood.
    METHOD: We investigated the effects of Hed on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in SH-SY5Y cells by assessing cell viability, mitochondrial function, and oxidative stress markers. Mitophagy induction was evaluated using autophagy and mitophagy inhibitors and fluorescent staining techniques. Additionally, transgenic Caenorhabditis elegans (C. elegans) models of PD were used to validate the neuroprotective effects of Hed in vivo by focusing on α-synuclein aggregation, mobility, and dopaminergic neuron integrity.
    RESULTS: Hed significantly enhanced cell viability in 6-OHDA-treated SH-SY5Y cells by inhibiting cell death and reducing oxidative stress. It ameliorated mitochondrial damage, evidenced by decreased mitochondrial superoxide production, restored membrane potential, and improved mitochondrial morphology. Hed also induced mitophagy, as shown by increased autophagosome formation and reduced oxidative stress; these effects were diminished by autophagy and mitophagy inhibitors. In C. elegans models, Hed activated mitophagy and reduced α-synuclein aggregation, improved mobility, and mitigated the loss of dopaminergic neurons. RNA interference targeting the mitophagy-related genes pdr-1 and pink-1 partially reversed these benefits, underscoring the role of mitophagy in Hed's neuroprotective actions.
    CONCLUSION: Hed exhibits significant neuroprotective effects in both in vitro and in vivo PD models by enhancing mitophagy, reducing oxidative stress, and mitigating mitochondrial dysfunction. These findings suggest that Hed holds promise as a therapeutic agent for PD, offering new avenues for future research and potential drug development.
    Keywords:  6-OHDA; Caenorhabditis elegans; Hederagenin; Mitochondrial dysfunction; Mitophagy; Parkinson's disease; α-synuclein
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.030
  54. Exp Gerontol. 2024 Sep 24. pii: S0531-5565(24)00235-3. [Epub ahead of print]197 112589
    Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy.
    Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.
      Mitochondrial dysfunction with aging is associated with the development of age-related hearing loss. Mitophagy is a cardinal mechanism to maintain a healthy mitochondrial population through the turnover of damaged mitochondria. Declining mitophagy with age causes a buildup of damaged mitochondria, leading to sensory organ dysfunction. The effect of Urolithin A (UA), a mitophagy inducer, was investigated on age-related hearing loss in a mouse model. C57BL/6J mice were treated with UA from 6 to 10 months of age. UA attenuated an auditory brainstem responses (ABR) threshold shift at 8, 16, and 32 kHz frequencies, and improved mitochondrial DNA integrity and ATP production in the cochlea and auditory cortex. The mRNA levels of mitophagy-related genes and protein levels of PINK1, Parkin, BNIP3, and LC3B increased in the cochlea and auditory cortex. The expression of mitophagosomes and mitophagolysosomes in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus increased, together with the expression of Parkin and BNIP3 in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus. These results indicate that UA counteracted mitophagy decline in the auditory system and prevented age-related hearing loss. UA can be used as a potential agent to prevent age-related hearing loss.
    Keywords:  Age-related hearing loss; Mitochondria; Mitophagy; Urolithin A
    DOI:  https://doi.org/10.1016/j.exger.2024.112589
  55. Microbiol Spectr. 2024 Sep 23. e0118824
    Mycobacterium tuberculosis VII secretion system effector molecule Rv2347c blocks the maturation of phagosomes and activates the STING/TBK1 signaling pathway to inhibit cell autophagy.
    Zhiyong Jiang, Junfeng Zhen, Yuerigu Abulikena, Chaoyun Gao, Lingxi Huang, Tingting Huang, Jianping Xie.
      The VII secretion system is the main channel for Mycobacterium tuberculosis (MTB) to secrete virulence proteins. The ESAT-like proteins EsxA/B and EsxW/V in the RD region of its genome have been used as targets for vaccine antigens. However, the function of EsxO/P has not been explored, although it was predicted to potentially induce Th1 cell responses as a vaccine development target. In this study, the VII secretion system effector molecule Rv2347c was heterologously expressed in Mycobacterium smegmatis and found to inhibit the expression of the early marker RAB5 of phagosomes, thus preventing the maturation process of phagosomes toward lysosomes, and activated the host cytoplasmic sensing pathway. It inhibited autophagy and activated IFNβ transcription through the STING/TBK1 pathway promoting the host's survival. Therefore, Rv2347c plays an important role in the pathogenesis of MTB with the potential to be utilized as a new target for tuberculosis vaccine development.
    IMPORTANCE: We found that the ESAT-like protein Rv2347c (EsxP) can inhibit the maturation of phagosomes, leading to mycobacterium escape from phagosomes into the cytoplasm, which triggers the host's cytoplasmic sensing pathway STING/TBK1, inhibiting autophagy and upregulating IFNβ transcription, which contributes to the survival of mycobacterium in the host cell. We also found that Rv2347c was able to activate host immunity by activating NF-κB via STING and promoting the transcription of downstream pro-inflammatory factors. Meanwhile, the host also produces IL-1β to repair phagosome maturation arrest via the STING-mediated non-NF-κB pathway.
    Keywords:  STING; autophagy; phagolysosome
    DOI:  https://doi.org/10.1128/spectrum.01188-24
  56. Ageing Res Rev. 2024 Sep 21. pii: S1568-1637(24)00329-5. [Epub ahead of print]101 102511
    Valosin-containing protein: A potential therapeutic target for cardiovascular diseases.
    Nameerah Rakhe, Lokesh Kumar Bhatt.
      Valosin-containing protein (VCP), also known as p97, plays a crucial role in various cellular processes, including protein degradation, endoplasmic reticulum-associated degradation, and cell cycle regulation. While extensive research has been focused on VCP's involvement in protein homeostasis and its implications in neurodegenerative diseases, emerging evidence suggests a potential link between VCP and cardiovascular health. VCP is a key regulator of mitochondrial function, and its overexpression or mutations lead to pathogenic diseases and cellular stress responses. The present review explores VCP's roles in numerous cardiovascular disorders including myocardial ischemia/reperfusion injury, cardiac hypertrophy, and heart failure. The review dwells on the roles of VCP in modifying mitochondrial activity, promoting S-nitrosylation, regulating mTOR signalling and demonstrating cardioprotective effects. Further research into VCP might lead to novel interventions for cardiovascular disease, particularly those involving ischemia/reperfusion injury and hypertrophy.
    Keywords:  Cardiac hypertrophy; ER-associated degradation; Mitophagy; Myocardial ischemia; Valosin containing protein
    DOI:  https://doi.org/10.1016/j.arr.2024.102511
  57. J Periodontol. 2024 Sep 23.
    Bmi-1 alleviates alveolar bone resorption through the regulation of autophagy.
    Yiting Chu, Shuying Liu, Lixueer Yan, Aixiu Gong.
       BACKGROUND: B-cell‑specific Moloney MLV insertion site-1(Bmi-1)is a crucial osteopenic target molecule. The aim of this study is to explore the effects of Bmi-1 on alveolar bone resorption and the underlying mechanisms in vitro and vivo.
    METHODS: A Bmi-1-knockout (Bmi-1-/-) mouse model was used to investigate the effect of Bmi-1 on alveolar bone metabolism, with micro-computed tomography imaging, histology, and immunohistochemistry staining. Furthermore, we utilized a ligature-induced experimental periodontitis model to examine the impact of Bmi-1-knockdown (Bmi-1±) on inflammatory alveolar bone resorption. Finally, we stimulated human periodontal ligament stem cells (hPDLSCs) with lipopolysaccharide (LPS) to explore the potential mechanism of Bmi-1 overexpression in the process of osteogenesis.
    RESULTS: Compared with wild-type mice, Bmi-1-/- mice demonstrated more alveolar bone resorption by inhibiting osteogenesis, which was characterized by decreases in Runt-related transcription factor 2 and type 1 collagen formation. In addition, Bmi-1-/- mice had lower levels of autophagy markers such as Parkin and LC3, but higher levels of inflammation-related factors such as interleukin (IL)-6 and IL-1β in periodontal tissues. In addition, Bmi-1-knockdown aggravated ligature-induced alveolar bone loss. Under in vitro inflammatory conditions, Bmi-1 overexpression stimulated osteoblast differentiation and inhibited the production of inflammatory factors, as well as the autophagy and apoptosis in hPDLSCs stimulated with LPS. When 3-methyladenine (3-MA), an autophagy inhibitor, was added, the osteogenic effect of Bmi-1 was further enhanced.
    CONCLUSIONS: Bmi-1 alleviates alveolar bone resorption by regulating autophagy, indicating that it could be a potential target for periodontitis prevention and treatment.
    PLAIN LANGUAGE SUMMARY: Periodontitis is a chronic inflammatory disease, which leads to progressive destruction of periodontal tissues, manifested as periodontal pocket formation, loss of periodontal attachment and alveolar bone resorption. Currently, there is a lack of effective treatments to regenerate damaged periodontal tissues. Therefore, it is of great clinical significance to explore new mechanisms of periodontitis and effective intervention targets. B-cell‑specific Moloney MLV insertion site-1 (Bmi-1) is involved in the regulation of the cell cycle, DNA damage repair, autophagy, bone metabolism, tumor, and other physiopathological processes. Autophagy, as an important mechanism of intracellular self-regulation, plays an indispensable role in the destruction and repair of periodontal tissues. The aim of this study was to investigate the role of Bmi-1 on periodontal tissues and its intrinsic mechanism. The results revealed that Bmi-1 regulates autophagy to protect periodontal tissues, suggesting that it may be a potential target for the prevention and treatment of periodontitis.
    Keywords:  Bmi‐1; alveolar bone resorption; apoptosis; autophagy; hPDLSCs; periodontitis
    DOI:  https://doi.org/10.1002/JPER.23-0796
  58. J Cell Biol. 2024 Nov 04. pii: e202401167. [Epub ahead of print]223(11):
    Arf1-dependent LRBA recruitment to Rab4 endosomes is required for endolysosome homeostasis.
    Viktória Szentgyörgyi, Leon Maximilian Lueck, Daan Overwijn, Danilo Ritz, Nadja Zoeller, Alexander Schmidt, Maria Hondele, Anne Spang, Shahrzad Bakhtiar.
      Deleterious mutations in the lipopolysaccharide responsive beige-like anchor protein (LRBA) gene cause severe childhood immune dysregulation. The complexity of the symptoms involving multiple organs and the broad range of unpredictable clinical manifestations of LRBA deficiency complicate the choice of therapeutic interventions. Although LRBA has been linked to Rab11-dependent trafficking of the immune checkpoint protein CTLA-4, its precise cellular role remains elusive. We show that LRBA, however, only slightly colocalizes with Rab11. Instead, LRBA is recruited by members of the small GTPase Arf protein family to the TGN and to Rab4+ endosomes, where it controls intracellular traffic. In patient-derived fibroblasts, loss of LRBA led to defects in the endosomal pathway promoting the accumulation of enlarged endolysosomes and lysosome secretion. Thus, LRBA appears to regulate flow through the endosomal system on Rab4+ endosomes. Our data strongly suggest functions of LRBA beyond CTLA-4 trafficking and provide a conceptual framework to develop new therapies for LRBA deficiency.
    DOI:  https://doi.org/10.1083/jcb.202401167
  59. J Cell Physiol. 2024 Sep 22. e31448
    N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy.
    Pingping Qi, Wei Zhang, Yang Gao, Shengkui Chen, Minghe Jiang, Rong He, Wenzhong Chen, Xiawei Wei, Bingquan Hu, Hao Xu, Minsheng Wu, Rong Tang.
      N6-methyladenosine (m6A) is known to be crucial in various biological processes, but its role in sepsis-induced circulatory and cardiac dysfunction is not well understood. Specifically, mitophagy, a specialized form of autophagy, is excessively activated during lipopolysaccharide (LPS)-induced myocardial injury. This study aimed to investigate the impact of LPS-induced endotoxemia on m6A-RNA methylation and its role in regulating mitophagy in sepsis-induced myocardial dysfunction. Our research demonstrated that FTO (fat mass and obesity-associated protein), an m6A demethylase, significantly affects abnormal m6A modification in the myocardium and cardiomyocytes following LPS treatment. In mice, cardiac dysfunction and cardiomyocyte apoptosis worsened after adeno-associated virus serotype 9 (AAV9)-mediated FTO knockdown. Further analyses to uncover the cellular mechanisms improving cardiac function showed that FTO reduced mitochondrial reactive oxygen species, restored both basal and maximal respiration, and preserved mitochondrial membrane potential. We revealed that FTO plays a critical role in activating mitophagy by targeting BNIP3. Additionally, the cardioprotective effects of AAV-FTO were significantly compromised by mdivi-1, a mitophagy inhibitor. Mechanistically, FTO interacted with BNIP3 transcripts and regulated their expression in an m6A-dependent manner. Following FTO silencing, BNIP3 transcripts with elevated m6A modification levels in their coding regions were bound by YTHDF2 (YT521-B homology m6A RNA-binding protein 2), leading to mRNA destabilization and decreased BNIP3 protein levels. These findings highlight the importance of FTO-dependent cardiac m6A methylation in regulating mitophagy and enhance our understanding of this critical interplay, which is essential for developing therapeutic strategies to protect cardiac mitochondrial function, alleviate cardiac dysfunction, and improve survival during sepsis.
    Keywords:  BNIP3; FTO; N6‐methyladenosine; mitophagy; sepsis
    DOI:  https://doi.org/10.1002/jcp.31448
  60. Oncogene. 2024 09 22.
    MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation.
    Rosa Bordone, Devon Michael Ivy, Rodrigo D'Amico, Martina Barba, Miriam Gaggianesi, Fiorella Di Pastena, Bianca Cesaro, Francesca Bufalieri, Alessio Balzerano, Enrico De Smaele, Giuseppe Giannini, Lucia Di Marcotullio, Alessandro Fatica, Giorgio Stassi, Laura Di Magno, Sonia Coni, Gianluca Canettieri.
      The MYC oncogene is frequently overexpressed in tumors and inhibition of its translation is considered an attractive therapeutic opportunity. Despite numerous reports proposing an internal ribosome entry site (IRES) within the MYC Upstream Region (MYC UR) to sustain MYC translation during cellular stress or chemotherapy, conflicting evidence remains regarding the validity of such a mechanism. Through comprehensive investigations in MYC-driven Colorectal Cancer (CRC) and Burkitt Lymphoma (BL) cells, we demonstrate that MYC UR does not facilitate cap-independent translation, but instead orchestrates resistance to PI3K inhibitors. Genomic deletion of MYC UR neither impacts MYC protein levels nor viability in CRC cells, either untreated or exposed to cellular stress. However, in response to PI3K inhibitors, MYC UR drives a FOXO3a-dependent transcriptional upregulation of MYC, conferring drug resistance. This resistance is mediated by enhanced autophagic flux, governed by MYC, and blockade of autophagy sensitizes CRC cells to PI3K inhibition in vitro and in vivo. Remarkably, BL cells lacking the translocation of MYC UR exhibit sensitivity to PI3K inhibitors, whereas MYC UR-translocated cells respond to these drugs only when autophagy is inhibited. These findings challenge previous notions regarding IRES-mediated translation and highlight a promising strategy to overcome resistance to PI3K inhibitors in MYC-driven malignancies, offering potential clinical implications for CRC and BL treatment.
    DOI:  https://doi.org/10.1038/s41388-024-03170-6
  61. Cells. 2024 Sep 13. pii: 1540. [Epub ahead of print]13(18):
    Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.
    Bernardo A Bustillos, Liam T Cocker, Mathew A Coban, Caleb A Weber, Jenny M Bredenberg, Paige K Boneski, Joanna Siuda, Jaroslaw Slawek, Andreas Puschmann, Derek P Narendra, Neill R Graff-Radford, Zbigniew K Wszolek, Dennis W Dickson, Owen A Ross, Thomas R Caulfield, Wolfdieter Springer, Fabienne C Fiesel.
      Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.
    Keywords:  PINK1; PRKN; Parkinson disease; mitophagy; parkin; ubiquitin
    DOI:  https://doi.org/10.3390/cells13181540
  62. PLoS One. 2024 ;19(9): e0309794
    Aβ25-35-induced autophagy and apoptosis are prevented by the CRMP2-derived peptide ST2-104 (R9-CBD3) via a CaMKKβ/AMPK/mTOR signaling hub.
    Yingshi Ji, Jinghong Ren, Yuan Qian, Jiaxin Li, Huanyu Liu, Yuan Yao, Jianfeng Sun, Rajesh Khanna, Li Sun.
      We previously reported that the peptide ST2-104 (CBD3, for Ca2+ channel-binding domain 3), derived from the collapsin response mediator protein 2 (CRMP2)-a cytosolic phosphoprotein, protects neuroblastoma cells against β-amyloid (Aβ) peptide-mediated toxicity through engagement of a phosphorylated CRMP2/NMDAR pathway. Abnormal aggregation of Aβ peptides (e.g., Aβ25-35) leads to programmed cell death (apoptosis) as well autophagy-both of which contribute to Alzheimer's disease (AD) progression. Here, we asked if ST2-104 affects apoptosis and autophagy in SH-SY5Y neuroblastoma challenged with the toxic Aβ25-35 peptide and subsequently mapped the downstream signaling pathways involved. ST2-104 protected SH-SY5Y cells from death following Aβ25-35 peptide challenge by reducing apoptosis and autophagy as well as limiting excessive calcium entry. Cytotoxicity of SHY-SY5Y cells challenged with Aβ25-35 peptide was blunted by ST2-104. The autophagy activator Rapamycin blunted the anti-apoptotic activity of ST2-104. ST2-104 reversed Aβ25-35-induced apoptosis via inhibiting Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-mediated autophagy, which was partly enhanced by STO-609 (an inhibitor of CaMKKβ). ST2-104 attenuated neuronal apoptosis by inhibiting autophagy through a CaMKKβ/AMPK/mTOR signaling hub. These findings identify a mechanism whereby, in the face of Aβ25-35, the concerted actions of ST2-104 leads to a reduction in intracellular calcium overload and inhibition of the CaMKKβ/AMPK/mTOR pathway resulting in attenuation of autophagy and cellular apoptosis. These findings define a mechanistic framework for how ST2-104 transduces "outside" (calcium channels) to "inside" signaling (CaMKKβ/AMPK/mTOR) to confer neuroprotection in AD.
    DOI:  https://doi.org/10.1371/journal.pone.0309794
  63. Ecotoxicol Environ Saf. 2024 Sep 20. pii: S0147-6513(24)01142-4. [Epub ahead of print]285 117066
    The role of Drp1 - Pink1 - Parkin - mediated mitophagy in perfluorobutane sulfonate- induced hepatocyte damage.
    Yuan Feng, Yongheng Huang, Bin Lu, Jianliang Xu, Hui Wang, Fei Wang, Nan Lin.
      Perfluorobutane sulfonate (PFBS) is recognized as a highly persistent environmental contaminant, notorious for its chemical stability and enduring presence in ecosystems. Its propensity for persistence and environmental mobility allows PFBS to infiltrate the human body, predominantly accumulating in the liver where it poses a potential risk for hepatic damage. This investigation aimed to explore the outcomes of PFBS on the physiological functionalities of hepatocytes in vitro. To this end, hepatocytes were exposed to 750 ug/ml PFBS, followed by an analysis of various cellular phenotypes and functionalities, including assessments of cell viability and mitochondrial integrity. The findings indicated that PFBS exposure led to a suppression of cell proliferation and an increase in apoptotic cell death. Moreover, PFBS exposure was found to augment the generation of reactive oxygen species (ROS) and induce significant mitochondrial dysfunction. Gene expression analysis identified significant changes in genes associated with numerous tumor signaling pathways and autophagy signaling pathways. Further examinations revealed an increase in cellular mitophagy following PFBS exposure, coupled with the activation of the mitophagy-associated Drp1/Pink1/Parkin pathway. Inhibition of mitophagy was observed to concurrently amplify cellular damage and inhibit the Drp1/Pink1/Parkin pathway. Together, these findings highlight PFBS's capacity to inflict hepatocyte injury through mitochondrial disruption, positioning Drp1/Pink1/Parkin-mediated mitophagy as a crucial cellular defense mechanism against PFBS-induced toxicity.
    Keywords:  Apoptosis; Cytotoxicity; Mitophagy; PFBS; ROS
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117066
  64. Metallomics. 2024 Sep 23. pii: mfae043. [Epub ahead of print]
    Bile from the hemojuvelin-deficient mouse model of iron excess is enriched in iron and ferritin.
    Milankumar Prajapati, Lauren Chiu, Jared Z Zhang, Grace S Chong, Nicholas A DaSilva, Thomas B Bartnikas.
      Iron is an essential nutrient but is toxic in excess. Iron deficiency is the most prevalent nutritional deficiency and typically linked to inadequate intake. Iron excess is also common and usually due to genetic defects that perturb expression of hepcidin, a hormone that inhibits dietary iron absorption. Our understanding of iron absorption far exceeds that of iron excretion, which is believed to contribute minimally to iron homeostasis. Prior to the discovery of hepcidin, multiple studies showed that excess iron undergoes biliary excretion. We recently reported that wild-type mice raised on an iron-rich diet have increased bile levels of iron and ferritin, a multi-subunit iron storage protein. Given that genetic defects leading to excessive iron absorption are much more common causes of iron excess than dietary loading, we set out to determine if an inherited form of iron excess known as hereditary hemochromatosis also results in bile iron loading. We employed mice deficient in hemojuvelin, a protein essential for hepcidin expression. Mutant mice developed bile iron and ferritin excess. While lysosomal exocytosis has been implicated in ferritin export into bile, knockdown of Tfeb, a regulator of lysosomal biogenesis and function, did not impact bile iron or ferritin levels. Bile proteomes differed between female and male mice for wild-type and hemojuvelin-deficient mice, suggesting sex and iron excess impact bile protein content. Overall, our findings support the notion that excess iron undergoes biliary excretion in genetically determined iron excess.
    Keywords:  bile; ferritin; hemochromatosis; hemojuvelin; iron; liver
    DOI:  https://doi.org/10.1093/mtomcs/mfae043
  65. Curr Issues Mol Biol. 2024 Aug 28. 46(9): 9463-9479
    NOD1 and NOD2: Essential Monitoring Partners in the Innate Immune System.
    Zhenjia Li, Dejing Shang.
      Nucleotide-binding oligomerization domain containing 1 (NOD1) and NOD2 are pivotal cytoplasmic pattern-recognition receptors (PRRs) that exhibit remarkable evolutionary conservation. They possess the ability to discern specific peptidoglycan (PGN) motifs, thereby orchestrating innate immunity and contributing significantly to immune homeostasis maintenance. The comprehensive understanding of both the structure and function of NOD1 and NOD2 has been extensively elucidated. These receptors proficiently recognize an array of damage-associated molecular patterns (DAMPs) as well as pathogen-associated molecular patterns (PAMPs), subsequently mediating inflammatory responses and autophagy. In recent years, emerging evidence has highlighted the crucial roles played by NOD1 and NOD2 in regulating infectious diseases, metabolic disorders, cancer, and autoimmune conditions, among others. Perturbation in either their loss or excessive activation can detrimentally impact immune homeostasis. This review offers a comprehensive overview of the structural characteristics, subcellular localization, activation mechanisms, and significant roles of NOD1 and NOD2 in innate immunity and related disease.
    Keywords:  NOD1; NOD2; inflammatory response; innate immunity
    DOI:  https://doi.org/10.3390/cimb46090561
  66. Mater Today Bio. 2024 Oct;28 101240
    In vivo targeted-imaging of mitochondrial acidification in an aristolochic acid I-induced nephrotoxicity mouse model by a fluorescent/photoacoustic bimodal probe.
    Li Xu, Li Chen, Hongwen Liu, Xingwang Chen, Shenghang Zhang.
      Aristolochic acid I (AAI), a natural compound in aristolochia type Chinese medicinal herb, is generally acknowledged to have nephrotoxicity, which may be associated with mitophagy. Mitophagy is a cellular process with important functions that drive AAI-induced renal injury. Mitochondrial pH is currently measured by fluorescent probes in cell culture, but existing probes do not allow for in situ imaging of AAI-induced mitophagy in vivo. We developed a ratiometric fluorescent/PA dual-modal probe with a silicon rhodamine fluorophore and a pH-sensitive hemicyanine dye covalently linked via a short chain to obtain a FRET type probe. The probe was used to measure AAI-mediated mitochondrial acidification in live cells and in vivo. The Förster resonance energy transfer (FRET)-mediated ratiometric and bimodal method can efficiently eliminate signal variability associated with the commonly used one-emission and single detection mode by ratiometric two channels of the donor and acceptor. The probe has good water-solubility and low molecular weight with two positively charged, facilitating its precise targeting into renal mitochondria, where the fluorescent/PA changes in response to mitochondrial acidification, enabling dynamic and semi-quantitative mapping of subtle changes in mitochondrial pH in AAI-induced nephrotoxicity mouse model for the first time. Also, the joint use of L-carnitine could mitigate the mitophagy in AAI-induced nephrotoxicity.
    Keywords:  Aristolochic acid; Fluorescent imaging; In vivo mitophagy; Nephrotoxicity; Photoacoustic imaging
    DOI:  https://doi.org/10.1016/j.mtbio.2024.101240
  67. Phytother Res. 2024 Sep 22.
    Eleutheroside B Pretreatment Attenuates Hypobaric Hypoxia-Induced High-Altitude Pulmonary Edema by Regulating Autophagic Flux via the AMPK/mTOR Pathway.
    Caixia Pei, Zherui Shen, Yongcan Wu, Sijing Zhao, Yilan Wang, Shihua Shi, Demei Huang, Nan Jia, Junling Liu, Xiaomin Wang, Yacong He, Zhenxing Wang.
      High-altitude pulmonary edema (HAPE) is a life-threatening disease, and autophagy deficiency is implicated in the pathogenesis of HAPE. Eleutheroside B (EB), which is the main bioactive component of Acanthopanax senticosus, exhibits various pharmacological activities. Our previous research demonstrated that autophagic structures were widely found in the ultrastructure of lung tissue in HAPE rats. However, whether EB regulates autophagy deficiency in HAPE remains unknown. This study aimed to investigate the protective effects of EB on hypobaric hypoxia-induced HAPE and explore the underlying molecular mechanism of regulating autophagy. The rat model of high-altitude pulmonary edema was replicated using a hypobaric hypoxic chamber. Rats were pretreated with EB or in combination with chloroquine or compound C. The pulmonary edema was assessed by the lung wet/dry ratio, total protein concentration in bronchoalveolar lavage fluid, and histological analysis. Inflammation and oxidative stress were measured using commercial biochemical kits. Autophagy and autophagic flux were evaluated by western blotting, transmission electron microscopy, and adeno-associated virus-mRFP-GFP-labeled tandem fluorescence LC3. The AMPK/mTOR signaling pathway was detected by western blotting. EB alleviated hypobaric hypoxia-induced pulmonary edema, hypoxemia, acid-base imbalance in the blood, inflammation, and oxidative stress in a dose-dependent manner. EB restored impaired autophagic flux by activating the AMPK/mTOR signaling pathway. However, chloroquine or compound C abolished eleutheroside B-mediated autophagy flux restoration. EB has the potential to restore impaired autophagic flux in the lung of hypobaric hypoxia-induced HAPE rats, which could be attributed to the activation of AMPK/mTOR signaling pathway.
    Keywords:  AMPK/mTOR signaling pathway; autophagic flux; autophagy; eleutheroside B; high‐altitude pulmonary edema
    DOI:  https://doi.org/10.1002/ptr.8333
  68. Exp Eye Res. 2024 Sep 24. pii: S0014-4835(24)00332-4. [Epub ahead of print] 110110
    Current Insights on Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and their significance in the pathophysiology of ocular disorders.
    Xin-Yu Zhang, Cheng Han, Yong Yao, Ting-Ting Wei.
      The intricate interaction network necessary for essential physiological functions underscores the interdependence among eukaryotic cells. Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs), specialized junctions between mitochondria and the ER, were recently discovered. These junctions participate in various cellular processes, including calcium level regulation, lipid metabolism, mitochondrial integrity maintenance, autophagy, and inflammatory responses via modulating the structure and molecular composition of various cellular components. Therefore, MAMs contribute to the pathophysiology of numerous ocular disorders, including Diabetic Retinopathy (DR), Age-related Macular Degeneration (AMD) and glaucoma. In addition to providing a concise overview of the architectural and functional aspects of MAMs, this review explores the key pathogenetic pathways involving MAMs in the development of several ocular disorders.
    Keywords:  Eye Diseases; Mitochondria-Associated Endoplasmic Reticulum Membranes; Pathophysiology
    DOI:  https://doi.org/10.1016/j.exer.2024.110110
  69. PLoS One. 2024 ;19(9): e0310157
    Morphological multiparameter filtration and persistent homology in mitochondrial image analysis.
    Yu-Min Chung, Chuan-Shen Hu, Emily Sun, Henry C Tseng.
      The complexity of branching and curvilinear morphology of a complete mitochondrial network within each cell is challenging to analyze and quantify. To address this challenge, we developed an image analysis technique using persistent homology with a multiparameter filtration framework, combining image processing techniques in mathematical morphology. We show that such filtrations contain both topological and geometric information about complex cellular organelle structures, which allows a software program to extract meaningful features. Using this information, we also develop a connectivity index that describes the morphology of the branching patterns. As proof of concept, we utilize this approach to study how mitochondrial networks are altered by genetic changes in the Optineurin gene. Mutations in the autophagy gene Optineurin (OPTN) are associated with primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), and Paget's disease of the bone, but the pathophysiological mechanism is unclear. We utilized the proposed mathematical morphology-based multiparameter filtration and persistent homology approach to analyze and quantitatively compare how changes in the OPTN gene alter mitochondrial structures from their normal interconnected, tubular morphology into scattered, fragmented pieces.
    DOI:  https://doi.org/10.1371/journal.pone.0310157
  70. Bioorg Chem. 2024 Sep 13. pii: S0045-2068(24)00725-9. [Epub ahead of print]153 107820
    Y9, a Gboxin analog, displays anti-tumor effect in non-small cell lung cancer by inducing lysosomal dysfunction and apoptosis.
    Jie Yin, Longjie Ding, Si Yao, Jianzheng Huang, Yang Xiao, Yue Wang, Biqiong Zhang, Mewlude Rehmutulla, Lianghu Gu, Qingyi Tong, Yonghui Zhang.
      Non-small cell lung cancer (NSCLC) ranks among the most prevalent malignancies globally. Gboxin, a novel inhibitor of mitochondrial complex V that exerts unique anti-tumor effects via oxidative phosphorylation inhibition, but shows no efficacy against NSCLC in vivo. Through chemical structure optimization, we designed and synthesized Gboxin analog Y9, which demonstrates significantly enhanced potency over its predecessor. Specifically, Y9 inhibited NSCLC significantly more strongly than Gboxin and possessed the ability to inhibit cell cycle progression and induce oxidative stress similar to Gboxin. Further investigation revealed that unlike Gboxin, Y9 selectively acidifies lysosomes and induces lysosomal dysfunction. This leads to hyperactive autophagy with impaired substrate clearance, and ultimately resulting in apoptosis. Animal studies confirmed the efficacy of Y9 in suppressing tumor growth in a xenograft mouse model. Collectively, Y9 is a distinctive Gboxin analog that outperforms its prototype by inducing lysosomal dysfunction and apoptosis, and has the potential to be developed as a novel anti-NSCLC lead compound.
    Keywords:  Apoptosis; Gboxin derivatives; Lysosomal damage; Mitochondrial targeting; NSCLC
    DOI:  https://doi.org/10.1016/j.bioorg.2024.107820
  71. MedComm (2020). 2024 Oct;5(10): e736
    The role of ubiquitination in health and disease.
    Yan Liao, Wangzheqi Zhang, Yang Liu, Chenglong Zhu, Zui Zou.
      Ubiquitination is an enzymatic process characterized by the covalent attachment of ubiquitin to target proteins, thereby modulating their degradation, transportation, and signal transduction. By precisely regulating protein quality and quantity, ubiquitination is essential for maintaining protein homeostasis, DNA repair, cell cycle regulation, and immune responses. Nevertheless, the diversity of ubiquitin enzymes and their extensive involvement in numerous biological processes contribute to the complexity and variety of diseases resulting from their dysregulation. The ubiquitination process relies on a sophisticated enzymatic system, ubiquitin domains, and ubiquitin receptors, which collectively impart versatility to the ubiquitination pathway. The widespread presence of ubiquitin highlights its potential to induce pathological conditions. Ubiquitinated proteins are predominantly degraded through the proteasomal system, which also plays a key role in regulating protein localization and transport, as well as involvement in inflammatory pathways. This review systematically delineates the roles of ubiquitination in maintaining protein homeostasis, DNA repair, genomic stability, cell cycle regulation, cellular proliferation, and immune and inflammatory responses. Furthermore, the mechanisms by which ubiquitination is implicated in various pathologies, alongside current modulators of ubiquitination are discussed. Enhancing our comprehension of ubiquitination aims to provide novel insights into diseases involving ubiquitination and to propose innovative therapeutic strategies for clinical conditions.
    Keywords:  protein degradation; protein homeostasis; ubiquitin; ubiquitination
    DOI:  https://doi.org/10.1002/mco2.736
  72. Elife. 2024 Sep 26. pii: RP97662. [Epub ahead of print]13
    Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis.
    Kyusang Yoo, Young-Woo Jo, Takwon Yoo, Sang-Hyeon Hann, Inkuk Park, Yea-Eun Kim, Ye Lynne Kim, Joonwoo Rhee, In-Wook Song, Ji-Hoon Kim, Daehyun Baek, Young-Yun Kong.
      Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs' response to peripheral nerve injury.
    Keywords:  BDNF; GDNF; fibro-adipogenic progenitor; mouse; neuroscience; peripheral nerve injury; regenerative medicine; schwann cell myelination; single-cell RNA-sequencing; stem cells
    DOI:  https://doi.org/10.7554/eLife.97662
  73. Acta Neuropathol. 2024 Sep 21. 148(1): 45
    TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition.
    Pascual Torres, Santiago Rico-Rios, Miriam Ceron-Codorniu, Marta Santacreu-Vilaseca, David Seoane-Miraz, Yahya Jad, Victòria Ayala, Guillermo Mariño, Maria Beltran, Maria P Miralles, Pol Andrés-Benito, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Carlos López-Otín, Rosa M Soler, Monica Povedano, Isidro Ferrer, Reinald Pamplona, Matthew J A Wood, Miguel A Varela, Manuel Portero-Otin.
      Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b-/- mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.
    Keywords:  ALS; Antisense oligonucleotides; Autophagy; Digital PCR; Post-translational modification
    DOI:  https://doi.org/10.1007/s00401-024-02780-4
  74. bioRxiv. 2024 Sep 09. pii: 2024.09.09.612072. [Epub ahead of print]
    SIRT6 loss causes intervertebral disc degeneration in mice by promoting senescence and SASP status.
    Pranay Ramteke, Bahiyah Watson, Mallory Toci, Victoria A Tran, Shira Johnston, Maria Tsingas, Ruteja A Barve, Ramkrishna Mitra, Richard F Loeser, John A Collins, Makarand V Risbud.
      Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc ( Acan CreERT2 ; Sirt6 fl/fl ). Histological studies showed a degenerative phenotype in knockout mice compared to Sirt6 fl/fl control mice at 12 months which became pronounced at 24 months. RNA-Seq analysis of NP and AF tissues, quantitative histone analysis, and in vitro multiomics employing RNA-seq with ATAC-seq revealed that SIRT6-loss resulted in changes in acetylation and methylation status of specific Histone 3 lysine residues, thereby affecting DNA accessibility and transcriptomic landscape. A decrease in autophagy and an increase in DNA damage were also noted in Sirt6 -deficient cells. Further mechanistic insights revealed that loss of SIRT6 increased senescence and SASP burden in the disc characterized by increased p21, γH2AX, IL-6, and TGF-β abundance. Taken together our study highlights the contribution of SIRT6 in modulating DNA damage, autophagy and cell senescence, and its importance in maintaining disc health during aging thereby underscoring it as a potential therapeutic target to treat intervertebral disc degeneration.
    DOI:  https://doi.org/10.1101/2024.09.09.612072
  75. Mol Biol Rep. 2024 Sep 27. 51(1): 1021
    The senescent marker p16INK4a enhances macrophage foam cells formation.
    Wei Sheng Siew, Yin Quan Tang, Bey Hing Goh, Wei Hsum Yap.
       BACKGROUND: The senescence marker p16INK4a, which constitutes part of the genome 9p21.3 cardiovascular disease (CVD) risk allele, is believed to play a role in foam cells formation. This study aims to unravel the role of p16INK4a in mediating macrophage foam cells formation, cellular senescence, and autophagy lysosomal functions.
    METHODS: The mammalian expression plasmid pCMV-p16INK4a was used to induce p16INK4a overexpression in THP-1 macrophages. Next, wild-type and p16INK4a-overexpressed macrophages were incubated with oxidized LDL to induce foam cells formation. Lipids accumulation was evaluated using Oil-red-O staining and cholesterol efflux assay, as well as expression of scavenger receptors CD36 and LOX-1. Cellular senescence in macrophage foam cells were determined through analysis of senescence-associated β-galactosidase activity and other SASP factors expression. Meanwhile, autophagy induction was assessed through detection of autophagosome formation and LC3B/p62 markers expression.
    RESULTS: The findings showed that p16INK4a enhanced foam cells formation with increased scavenger receptors CD36 and LOX-1 expression and reduced cholesterol efflux in THP-1 macrophages. Besides, β-galactosidase activity was enhanced, and SASP factors such as IL-1α, TNF-α, and MMP9 were up-regulated. In addition, p16INK4a is also shown to induce autophagy, as well as increasing autophagy markers LC3B and p62 expression.
    CONCLUSIONS: This study provides insights on p16INK4a in mediating macrophages foam cells formation, cellular senescence, and foam cells formation.
    Keywords:  Autophagy; Cellular Senescence; Macrophage foam cell; p16INK4a
    DOI:  https://doi.org/10.1007/s11033-024-09946-z
  76. J Hazard Mater. 2024 Sep 23. pii: S0304-3894(24)02517-2. [Epub ahead of print]480 135938
    Environmentally relevant concentrations of perfluorobutane sulfonate impair locomotion behaviors and healthspan by downregulating mitophagy in C. elegans.
    Yahui Shang, Kelie Chen, Heng Ni, Xiaoyu Zhu, Xiaoyu Yuan, Yuwei Wang, Xinxin Liu, Zhenyan Cui, Yuequn Niu, Yu Shi, Han Wu, Dajing Xia, Yihua Wu.
      Perfluorobutane sulfonate (PFBS), a chemical compound within the group of per- and polyfluoroalkyl substances (PFAS), has been utilized as an alternative to perfluorooctane sulfonate (PFOS) recently. Previous research has indicated that PFBS might be linked to a range of health concerns. However, the potential impacts of environmentally relevant concentrations of PFBS (25 nM) on aging as well as the underlying mechanisms remained largely unexplored. In this study, we investigated the impact of PFBS exposure on aging and the associated mechanisms in Caenorhabditis elegans. Our findings indicated that exposure to PFBS impaired healthspan of C. elegans. Through bioinformatic screening analyses, we identified that the dysfunctions of pink-1 mediated mitophagy might play a critical role in PFBS induced aging. The results furtherly revealed that PFBS exposure led to elevated levels of reactive oxygen species (ROS) and mitophagy impairment through downregulating pink-1/pdr-1 pathway. Furthermore, the mitophagy agonist Urolithin A (UA) effectively reversed PFBS-induced mitophagy dysfunction and enhanced healthspan in C. elegans. Taken together, our study suggested that exposure to environmentally relevant concentrations of PFBS could accelerate aging by downregulating the pink-1 mediated mitophagy. Promoting mitophagy within cells could be a promising therapeutic strategy for delaying PFBS-induced aging.
    Keywords:  Caenorhabditis elegans; Mitophagy; Perfluorobutane sulfonate; Reactive oxygen species; pink-1
    DOI:  https://doi.org/10.1016/j.jhazmat.2024.135938
  77. Curr Cancer Drug Targets. 2024 Sep 23.
    Deoxypodophyllotoxin Mediates Autophagy Death through Inhibition of GRP78 in Human Osteosarcoma.
    Xiao-Jun Tang, Ling-Li Luo, Wen-Chao Zhou, Gang-Qing Shi, Xiao-Xu Wang, Tian Zeng, Xiong-Jin Tan, Wei-Ming Guo, An-Bo Gao, Yukun Li, Juan Zou.
       BACKGROUND: Glucose-regulated protein 78 (GRP78), as a chaperone protein, can protect the endoplasmic reticulum of cells and is expressed to influence chemoresistance and prognosis in cancer. Deoxypodophyllotoxin (DPT) is a compound with antitumor effects on cancers. DPT inhibits the proliferation of osteosarcoma by inducing apoptosis, necrosis, or cell cycle arrest.
    OBJECT: This study was performed to demonstrate the molecular mechanism by which DPT attenuates osteosarcoma progression through GRP78.
    METHODS: Natural compound libraries and western blot (WB) were used to screen the inhibitors of osteosarcoma GRP78. The expression of mitochondria-related genes in cancer cells of the treatment group was detected by quantitative real-time PCR (qPCR) and WB. 3-(4,5)- Dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and 5-ethynyl-2'- deoxyuridine (EDU) were used to discover the activity and proliferation of osteosarcoma cells treated with DPT. We constructed an in vivo mouse model of DPT drug therapy and carried out immunohistochemical detection of xenografts. The treated osteosarcoma cells were analyzed using bioinformatics and electron microscopy. The data were analyzed finally.
    RESULTS: DPT inhibited osteosarcoma cell survival and the growth of tumor xenografts. It promoted up-regulation of BCL2-associated X protein (Bax) and B-cell CLL/lymphoma 2 (Bcl-2), which serves to mediate and attenuate, respectively, the killing activities of DPT through mitochondria dysfunction. The effect of DPT against cancer cells could be attenuated by the overexpression of GRP78, characterized by the inactivation of the caspase cascade. The loss of GRP78 in osteosarcoma cells negatively mediated the basal level of autophagyassociated genes. DPT stimulated autophagy via the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog (AKT), a mechanistic target of rapamycin (mTOR) axis. The autophagy caused by DPT played an active role in the osteosarcoma of humans and blocked the apoptotic cascade.
    CONCLUSION: Combination treatment with the GRP78 inhibitor DPT and pharmacological autophagy inhibitors will be a meaningful method of obviating osteosarcoma cells.
    Keywords:  DPT; GRP78; apoptosis; autophagy; combination treatment; osteosarcoma
    DOI:  https://doi.org/10.2174/0115680096312622240812093046
  78. Nat Commun. 2024 Sep 27. 15(1): 8274
    Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
    Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.
      A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.
    DOI:  https://doi.org/10.1038/s41467-024-52183-y
  79. J Cell Mol Med. 2024 Sep;28(18): e70074
    Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection.
    Sohrab Rahmani, Ali Roohbakhsh, Vahid Pourbarkhordar, A Wallace Hayes, Gholamreza Karimi.
      Despite extensive progress in the knowledge and understanding of cardiovascular diseases and significant advances in pharmacological treatments and procedural interventions, cardiovascular diseases (CVD) remain the leading cause of death globally. Mitochondrial dynamics refers to the repetitive cycle of fission and fusion of the mitochondrial network. Fission and fusion balance regulate mitochondrial shape and influence physiology, quality and homeostasis. Mitophagy is a process that eliminates aberrant mitochondria. Melatonin (Mel) is a pineal-synthesized hormone with a range of pharmacological properties. Numerous nonclinical trials have demonstrated that Mel provides cardioprotection against ischemia/reperfusion, cardiomyopathies, atherosclerosis and cardiotoxicity. Recently, interest has grown in how mitochondrial dynamics contribute to melatonin cardioprotective effects. This review assesses the literature on the protective effects of Mel against CVD via the regulation of mitochondrial dynamics and mitophagy in both in-vivo and in-vitro studies. The signalling pathways underlying its cardioprotective effects were reviewed. Mel modulated mitochondrial dynamics and mitophagy proteins by upregulation of mitofusin, inhibition of DRP1 and regulation of mitophagy-related proteins. The evidence supports a significant role of Mel in mitochondrial dynamics and mitophagy quality control in CVD.
    Keywords:  cardiovascular disease; dynamin‐related protein 1; heart; melatonin; mitochondrial fission; mitochondrial fusion; mitophagy
    DOI:  https://doi.org/10.1111/jcmm.70074
  80. Anim Reprod Sci. 2024 Sep 16. pii: S0378-4320(24)00192-1. [Epub ahead of print]270 107601
    The dual role of ATG7: Regulation of autophagy and apoptosis in porcine ovarian follicular granulosa cells.
    Wenwen Xing, Binbin Wang, Mengxuan Li, Nannan Qi, Jiying Liu.
      The regulation of mammalian ovarian development involves the coordinated processes of autophagy and apoptosis. The autophagy-related gene ATG7 plays a pivotal role in mediating crosstalk between these pathways. Despite its recognized importance, the specific function of ATG7 in ovarian follicular granulosa cells remains poorly understood. This study aimed to explore the effects of ATG7 overexpression on apoptosis and autophagy in porcine ovarian follicular granulosa cells and thereby provide insights into the interplay between these fundamental cellular mechanisms. An ATG7 overexpression vector was introduced into cells, followed by assessment of cell proliferation using the CCK-8 assay, quantification of related gene expression via real-time quantitative PCR and western blotting, and evaluation of apoptosis using TUNEL staining. ATG7 exhibited a predominant cytoplasmic localization and additional nuclear expression in porcine ovarian follicular granulosa cells. The transfection efficiency of the vector was initially verified, indicating that its overexpression notably increased expression of ATG7 protein. Further investigations confirmed that overexpression of ATG7 inhibited cell proliferation, stimulated autophagy, and promoted apoptosis in these cells. In summary, overexpression of ATG7 influences the viability of porcine ovarian follicular granulosa cells by regulating the interplay between autophagy and apoptosis. This study not only broadens the understanding of functional regulation of autophagy and apoptosis by ATG7, but also sheds light on the intricate mechanisms governing ovarian follicular atresia.
    Keywords:  ATG7; Apoptosis; Autophagy; Porcine ovarian follicular granulosa cells
    DOI:  https://doi.org/10.1016/j.anireprosci.2024.107601
  81. Vet Microbiol. 2024 Sep 24. pii: S0378-1135(24)00285-2. [Epub ahead of print]298 110263
    Thioredoxin C of Streptococcus suis serotype 2 contributes to virulence by inducing antioxidative stress and inhibiting autophagy via the MSR1/PI3K-Akt-mTOR pathway in macrophages.
    Chunxiao Ji, Yanying Pan, Bocheng Liu, Jianying Liu, Chijun Zhao, Zhuyuan Nie, Simeng Liao, Guangwei Kuang, Xin Wu, Quan Liu, Jie Ning, Yulong Tang, Lihua Fang.
      The thioredoxin (Trx) system plays a vital role in protecting against oxidative stress and ensures correct disulfide bonding to maintain protein function. Our previous research demonstrated that TrxA of Streptococcus suis Serotype 2 (SS2), a clinical strain from the lung of a diseased pig, contributes to virulence but is not involved in antioxidative stress. In this study, we identified another gene in the Trx family, TrxC, which encodes a protein of 104 amino acids with a CGDC active motif and 22.4 % amino acid sequence homology with TrxA. Unlike the TrxA, TrxC mutant strains were more susceptible to oxidative stresses induced by hydrogen peroxide and paraquat. In vitro experiments, the survival rate of the TrxC deletion mutant in RAW264.7 macrophages was only one-eighth of that of TrxA mutant strains. Transcriptome analysis revealed that autophagy-related genes were significantly upregulated in the TrxC mutant compared to those in the wild-type or TrxA mutant strains. Co-localization of LC3 puncta with TrxC was confirmed using laser confocal microscopy, and autophagy-related indicators were quantified using western blotting. Autophagy deficiency induced by ATG5 knockout significantly increased SS2 survival rate, especially in TrxC mutant strains. For the upstream signal regulation pathways, we found ΔTrxC strains regulate autophagy by activation of PI3K/Akt/mTOR signaling in RAW264.7 macrophages. In the Akt1-overexpressing cell line, ΔTrxC infection significantly decreased the autophagic response and promoted ΔTrxC mutant strain survival, while inhibition of Akt with MK2206 resulted in reduced ΔTrxC mutant strain survival and enhance the autophagic response. Furthermore, loss of TrxC increased the activity of MSR1, thereby inducing cellular autophagy and phagocytosis. Our data demonstrate that TrxC of SS2 contributes to virulence by inducing antioxidative stress and inhibits autophagy via the PI3K-Akt-mTOR pathway in macrophages, with MSR1 acting as a key factor in controlling infection.
    DOI:  https://doi.org/10.1016/j.vetmic.2024.110263
  82. Nat Rev Cardiol. 2024 Sep 20.
    Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.
    Fabrizia Bonacina, Xiangyu Zhang, Nicolas Manel, Laurent Yvan-Charvet, Babak Razani, Giuseppe D Norata.
      Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.
    DOI:  https://doi.org/10.1038/s41569-024-01072-4
  83. Int Immunopharmacol. 2024 Sep 24. pii: S1567-5769(24)01581-9. [Epub ahead of print]142(Pt B): 113060
    SAL protects endothelial cells from H2O2-induced endothelial dysfunction: Regulation of inflammation and autophagy by EZH2.
    Li Sun, Xuefang Li, Jie Zhang, Jiachao Pei, Jianhua Zhang, Yinghua Wang, Fei Lin, Guoan Zhao.
      One component of the polycomb repressor complex 2 is histone methyltransferase zeste homolog 2 (EZH2), which is also called Enhancer of zeste homolog 2. It is considered a potential therapeutic target for inhibiting endothelial dysfunction.. Hence, directing efforts towards EZH2 to weaken endothelium damage and regulate vascular lesions proves to be a highly successful therapeutic approach for enhancing endothelial dysfunction. This study aimed to investigate the mechanism by which salidroside (SAL) improves hydrogen peroxide (H2O2)-induced endothelial dysfunction. The investigation involved the use of many techniques, including western blotting, real-time polymerase chain reaction (RT-PCR), a scratch test, molecular docking, and other methods. The experimental findings demonstrated that SAL has the ability to inhibit the impaired functioning of endothelial cells caused by H2O2 and decrease the levels of NF-κB p65, NLRP3, TNF-α, Beclin1, LC3, and P62 proteins. Additionally, there seems to be a targeting relationship between SAL and EZH2, and EZH2 knockdown can reproduce the protective effect of SAL on endothelial function. Overall, SAL inhibits H2O2-induced HUVEC dysfunction by regulating autophagy and inflammatory signaling pathways through EZH2.
    Keywords:  Autophagy; EZH2; Endothelial dysfunction; HUVEC cells; Inflammation; Salidroside
    DOI:  https://doi.org/10.1016/j.intimp.2024.113060
  84. Circ Res. 2024 Sep 27.
    Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.
    Akira Yoshii, Timothy S McMillen, Yajun Wang, Bo Zhou, Hongye Chen, Durba Banerjee, Melisa Herrero, Pei Wang, Naoto Muraoka, Wang Wang, Charles E Murry, Rong Tian.
       BACKGROUND: Metabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood.
    METHODS: In a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31P NMR spectroscopy and substrate oxidation profile was assessed by 13C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes.
    RESULTS: HFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes.
    CONCLUSIONS: Maladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation.
    Keywords:  arginine methyl ester; fatty acids; heart diseases; mitophagy; ventricular dysfunction, left
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324103
  85. bioRxiv. 2024 Sep 15. pii: 2024.09.14.613064. [Epub ahead of print]
    Stress granule formation enables anchorage-independence survival in cancer cells.
    Seungwon Yang, Anaïs Aulas, Paul J Anderson, Pavel Ivanov.
      Stress granules (SGs) are dynamic cytoplasmic structures assembled in response to various stress stimuli that enhance cell survival under adverse environmental conditions. Here we show that SGs contribute to breast cancer progression by enhancing the survival of cells subjected to anoikis stress. SG assembly is triggered by inhibition of Focal Adhesion Kinase (FAK) or loss of adhesion signals. Combined proteomic analysis and functional studies reveal that SG formation enhances cancer cell proliferation, resistance to metabolic stress, anoikis resistance, and migration. Importantly, inhibiting SG formation promotes the sensitivity of cancer cells to FAK inhibitors being developed as cancer therapeutics. Furthermore, we identify the Rho-ROCK- PERK-eIF2α axis as a critical signaling pathway activated by loss of adhesion signals and inhibition of the FAK-mTOR-eIF4F complex in breast cancer cells. By triggering SG assembly and AKT activation in response to anoikis stress, PERK functions as an oncoprotein in breast cancer cells. Overall, our study highlights the significance of SG formation in breast cancer progression and suggests that therapeutic inhibition of SG assembly may reverse anoikis resistance in treatment-resistant cancers such as triple-negative breast cancer (TNBC).
    Highlights: Either anoikis stress or loss of adhesion induce stress granule (SG) formationThe Rho-ROCK-PERK-eIF2α axis is a crucial signaling pathway triggered by the absence of adhesion signals, leading to the promotion of SG formation along with the inhibition of the FAK- AKT/mTOR-eIF4F complex under anoikis stress.PERK functions as an oncogene in breast cancer cells, initiating SG formation and activating AKT under anoikis stress.Inhibiting SG formation significantly enhances the sensitivity to Focal Adhesion Kinase (FAK) inhibitors, suggesting a potential for combined therapy to improve cancer treatment efficacy.
    DOI:  https://doi.org/10.1101/2024.09.14.613064
  86. Res Sq. 2024 Sep 10. pii: rs.3.rs-4870330. [Epub ahead of print]
    FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway.
    Swati Maitra, Minwoo Baek, Yun-Jeong Choe, Nam Chul Kim.
      Background Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 ( CHCHD10 ) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10 S59L , and human cell models expressing CHCHD10 S59L , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 S59L . Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 S59L -induced diseases. Methods An in vivo human cell culture and in vivo Drosophila models expressing CHCHD10 S59L mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance. Results We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 S59L -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 S59L -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H S81L . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 S59L . Conclusion These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 S59L -induced ALS-FTD and possibly other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.
    DOI:  https://doi.org/10.21203/rs.3.rs-4870330/v1
  87. J Clin Invest. 2024 Sep 26. pii: e174415. [Epub ahead of print]
    TSC/mTORC1 mediates mTORC2/AKT1 signaling in c-MYC-induced murine hepatocarcinogenesis via centromere protein M.
    Yi Zhou, Shu Zhang, Guoteng Qiu, Xue Wang, Andrew Yonemura, Hongwei Xu, Guofei Cui, Shanshan Deng, Joanne Chun, Nianyong Chen, Meng Xu, Xinhua Song, Jingwen Wang, Zijing Xu, Youping Deng, Matthias Evert, Diego F Calvisi, Shumei Lin, Haichuan Wang, Xin Chen.
      Activated mTORC2/AKT signaling plays a role in hepatocellular carcinoma (HCC). Research has shown that TSC/mTORC1 and FOXO1 are distinct downstream effectors of AKT signaling in liver regeneration and metabolism. However, the mechanisms by which these pathways mediate mTORC2/AKT activation in HCC are not yet fully understood. Amplification and activation of c-MYC is a key molecular event in HCC. In this study, we explored the roles of TSC/mTORC1 and FOXO1 as downstream effectors of mTORC2/AKT1 in c-MYC-induced hepatocarcinogenesis. Using various genetic approaches in mice, we found that manipulating the FOXO pathway had minimal impact on c-MYC-induced HCC. In contrast, loss of mTORC2 inhibited c-MYC-induced HCC, an effect that was completely reversed by ablating TSC2, which activated mTORC1. Additionally, we discovered that p70/RPS6 and 4EBP1/eIF4E act downstream of mTORC1, regulating distinct molecular pathways. Notably, the 4EBP1/eIF4E cascade is crucial for cell proliferation and glycolysis in c-MYC-induced HCC. We also identified centromere protein M (CENPM) as a downstream target of the TSC2/mTORC1 pathway in c-MYC-driven hepatocarcinogenesis, and its ablation entirely inhibited c-MYC-dependent HCC formation. Our findings demonstrate that the TSC/mTORC1/CENPM pathway, rather than the FOXO cascade, is the primary signaling pathway regulating c-MYC-driven hepatocarcinogenesis. Targeting CENPM holds therapeutic potential for treating c-MYC-driven HCC.
    Keywords:  Hepatology; Liver cancer; Mouse models; Oncology; Signal transduction
    DOI:  https://doi.org/10.1172/JCI174415
  88. Cell. 2024 Sep 18. pii: S0092-8674(24)00977-2. [Epub ahead of print]
    mTOR activity paces human blastocyst stage developmental progression.
    Dhanur P Iyer, Heidar Heidari Khoei, Vera A van der Weijden, Harunobu Kagawa, Saurabh J Pradhan, Maria Novatchkova, Afshan McCarthy, Teresa Rayon, Claire S Simon, Ilona Dunkel, Sissy E Wamaitha, Kay Elder, Phil Snell, Leila Christie, Edda G Schulz, Kathy K Niakan, Nicolas Rivron, Aydan Bulut-Karslioğlu.
      Many mammals can temporally uncouple conception from parturition by pacing down their development around the blastocyst stage. In mice, this dormant state is achieved by decreasing the activity of the growth-regulating mTOR signaling pathway. It is unknown whether this ability is conserved in mammals in general and in humans in particular. Here, we show that decreasing the activity of the mTOR signaling pathway induces human pluripotent stem cells (hPSCs) and blastoids to enter a dormant state with limited proliferation, developmental progression, and capacity to attach to endometrial cells. These in vitro assays show that, similar to other species, the ability to enter dormancy is active in human cells around the blastocyst stage and is reversible at both functional and molecular levels. The pacing of human blastocyst development has potential implications for reproductive therapies.
    Keywords:  blastoid; development; diapause; dormancy; human; mTOR; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2024.08.048
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:11.