bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–09–01
sixty-four papers selected by
Viktor Korolchuk, Newcastle University
  1. Lipophagy and mitophagy in renal pathophysiology.
  2. Phosphorylation of the selective autophagy receptor TAX1BP1 by TBK1 and IKBKE/IKKi promotes Atg8-family protein-dependent clearance of MAVS aggregates.
  3. Function of CSNK2/CK2 selectively affects the endoplasmic reticulum and the Golgi apparatus in mtor-mediated autophagy induction.
  4. Molecular Mechanisms of Autophagy Decline during Aging.
  5. Therapeutic potential of curcumin in autophagy modulation: Insights into the role of transcription factor EB.
  6. Autophagy: Are Amino Acid Signals Dependent on the mTORC1 Pathway or Independent?
  7. USP8 PROMOTES INTRACELLULAR INFECTION by ENHANCING ESCRT-MEDIATED MEMBRANE REPAIR, LIMITING XENOPHAGY, and REDUCING OXIDATIVE STRESS.
  8. Premature senescence is regulated by crosstalk among TFEB, the autophagy lysosomal pathway and ROS derived from damaged mitochondria in NaAsO2-exposed auditory cells.
  9. Impact of oxytosis on the cross-talk of mTORC with mitochondrial proteins in drug-resistant cancer stem cells.
  10. Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
  11. Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance.
  12. An Update on the Study of the Molecular Mechanisms Involved in Autophagy during Bacterial Pathogenesis.
  13. Autophagy Regulates Age-Related Jawbone Loss via LepR+ Stromal Cells.
  14. A Negative Feedback Loop Compromises NMD-Mediated Virus Restriction by the Autophagy Pathway in Plants.
  15. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer.
  16. Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic.
  17. Osteoclasts control endochondral ossification via regulating acetyl-CoA availability.
  18. Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.
  19. Neohesperidin exerts antidepressant-like effect via the mechanistic target of rapamycin complex 1 in the medial prefrontal cortex in male mice.
  20. mTORC1 mediates the expansion of hematopoietic stem and progenitor cells through ribosome biogenesis protein Urb2 in zebrafish.
  21. Bunyavirus SFTSV nucleoprotein exploits tufm-mediated mitophagy to impair antiviral innate immunity.
  22. GHSR deficiency exacerbates Parkinson's disease pathology by impairing autophagy.
  23. Lysosomal membrane contact sites: Integrative hubs for cellular communication and homeostasis.
  24. Mitophagy in fibrotic diseases: molecular mechanisms and therapeutic applications.
  25. The mechanisms of Ca2+ regulating autophagy and its research progress in neurodegenerative diseases: A review.
  26. Navigating the autophagic landscape: Epigenetic modulation in gastrointestinal cancer.
  27. RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions.
  28. TFEB alleviates periodontitis by activating autophagy and inhibiting inflammation.
  29. mTORC1 hampers Hedgehog signaling in Tsc2 deficient cells.
  30. Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?
  31. MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.
  32. AMPK: The energy sensor at the crossroads of aging and cancer.
  33. Complex Interplay between DNA Damage and Autophagy in Disease and Therapy.
  34. HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.
  35. Autophagy and Female Fertility: Mechanisms, Clinical Implications, and Emerging Therapies.
  36. The Mitochondrial Distribution and Morphology Family 33 Gene FgMDM33 Is Involved in Autophagy and Pathogenesis in Fusarium graminearum.
  37. HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B.
  38. Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors.
  39. In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke.
  40. The Impairment of Endothelial Autophagy Accelerates Renal Senescence by Ferroptosis and NLRP3 Inflammasome Signaling Pathways with the Disruption of Endothelial Barrier.
  41. The crucial role of VPS35 and SHH in Parkinson's disease: Understanding the mechanisms behind the neurodegenerative disorder.
  42. Hypomyelination Leukodystrophy 16 (HLD16)-Associated Mutation p.Asp252Asn of TMEM106B Blunts Cell Morphological Differentiation.
  43. A LAT1-Like Amino Acid Transporter Regulates Neuronal Activity in the Drosophila Mushroom Bodies.
  44. Metformin as a Modulator of Autophagy and Hypoxia Responses in the Enhancement of Wound Healing in Diabetic Rats.
  45. Taurine rescues intervertebral disc degeneration by activating mitophagy through the PINK1/Parkin pathway.
  46. Mitochondrial dysfunction in acute kidney injury.
  47. Regulation of TIR-1/SARM-1 by miR-71 Protects Dopaminergic Neurons in a C. elegans Model of LRRK2-Induced Parkinson's Disease.
  48. mTOR Dysregulation, Insulin Resistance, and Hypertension.
  49. BNIP3-mediated mitophagy attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis through P62-KEAP1-NRF2 pathway activation to maintain iron and redox homeostasis.
  50. Structure of a truncated human GlcNAc-1-phosphotransferase variant reveals the basis for its hyperactivity.
  51. Macrophage autophagy protects against acute kidney injury by inhibiting renal inflammation through the degradation of TARM1.
  52. MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease.
  53. The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis.
  54. The preventive and therapeutic role of Lactobacillus spp. in in vitro model of inflammation via affecting autophagy signaling pathway.
  55. ATF family members as therapeutic targets in cancer: From mechanisms to pharmacological interventions.
  56. KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons.
  57. Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1.
  58. NLRP4 renders pancreatic cancer resistant to olaparib through promotion of the DNA damage response and ROS-induced autophagy.
  59. Loss of BACH1 improves osteogenic differentiation in glucocorticoid-induced hBMSCs through restoring autophagy.
  60. Role of fibroblast autophagy and proliferation in skin anti-aging.
  61. Trehalose attenuates testicular aging by activating autophagy and improving mitochondrial quality.
  62. Docosahexaenoic acid enhances the treatment efficacy for castration-resistant prostate cancer by inhibiting autophagy through Atg4B inhibition.
  63. Ferritinophagy: Molecular mechanisms and role in disease.
  64. Structural Analyses of a GABARAP~ATG3 Conjugate Uncover a Novel Non-covalent Ubl-E2 Backside Interaction.
  1. Nephron. 2024 Aug 23.
    Lipophagy and mitophagy in renal pathophysiology.
    Nicolas Dupont, Fabiola Terzi.
       BACKGROUND: The lysosomal autophagic pathway plays a fundamental role in cellular and tissue homeostasis, its deregulation is linked to human pathologies including kidney diseases. Autophagy can randomly degrade cytoplasmic components in a non-selective manner commonly referred to as bulk autophagy. In contrast, selective forms of autophagy specifically target cytoplasmic structures such as organelles and protein aggregates thereby being important for cellular quality control and organelle homeostasis.
    SUMMARY: Research during the past decades has begun to elucidate the role of selective autophagy in kidney physiology and kidney diseases.
    KEY MESSAGES: In this review, we will summarize the knowledge on lipophagy and mitophagy, two forms of selective autophagy important in renal epithelium homeostasis and discuss how their deregulations contribute to renal disease progression.
    DOI:  https://doi.org/10.1159/000540688
  2. Autophagy. 2024 Aug 28.
    Phosphorylation of the selective autophagy receptor TAX1BP1 by TBK1 and IKBKE/IKKi promotes Atg8-family protein-dependent clearance of MAVS aggregates.
    Jesse White, Young Bong Choi, Jiawen Zhang, Mai Tram Vo, Chaoxia He, Kashif Shaikh, Edward W Harhaj.
      TAX1BP1 is a selective macroautophagy/autophagy receptor that inhibits NFKB and RIGI-like receptor (RLR) signaling to prevent excessive inflammation and maintain homeostasis. Selective autophagy receptors such as SQSTM1/p62 and OPTN are phosphorylated by the kinase TBK1 to stimulate their selective autophagy function. However, it is unknown if TAX1BP1 is regulated by TBK1 or other kinases under basal conditions or during RNA virus infection. Here, we found that TBK1 and IKBKE/IKKi function redundantly to phosphorylate TAX1BP1 and regulate its autophagic turnover through canonical macroautophagy. TAX1BP1 phosphorylation promotes its localization to lysosomes resulting in its degradation. Additionally, we found that during vesicular stomatitis virus infection, TAX1BP1 is targeted to lysosomes in an Atg8-family protein-independent manner. Furthermore, TAX1BP1 plays a critical role in the clearance of MAVS aggregates, and phosphorylation of TAX1BP1 controls its MAVS aggrephagy function. Together, our data support a model whereby TBK1 and IKBKE license TAX1BP1-selective autophagy function to inhibit MAVS and RLR signaling.
    Keywords:  Aggrephagy; IKBKE/Ikki; MAVS; TAX1BP1; TBK1; autophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2394306
  3. Autophagy. 2024 Aug 23.
    Function of CSNK2/CK2 selectively affects the endoplasmic reticulum and the Golgi apparatus in mtor-mediated autophagy induction.
    Pablo Sanz-Martinez, Rayene Berkane, Alexandra Stolz.
      Selective macroautophagy/autophagy of the endoplasmic reticulum, known as reticulophagy/ER-phagy, is essential to maintain ER homeostasis. We recently showed that members of the autophagy receptor family RETREG/FAM134 are regulated by phosphorylation-dependent ubiquitination. In an unbiased screen we had identified several kinases downstream of MTOR with profound impact on reticulophagy flux, including ATR and CSNK2/CK2. Inhibition of CSNK2 by SGC-CK2-1 prevented regulatory ubiquitination of RETREG1/FAM134B and RETREG3/FAM134C upon autophagy activation as well as the formation of high-density RETREG1- and RETREG3-clusters. Here we report on additional resource data of global proteomics upon CSNK2 and ATR inhibition, respectively. Our data suggests that the function of CSNK2 is mainly limited to the ER/reticulophagy and Golgi/Golgiphagy, while ATR inhibition by VE-822 affects the vast majority of organelles/selective autophagy pathways.
    Keywords:  Kinase signaling; LAMP1; RETREG; methuosis; selective autophagy; vacuolization
    DOI:  https://doi.org/10.1080/15548627.2024.2395725
  4. Cells. 2024 Aug 16. pii: 1364. [Epub ahead of print]13(16):
    Molecular Mechanisms of Autophagy Decline during Aging.
    Shaun H Y Lim, Malene Hansen, Caroline Kumsta.
      Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age. In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy.
    Keywords:  aging; autophagy; lysosomes; proteolysis; proteostasis
    DOI:  https://doi.org/10.3390/cells13161364
  5. Mutat Res. 2024 Aug 12. pii: S0027-5107(24)00029-0. [Epub ahead of print]829 111879
    Therapeutic potential of curcumin in autophagy modulation: Insights into the role of transcription factor EB.
    Shabnam Radbakhsh, Prashant Kesharwani, Amirhossein Sahebkar.
      Transcription factor EB (TFEB) is a basic Helix-Loop-Helix/Leucine Zipper (bHLHZip) class of DNA-binding proteins, which can control the expression of genes included in the autophagy-lysosomal pathway. TFEB regulates the autophagic flux by enhancing lysosome biogenesis, forming autophagosomes, and fusion with lysosomes, thereby facilitating cellular clearance of pathogenic protein structures. Curcumin is a natural polyphenolic molecule with pharmacological properties that make it a potential therapeutic candidate for a wide range of diseases. One of the important curcumin mechanisms of action includes modulation of autophagy through affecting various signaling components such as TFEB. This review discusses in vitro and in vivo evidence on the effects of curcumin on autophagy process via modulating TFEB activity in different disorders.
    Keywords:  Autophagy; Cancer; Curcumin; Lysosomal pathway; Neurological disease; TFEB
    DOI:  https://doi.org/10.1016/j.mrfmmm.2024.111879
  6. Curr Issues Mol Biol. 2024 Aug 13. 46(8): 8780-8793
    Autophagy: Are Amino Acid Signals Dependent on the mTORC1 Pathway or Independent?
    Chenglong Jin, Min Zhu, Jinling Ye, Zhiwen Song, Chuntian Zheng, Wei Chen.
      Autophagy is a kind of "self-eating" phenomenon that is ubiquitous in eukaryotic cells. It mainly manifests in the damaged proteins or organelles in the cell being wrapped and transported by the autophagosome to the lysosome for degradation. Many factors cause autophagy in cells, and the mechanism of nutrient-deficiency-induced autophagy has been a research focus. It has been reported that amino-acid-deficiency-induced cellular autophagy is mainly mediated through the mammalian rapamycin target protein complex 1 (mTORC1) signaling pathway. In addition, some researchers also found that non-mTORC1 signaling pathways also regulate autophagy, and the mechanism of autophagy occurrence induced by the deficiency of different amino acids is not precisely the same. Therefore, this review aims to summarize the process of various amino acids regulating cell autophagy and provide a narrative review on the molecular mechanism of amino acids regulating autophagy.
    Keywords:  amino acid; autophagy; mTORC1; molecular mechanism
    DOI:  https://doi.org/10.3390/cimb46080519
  7. Autophagy. 2024 Aug 23.
    USP8 PROMOTES INTRACELLULAR INFECTION by ENHANCING ESCRT-MEDIATED MEMBRANE REPAIR, LIMITING XENOPHAGY, and REDUCING OXIDATIVE STRESS.
    Pallavi Chandra, Jennifer A Philips.
      The host ESCRT-machinery repairs damaged endolysosomal membranes. If damage persists, selective macroautophagy/autophagy clears the damaged compartment. Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that damages the phagosomal membrane and targets ESCRT-mediated repair as part of its virulence program. The E3 ubiquitin ligases PRKN and SMURF1 promote autophagic capture of damaged, Mtb-containing phagosomes. Because ubiquitination is a reversible process, we anticipated that host deubiquitinases (DUBs) would also be involved. Here, we screened all predicted mouse DUBs for their role in ubiquitin targeting and control of intracellular Mtb. We show that USP8 (ubiquitin specific peptidase 8) colocalizes with intracellular Mtb, recognizes phagosomal membrane damage, and is required for ESCRT-dependent membrane repair. Furthermore, we show that USP8 regulates the NFE2L2/NRF2-dependent antioxidant signature. Taken together, our study demonstrates a central role of USP8 in promoting Mtb intracellular growth by promoting phagosomal membrane repair, limiting ubiquitin-driven selective autophagy, and reducing oxidative stress.
    Keywords:  Autophagy; deubiquitinase; endomembrane damage; mycobacterium tuberculosis
    DOI:  https://doi.org/10.1080/15548627.2024.2395134
  8. Cell Death Discov. 2024 Aug 28. 10(1): 382
    Premature senescence is regulated by crosstalk among TFEB, the autophagy lysosomal pathway and ROS derived from damaged mitochondria in NaAsO2-exposed auditory cells.
    Yuna Suzuki, Ken Hayashi, Fumiyuki Goto, Yasuyuki Nomura, Chisato Fujimoto, Makoto Makishima.
      Age-related hearing loss (ARHL) is one of the most prevalent types of sensory decline in a superaging society. Although various studies have focused on the effect of oxidative stress on the inner ear as an inducer of ARHL, there are no effective preventive approaches for ARHL. Recent studies have suggested that oxidative stress-induced DNA damage responses (oxidative DDRs) drive cochlear cell senescence and contribute to accelerated ARHL, and autophagy could function as a defense mechanism against cellular senescence in auditory cells. However, the underlying mechanism remains unclear. Sodium arsenite (NaAsO2) is a unique oxidative stress inducer associated with reactive oxygen species (ROS) that causes high-tone hearing loss similar to ARHL. Transcription factor EB (TFEB) functions as a master regulator of the autophagy‒lysosome pathway (ALP), which is a potential target during aging and the pathogenesis of various age-related diseases. Here, we focused on the function of TFEB and the impact of intracellular ROS as a potential target for ARHL treatment in a NaAsO2-induced auditory premature senescence model. Our results suggested that short exposure to NaAsO2 leads to DNA damage, lysosomal damage and mitochondrial damage in auditory cells, triggering temporary signals for TFEB transport into the nucleus and, as a result, causing insufficient autophagic flux and declines in lysosomal function and biogenesis and mitochondrial quality. Then, intracellular ROS derived from damaged mitochondria play a role as a second messenger to induce premature senescence in auditory cells. These findings suggest that TFEB activation via transport into the nucleus contributes to anti-senescence activity in auditory cells and represents a new therapeutic target for ARHL. We have revealed the potential function of TFEB as a master regulator of the induction of oxidative stress-induced premature senescence and the senescence-associated secretion phenotype (SASP) in auditory cells, which regulates ALP and controls mitochondrial quality through ROS production.
    DOI:  https://doi.org/10.1038/s41420-024-02139-4
  9. J Cell Physiol. 2024 Aug 26. e31421
    Impact of oxytosis on the cross-talk of mTORC with mitochondrial proteins in drug-resistant cancer stem cells.
    Santhi L Pandrangi, Prasanthi Chittineedi, Ram K Manthari, Balaji Suhruth.
      By delivering the environmental inputs to transport nutrients and growth factors, Mechanistic Target of Rapamycin (mTOR) plays a significant role in the growth and metabolism of eukaryotic cells through the regulation of numerous elementary cellular processes such as autophagy, protein synthesis, via translation of mitochondrial protein transcription factor A mitochondrial, mitochondrial ribosomal proteins, and mitochondrial respiratory complexes I &V that are encoded in the nucleus with the help of translation initiation factor 4E-BP. These mitochondrial proteins are involved in cell signaling to regulate proper cell growth, proliferation, and death which are essential for tumor growth and proliferation. This suggests that tumor cells are dependent on mTORC1 for various metabolic pathways. However, this crucial regulator is activated and regulated by calcium homeostasis. Mounting evidence suggests the role of calcium ions in regulating mitochondrial enzymes and proteins. Hence, disrupting calcium homeostasis leads to calcium-dependent cell death called "Oxytosis" through hampering the expression of various mitochondrial proteins. "Oxytosis" is a novel non-apoptotic cell death characterized by glutamate cytotoxicity and ferritin degradation. The present review focuses on the crosstalk between mTORC1 and mitochondrial proteins in the cancer pathophysiology and the impact of calcium ions on disrupting mTORC1 leading to the induction of "Oxytosis."
    Keywords:  calcium; mTOR; mitochondria; oxytosis
    DOI:  https://doi.org/10.1002/jcp.31421
  10. Int J Mol Sci. 2024 Aug 15. pii: 8884. [Epub ahead of print]25(16):
    Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
    Nadia Papini, Paola Giussani, Cristina Tringali.
      Metformin is a widely employed drug in type 2 diabetes. In addition to warranting good short- and long-term glycemic control, metformin displays many intriguing properties as protection against cardiovascular and neurodegenerative diseases, anti-tumorigenic and longevity promotion. In addition to being a low-cost drug, metformin is generally well tolerated. However, despite the enthusiastic drive to aliment these novel studies, many contradictory results suggest the importance of better elucidating the complexity of metformin action in different tissues/cells to establish its possible employment in neurodegenerative diseases. This review summarises recent data identifying lysosomal-dependent processes and lysosomal targets, such as endosomal Na+/H+ exchangers, presenilin enhancer 2 (PEN2), the lysosomal pathway leading to AMP-activated protein kinase (AMPK) activation, and the transcription factor EB (TFEB), modulated by metformin. Lysosomal dysfunctions resulting in autophagic and lysosomal acidification and biogenesis impairment appear to be hallmarks of many inherited and acquired neurodegenerative diseases. Lysosomes are not yet seen as a sort of cellular dump but are crucial in determining key signalling paths and processes involved in the clearance of aggregated proteins. Thus, the possibility of pharmacologically modulating them deserves great interest. Despite the potentiality of metformin in this context, many additional important issues, such as dosing, should be addressed in the future.
    Keywords:  lysosome; metformin; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms25168884
  11. Cells. 2024 Aug 11. pii: 1332. [Epub ahead of print]13(16):
    Importance of Autophagy Regulation in Glioblastoma with Temozolomide Resistance.
    Young Keun Hwang, Dong-Hun Lee, Eun Chae Lee, Jae Sang Oh.
      Glioblastoma (GBM) is the most aggressive and common malignant and CNS tumor, accounting for 47.7% of total cases. Glioblastoma has an incidence rate of 3.21 cases per 100,000 people. The regulation of autophagy, a conserved cellular process involved in the degradation and recycling of cellular components, has been found to play an important role in GBM pathogenesis and response to therapy. Autophagy plays a dual role in promoting tumor survival and apoptosis, and here we discuss the complex interplay between autophagy and GBM. We summarize the mechanisms underlying autophagy dysregulation in GBM, including PI3K/AKT/mTOR signaling, which is most active in brain tumors, and EGFR and mutant EGFRvIII. We also review potential therapeutic strategies that target autophagy for the treatment of GBM, such as autophagy inhibitors used in combination with the standard of care, TMZ. We discuss our current understanding of how autophagy is involved in TMZ resistance and its role in glioblastoma development and survival.
    Keywords:  autophagy; chemoresistance; glioblastoma; temozolomide
    DOI:  https://doi.org/10.3390/cells13161332
  12. Biomedicines. 2024 Aug 05. pii: 1757. [Epub ahead of print]12(8):
    An Update on the Study of the Molecular Mechanisms Involved in Autophagy during Bacterial Pathogenesis.
    Md Ataur Rahman, Amily Sarker, Mohammed Ayaz, Ananya Rahman Shatabdy, Nabila Haque, Maroua Jalouli, M D Hasanur Rahman, Taslin Jahan Mou, Shuvra Kanti Dey, Ehsanul Hoque Apu, Muhammad Sohail Zafar, Md Anowar Khasru Parvez.
      Autophagy is a unique catabolic process that degrades irrelevant or damaged components in eukaryotic cells to maintain homeostasis and eliminate infections from pathogenesis. Pathogenic bacteria have developed many autophagy manipulation techniques that affect host immune responses and intracellular bacterial pathogens have evolved to avoid xenophagy. However, reducing its effectiveness as an innate immune response has not yet been elucidated. Bacterial pathogens cause autophagy in infected cells as a cell-autonomous defense mechanism to eliminate the pathogen. However, harmful bacteria have learned to control autophagy and defeat host defenses. Intracellular bacteria can stimulate and control autophagy, while others inhibit it to prevent xenophagy and lysosomal breakdown. This review evaluates the putative functions for xenophagy in regulating bacterial infection, emphasizing that successful pathogens have evolved strategies to disrupt or exploit this defense, reducing its efficiency in innate immunity. Instead, animal models show that autophagy-associated proteins influence bacterial pathogenicity outside of xenophagy. We also examine the consequences of the complex interaction between autophagy and bacterial pathogens in light of current efforts to modify autophagy and develop host-directed therapeutics to fight bacterial infections. Therefore, effective pathogens have evolved to subvert or exploit xenophagy, although autophagy-associated proteins can influence bacterial pathogenicity outside of xenophagy. Finally, this review implies how the complex interaction between autophagy and bacterial pathogens affects host-directed therapy for bacterial pathogenesis.
    Keywords:  autophagy; bacteria; bacterial toxins; pathogenesis; xenophagy
    DOI:  https://doi.org/10.3390/biomedicines12081757
  13. J Dent Res. 2024 Aug 26. 220345241264810
    Autophagy Regulates Age-Related Jawbone Loss via LepR+ Stromal Cells.
    B Sun, Y Xu, H Wang, F Wang, Q Li, Y Chen, Z Wang.
      Bone aging and decreased autophagic activity are related but poorly explored in the jawbone. This study aimed to characterize the aging jawbones and jawbone-derived stromal cells (JBSCs) and determine the role of autophagy in jawbone mass decline. We observed that the jawbones of older individuals and mice exhibited similar age-related bone loss. Furthermore, leptin receptor (LepR)-lineage cells served as the primary source for in vitro cultured and expanded JBSCs, referred to as LepR-Cre+/JBSCs. RNA-sequencing data from the jawbones and LepR-Cre+/JBSCs showed the upregulated expression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway during aging. Through single-cell transcriptomics, we identified a decrease in the proportion of osteogenic lineage cells and the activation of the PI3K/AKT pathway in LepR-lineage cells in aging bone tissues. Reduced basal autophagic activity, diminished autophagic flux, and decreased osteogenesis occurred in the jawbones and LepR-Cre+/JBSCs from older mice (O-mice; O-JBSCs). Pharmacologic and constitutive autophagy activation alleviated the impaired osteogenesis in O-JBSCs. In addition, the suppression of mTOR-induced autophagy improved the aging phenotype of O-JBSCs. The activation of autophagy in LepR-Cre+/JBSCs using chemical autophagic activators reduced the alveolar bone resorption in O-mice. Therefore, our study demonstrated that ATG molecules and pathways are crucial in jawbone aging, providing novel approaches to understanding age-related jawbone loss.
    Keywords:  RNA-seq; aging; bone resorption; jaw; leptin receptor; osteogenesis
    DOI:  https://doi.org/10.1177/00220345241264810
  14. Adv Sci (Weinh). 2024 Aug;11(32): e2400978
    A Negative Feedback Loop Compromises NMD-Mediated Virus Restriction by the Autophagy Pathway in Plants.
    Yalin Chen, Mingxuan Jia, Linhao Ge, Zhaolei Li, Hao He, Xueping Zhou, Fangfang Li.
      Nonsense-mediated decay (NMD) and autophagy play pivotal roles in restricting virus infection in plants. However, the interconnection between these two pathways in viral infections has not been explored. Here, it is shown that overexpression of NbSMG7 and NbUPF3 attenuates cucumber green mottle mosaic virus (CGMMV) infection by recognizing the viral internal termination codon and vice versa. NbSMG7 is subjected to autophagic degradation, which is executed by its interaction with one of the autophagy-related proteins, NbATG8i. Mutation of the ATG8 interacting motif (AIM) in NbSMG7 (SMG7mAIM1) abolishes the interaction and comprises its autophagic degradation. Silencing of NbSMG7 and NbATG8i, or NbUPF3 and NbATG8i, compared to silencing each gene individually, leads to more virus accumulations, but overexpression of NbSMG7 and NbATG8i fails to achieve more potent virus inhibition. When CGMMV is co-inoculated with NbSMG7mAIM1 or with NbUPF3, compared to co-inoculating with NbSMG7 in NbATG8i transgene plants, the inoculated plants exhibit milder viral phenotypes. These findings reveal that NMD-mediated virus inhibition is impaired by the autophagic degradation of SMG7 in a negative feedback loop, and a novel regulatory interplay between NMD and autophagy is uncovered, providing insights that are valuable in optimizing strategies to harness NMD and autophagy for combating viral infections.
    Keywords:  SMG7; UPF3; autophagic degradation; nonsense mediated RNA decay; virus restriction
    DOI:  https://doi.org/10.1002/advs.202400978
  15. Int J Mol Sci. 2024 Aug 08. pii: 8647. [Epub ahead of print]25(16):
    Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer.
    Lochana Kovale, Manish Kumar Singh, Joungmok Kim, Joohun Ha.
      Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.
    Keywords:  AMPK; autophagy; cancer stem cells
    DOI:  https://doi.org/10.3390/ijms25168647
  16. Curr Biol. 2024 Aug 16. pii: S0960-9822(24)01027-3. [Epub ahead of print]
    Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic.
    Judith Ottensmeyer, Alessandra Esch, Henrique Baeta, Sandro Sieger, Yamini Gupta, Maximilian F Rathmann, Andreas Jeschke, Daniel Jacko, Kirill Schaaf, Thorsten Schiffer, Bahareh Rahimi, Lukas Lövenich, Angela Sisto, Peter F M van der Ven, Dieter O Fürst, Albert Haas, Wilhelm Bloch, Sebastian Gehlert, Bernd Hoffmann, Vincent Timmerman, Pitter F Huesgen, Jörg Höhfeld.
      Proteome maintenance in contracting skeletal and cardiac muscles depends on the chaperone-regulating protein BAG3. Reduced BAG3 activity leads to muscle weakness and heart failure in animal models and patients. BAG3 and its chaperone partners recognize mechanically damaged muscle proteins and initiate their disposal through chaperone-assisted selective autophagy (CASA). However, molecular details of the force-dependent regulation of BAG3 have remained elusive so far. Here, we demonstrate that mechanical stress triggers the dephosphorylation of BAG3 in human muscle and in isolated cells. We identify force-regulated phospho-switches in BAG3 that control CASA complex assembly and CASA activity. Differential proteomics reveal RAB GTPases, which organize membrane traffic and fusion, as dephosphorylation-dependent interactors of BAG3. In fact, RAB7A and RAB11B are shown here to be essential for CASA in skeletal muscle cells. Moreover, BAG3 dephosphorylation is also observed upon induction of mitophagy, suggesting an involvement of the cochaperone in the RAB7A-dependent autophagic engulfment of damaged mitochondria in exercised muscle. Cooperation of BAG3 with RAB7A relies on a direct interaction of both proteins, which is regulated by the nucleotide state of the GTPase and by association with the autophagosome membrane protein LC3B. Finally, we provide evidence that BAG3 and RAB7A also cooperate in non-muscle cells and propose that overactivation of CASA in RAB7A-L129F patients contributes to the loss of peripheral neurons in Charcot-Marie-Tooth neuropathy.
    Keywords:  autophagy; exercise; membrane trafficking; molecular chaperones; myopathy; neurodegeneration; protein degradation
    DOI:  https://doi.org/10.1016/j.cub.2024.07.088
  17. Bone Res. 2024 Aug 28. 12(1): 49
    Osteoclasts control endochondral ossification via regulating acetyl-CoA availability.
    Daizhao Deng, Xianming Liu, Wenlan Huang, Sirui Yuan, Genming Liu, Shanshan Ai, Yijie Fu, Haokun Xu, Xinyi Zhang, Shihai Li, Song Xu, Xiaochun Bai, Yue Zhang.
      Osteoclast is critical in skeletal development and fracture healing, yet the impact and underlying mechanisms of their metabolic state on these processes remain unclear. Here, by using osteoclast-specific small GTPase Rheb1-knockout mice, we reveal that mitochondrial respiration, rather than glycolysis, is essential for cathepsin K (CTSK) production in osteoclasts and is regulated by Rheb1 in a mechanistic target of rapamycin complex 1 (mTORC1)-independent manner. Mechanistically, we find that Rheb1 coordinates with mitochondrial acetyl-CoA generation to fuel CTSK, and acetyl-CoA availability in osteoclasts is the central to elevating CTSK. Importantly, our findings demonstrate that the regulation of CTSK by acetyl-CoA availability is critical and may confer a risk for abnormal endochondral ossification, which may be the main cause of poor fracture healing on alcohol consumption, targeting Rheb1 could successfully against the process. These findings uncover a pivotal role of mitochondria in osteoclasts and provide a potent therapeutic opportunity in bone disorders.
    DOI:  https://doi.org/10.1038/s41413-024-00360-6
  18. J Cell Biol. 2024 Nov 04. pii: e202308099. [Epub ahead of print]223(11):
    Lactylation stabilizes TFEB to elevate autophagy and lysosomal activity.
    Yewei Huang, Gan Luo, Kesong Peng, Yue Song, Yusha Wang, Hongtao Zhang, Jin Li, Xiangmin Qiu, Maomao Pu, Xinchang Liu, Chao Peng, Dante Neculai, Qiming Sun, Tianhua Zhou, Pintong Huang, Wei Liu.
      The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.
    DOI:  https://doi.org/10.1083/jcb.202308099
  19. J Pharmacol Sci. 2024 Oct;pii: S1347-8613(24)00055-0. [Epub ahead of print]156(2): 82-85
    Neohesperidin exerts antidepressant-like effect via the mechanistic target of rapamycin complex 1 in the medial prefrontal cortex in male mice.
    Satoshi Deyama, Shun Aoki, Rinako Sugie, Katsuyuki Kaneda.
      Neohesperidin, a citrus flavonoid, shows potential for activating the mechanistic target of rapamycin complex 1 (mTORC1). Here, the antidepressant-like effect of neohesperidin was examined in male ICR mice (naïve mice and mice treated repeatedly with prednisolone, a synthetic glucocorticoid, which induces depression-like behavior). Oral neohesperidin administration exerted an antidepressant-like effect in the forced swim test 1 h post-treatment, in naïve mice; this effect was no longer observed at 24 h. Neohesperidin also reversed prednisolone-induced depression-like behavior. This effect was blocked by infusing rapamycin, an mTORC1 inhibitor, into the medial prefrontal cortex. Neohesperidin may rapidly produce an antidepressant-like effect.
    Keywords:  Antidepressant; Mechanistic target of rapamycin complex 1; Neohesperidin
    DOI:  https://doi.org/10.1016/j.jphs.2024.07.010
  20. Stem Cell Reports. 2024 Aug 19. pii: S2213-6711(24)00220-0. [Epub ahead of print]
    mTORC1 mediates the expansion of hematopoietic stem and progenitor cells through ribosome biogenesis protein Urb2 in zebrafish.
    Wenming Huang, Yu Yue, Weifeng Hao, Zhenan Zhang, Pengcheng Cai, Deqin Yang.
      Mammalian target of rapamycin (mTOR) serves as the key sensor to control protein synthesis, cell growth, and survival. Despite mTOR is reported to regulate hematopoietic stem and progenitor cell (HSPC) engraftment and multiple-lineage hematopoiesis in mice, the roles of unique mTOR complexes (mTORCs) in early HSPC development and HSPC pool formation have not been adequately elucidated. Here, we uncover that mTORC1 is essential for early HSPC expansion in zebrafish. mTORC1 signaling was highly activated in definitive HSPCs during the emerging and expanding stages. Pharmacological or genetic inactivation of mTORC1 would cause defective HSPC expansion and migration due to disrupted cell proliferation. Interestingly, mTORC2 is dispensable for early HSPC development. Ribosome biogenesis protein Urb2 was downregulated upon mTORC1 inhibition, and urb2 overexpression partially rescued the hematopoietic defects in mTORC1-deficient embryos. These data demonstrate that mTORC1 signaling regulates early HSPC expansion through Urb2, and this work will deepen our understanding of mTOR in different physiological processes.
    Keywords:  Urb2; hematopoietic; mTOR; proliferation; zebrafish
    DOI:  https://doi.org/10.1016/j.stemcr.2024.07.011
  21. Autophagy. 2024 Aug 27.
    Bunyavirus SFTSV nucleoprotein exploits tufm-mediated mitophagy to impair antiviral innate immunity.
    Wen-Kang Zhang, Jia-Min Yan, Min Chu, Bang Li, Xiao-Lan Gu, Ze-Zheng Jiang, Ze-Min Li, Pan-Pan Liu, Tian-Mei Yu, Chuan-Min Zhou, Xue-Jie Yu.
      Severe fever with thrombocytopenia syndrome is an emerging viral hemorrhagic fever caused by a tick-borne bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), with a high case fatality. We previously found that SFTSV nucleoprotein (NP) induces macroautophagy/autophagy to facilitate virus replication. However, the role of NP in antagonizing host innate immunity remains unclear. Mitophagy, a selected form of autophagy, eliminates damaged mitochondria to maintain mitochondrial homeostasis. Here, we demonstrate that SFTSV NP triggers mitophagy to degrade MAVS (mitochondrial antiviral signaling protein), thereby blocking MAVS-mediated antiviral signaling to escape the host immune response. Mechanistically, SFTSV NP translocates to mitochondria by interacting with TUFM (Tu translation elongation factor, mitochondrial), and mediates mitochondrial sequestration into phagophores through interacting with LC3, thus inducing mitophagy. Notably, the N-terminal LC3-interacting region (LIR) motif of NP is essential for mitophagy induction. Collectively, our results demonstrated that SFTSV NP serves as a novel virulence factor, inducing TUFM-mediated mitophagy to degrade MAVS and evade the host immune response.
    Keywords:  Bunyavirus; MAVS; SFTSV; interferon; mitophagy; nucleoprotein
    DOI:  https://doi.org/10.1080/15548627.2024.2393067
  22. Redox Biol. 2024 Aug 20. pii: S2213-2317(24)00300-8. [Epub ahead of print]76 103322
    GHSR deficiency exacerbates Parkinson's disease pathology by impairing autophagy.
    Xue Xiao, Tingting Tang, Mingxia Bi, Jing Liu, Mengru Liu, Qian Jiao, Xi Chen, Chunling Yan, Xixun Du, Hong Jiang.
      In Parkinson's disease (PD), exogenous ghrelin protects dopaminergic neurons through its receptor, growth hormone secretagogue receptor (GHSR). However, in contrast to the strikingly low levels of ghrelin, GHSR is highly expressed in the substantia nigra (SN). What role does GHSR play in dopaminergic neurons is unknown. In this study, using GHSR knockout mice (Ghsr-/- mice) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, we found that GHSR deletion aggravated dopaminergic neurons degeneration, and the expression and activity of GHSR were significantly reduced in PD. Furthermore, we explored the potential mechanism that GHSR deficiency aggregated PD-related neurodegeneration. We showed that DEPTOR, a subunit of mTORC1, was overexpressed in Ghsr-/- mice, positively regulating autophagy and enhancing autophagy initiation. The expression of lysosomal markers was abnormal, implying lysosomal dysfunction. As a result, the damaged mitochondria could not be effectively eliminated, which ultimately exacerbated the injury of nigral dopaminergic neurons. In particular, we demonstrated that DEPTOR could be transcriptionally regulated by KLF4. Specific knockdown of KLF4 in dopaminergic neurons effectively alleviated neurodegeneration in Ghsr-/- mice. In summary, our results suggested that endogenous GHSR deletion-compromised autophagy by impairing lysosomal function, is a key contributor to PD, which provided ideas for therapeutic approaches involving the manipulation of GHSR.
    Keywords:  Autophagy; DEPTOR; GHSR; KLF4; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.redox.2024.103322
  23. Curr Top Membr. 2024 ;pii: S1063-5823(24)00020-6. [Epub ahead of print]93 85-116
    Lysosomal membrane contact sites: Integrative hubs for cellular communication and homeostasis.
    Sumit Bandyopadhyay, Daniel Adebayo, Eseiwi Obaseki, Hanaa Hariri.
      Lysosomes are more than just cellular recycling bins; they play a crucial role in regulating key cellular functions. Proper lysosomal function is essential for growth pathway regulation, cell proliferation, and metabolic homeostasis. Impaired lysosomal function is associated with lipid storage disorders and neurodegenerative diseases. Lysosomes form extensive and dynamic close contacts with the membranes of other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and lipid droplets. These membrane contacts sites (MCSs) are vital for many lysosomal functions. In this chapter, we will explore lysosomal MCSs focusing on the machinery that mediates these contacts, how they are regulated, and their functional implications on physiology and pathology.
    Keywords:  Lipid homeostasis; Lysosomes; Membrane contact sites; Nutrient sensing; Organelles communication
    DOI:  https://doi.org/10.1016/bs.ctm.2024.07.001
  24. Front Physiol. 2024 ;15 1430230
    Mitophagy in fibrotic diseases: molecular mechanisms and therapeutic applications.
    Xinyan Cui, Zekun Zhou, Hua Tu, Jianjun Wu, Jian Zhou, Qiao Yi, Ousheng Liu, Xiaohan Dai.
      Mitophagy is a highly precise process of selective autophagy, primarily aimed at eliminating excess or damaged mitochondria to maintain the stability of both mitochondrial and cellular homeostasis. In recent years, with in-depth research into the association between mitophagy and fibrotic diseases, it has been discovered that this process may interact with crucial cellular biological processes such as oxidative stress, inflammatory responses, cellular dynamics regulation, and energy metabolism, thereby influencing the occurrence and progression of fibrotic diseases. Consequently, modulating mitophagy holds promise as a therapeutic approach for fibrosis. Currently, various methods have been identified to regulate mitophagy to prevent fibrosis, categorized into three types: natural drug therapy, biological therapy, and physical therapy. This review comprehensively summarizes the current understanding of the mechanisms of mitophagy, delves into its biological roles in fibrotic diseases, and introduces mitophagy modulators effective in fibrosis, aiming to provide new targets and theoretical basis for the investigation of fibrosis-related mechanisms and disease prevention.
    Keywords:  energy metabolism; fibrosis; inflammation; mitophagy; oxidative stress; treatment
    DOI:  https://doi.org/10.3389/fphys.2024.1430230
  25. Medicine (Baltimore). 2024 Aug 23. 103(34): e39405
    The mechanisms of Ca2+ regulating autophagy and its research progress in neurodegenerative diseases: A review.
    Meng Hou, Zhixiao Zhang, Zexin Fan, Lei Huang, Li Wang.
      Neurodegenerative diseases are complex disorders that significantly challenge human health, with their incidence increasing with age. A key pathological feature of these diseases is the accumulation of misfolded proteins. The underlying mechanisms involve an imbalance in calcium homeostasis and disturbances in autophagy, indicating a likely correlation between them. As the most important second messenger, Ca2+ plays a vital role in regulating various cell activities, including autophagy. Different organelles within cells serve as Ca2+ storage chambers and regulate Ca2+ levels under different conditions. Ca2+ in these compartments can affect autophagy via Ca2+ channels or other related signaling proteins. Researchers propose that Ca2+ regulates autophagy through distinct signal transduction mechanisms, under normal or stressful conditions, and thereby contributing to the occurrence and development of neurodegenerative diseases. This review provides a systematic examination of the regulatory mechanisms of Ca2+ in cell membranes and different organelles, as well as its downstream pathways that influence autophagy and its implications for neurodegenerative diseases. This comprehensive analysis may facilitate the development of new drugs and provide more precise treatments for neurodegenerative diseases.
    DOI:  https://doi.org/10.1097/MD.0000000000039405
  26. World J Gastroenterol. 2024 Aug 21. 30(31): 3628-3634
    Navigating the autophagic landscape: Epigenetic modulation in gastrointestinal cancer.
    Davide Ramoni, Federico Carbone, Fabrizio Montecucco.
      This editorial comments on the manuscript by Chang et al, focusing on the still elusive interplay between epigenetic regulation and autophagy in gastrointestinal diseases, particularly cancer. Autophagy, essential for cellular homeostasis, exhibits diverse functions ranging from cell survival to death, and is particularly implicated in physiological gastrointestinal cell functions. However, its role in pathological backgrounds remains intricate and context-dependent. Studies underscore the dual nature of autophagy in cancer, where its early suppressive effects in early stages are juxtaposed with its later promotion, contributing to chemoresistance. This discrepancy is attributed to the dysregulation of autophagy-related genes and their intricate involvement in cellular processes. Epigenetic modifications and regulations of gene expression, including non-coding RNAs (ncRNAs), emerge as critical players in exerting regulatory control over autophagy flux, influencing treatment responses and tumor progression. Targeting epigenetic mechanisms and improving strategies involving the inhibition or induction of autophagy through pharmacological or genetic means present potential avenues to sensitize tumor cells to chemotherapy. Additionally, nanocarrier-based delivery of ncRNAs offers innovative therapeutic approaches. Understanding the intricate interaction between autophagy and ncRNA regulation opens avenues for the development of targeted therapies, thereby improving the prognosis of gastrointestinal malignancies with poor outcomes.
    Keywords:  Autophagy; Epigenetic regulation; Gastrointestinal cancer; Non-coding RNAs; Target therapies
    DOI:  https://doi.org/10.3748/wjg.v30.i31.3628
  27. Cells. 2024 Aug 06. pii: 1313. [Epub ahead of print]13(16):
    RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions.
    Yang Han, Xiaoqing Liu, Liju Xu, Ziheng Wei, Yueting Gu, Yandan Ren, Wenyi Hua, Yongtao Zhang, Xiaoxi Liu, Cong Jiang, Ruijuan Zhuang, Wanjin Hong, Tuanlao Wang.
      Endoplasmic reticulum (ER)-endolysosome interactions regulate cholesterol exchange between the ER and the endolysosome. ER-endolysosome membrane contact sites mediate the ER-endolysosome interaction. VAP-ORP1L (vesicle-associated membrane protein-associated protein- OSBP-related protein 1L) interaction forms the major contact site between the ER and the lysosome, which is regulated by Rab7. RILP (Rab7-interacting lysosomal protein) is the downstream effector of Rab7, but its role in the organelle interaction between the ER and the lysosome is not clear. In this study, we found RILP interacts with ORP1L to competitively inhibit the formation of the VAP-ORP1L contact site. Immunofluorescence microscopy revealed that RILP induces late endosome/lysosome clustering, which reduces the contact of endolysosomes with the ER, interfering with the ER-endolysosome interaction. Further examination demonstrated that over-expression of RILP results in the accumulation of cholesterol in the clustered endolysosomes, which triggers cellular autophagy depending on RILP. Our results suggest that RILP interferes with the ER-endolysosome interaction to inhibit cholesterol flow from the endolysosome to the ER, which feedbacks to trigger autophagy.
    Keywords:  RILP; Rab7; autophagy; cholesterol transport; organelle interaction
    DOI:  https://doi.org/10.3390/cells13161313
  28. Transl Res. 2024 Aug 22. pii: S1931-5244(24)00148-8. [Epub ahead of print]273 127-136
    TFEB alleviates periodontitis by activating autophagy and inhibiting inflammation.
    Jie Ren, Jiaxin Li, Hong Tang, Liang Hao, Kai Yang.
      Periodontitis is a chronic inflammatory oral disease that impaired the tooth-supporting apparatus, including gingival tissue destruction and alveolar bone resorption. The initiation of periodontitis is linked to the presence of oral bacteria, particularly P. gingivalis within pathogenic biofilms. Here, we demonstrated the central role of the autophagy regulator Transcription Factor EB (TFEB) in orchestrating autophagy activation and modulating the host immune response against P. gingivalis in periodontitis. Upregulation of TFEB expression at the protein level and heightened nuclear localization occurred during the progressive stages of periodontitis. Functionally, TFEB overexpression emerges as a potent alleviator of periodontitis-associated phenotypes, operating through the activation of autophagy and the inhibition of the NF-κB pathway in both in vivo and in vitro models. In addition, TFEB knockdown exacerbates the inflammatory response by upregulating pro-inflammatory cytokines. The dual regulatory role of TFEB in governing both autophagy and inflammatory responses unveils novel insights into periodontitis pathogenesis, positioning TFEB as a promising therapeutic target for periodontitis intervention.
    Keywords:  Autophagy; Inflammation; Periodontitis; TFEB
    DOI:  https://doi.org/10.1016/j.trsl.2024.08.003
  29. Life Sci Alliance. 2024 Nov;pii: e202302419. [Epub ahead of print]7(11):
    mTORC1 hampers Hedgehog signaling in Tsc2 deficient cells.
    Lasse Jonsgaard Larsen, Elsebet Østergaard, Lisbeth Birk Møller.
      The mTORC1-complex is negatively regulated by TSC1 and TSC2. Activation of Hedgehog signaling is strictly dependent on communication between Smoothened and the Hedgehog-signaling effector and transcription factor, GLI2, in the primary cilium. Details about this communication are not known, and we wanted to explore this further. Here we report that in Tsc2 -/- MEFs constitutively activated mTORC1 led to mis-localization of Smoothened to the plasma membrane, combined with increased concentration of GLI2 in the cilia and reduced Hedgehog signaling, measured by reduced expression of the Hedgehog target gene, Gli1 Inhibition of mTORC1 rescued the cellular localization of Smoothened to the cilia, reduced the cilia concentration of GLI2, and restored Hedgehog signaling. Our results reveal evidence for a two-step activation process of GLI2. The first step includes GLI2 stabilization and cilium localization, whereas the second step includes communication with cilia-localized Smoothened. We found that mTORC1 inhibits the second step. This is the first demonstration that mTORC1 is involved in the regulation of Hedgehog signaling.
    DOI:  https://doi.org/10.26508/lsa.202302419
  30. Cells. 2024 Aug 19. pii: 1376. [Epub ahead of print]13(16):
    Iron Dyshomeostasis in Neurodegeneration with Brain Iron Accumulation (NBIA): Is It the Cause or the Effect?
    Francesco Agostini, Bibiana Sgalletta, Marco Bisaglia.
      Iron is an essential metal ion implicated in several cellular processes. However, the reactive nature of iron renders this metal ion potentially dangerous for cells, and its levels need to be tightly controlled. Alterations in the intracellular concentration of iron are associated with different neuropathological conditions, including neurodegeneration with brain iron accumulation (NBIA). As the name suggests, NBIA encompasses a class of rare and still poorly investigated neurodegenerative disorders characterized by an abnormal accumulation of iron in the brain. NBIA is mostly a genetic pathology, and to date, 10 genes have been linked to familial forms of NBIA. In the present review, after the description of the principal mechanisms implicated in iron homeostasis, we summarize the research data concerning the pathological mechanisms underlying the genetic forms of NBIA and discuss the potential involvement of iron in such processes. The picture that emerges is that, while iron overload can contribute to the pathogenesis of NBIA, it does not seem to be the causal factor in most forms of the pathology. The onset of these pathologies is rather caused by a combination of processes involving the interplay between lipid metabolism, mitochondrial functions, and autophagic activity, eventually leading to iron dyshomeostasis.
    Keywords:  NBIA; autophagy; iron; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3390/cells13161376
  31. Autophagy. 2024 Aug 28.
    MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.
    Zhigang Zhang, Shuai Chen, Shirui Jun, Xirong Xu, Yuchuan Hong, Xifei Yang, Liangyu Zou, You-Qiang Song, Yu Chen, Jie Tu.
      Individuals with genetic elimination of MLKL (mixed lineage kinase domain like pseudokinase) exhibit an increased susceptibility to neurodegenerative diseases like Alzheimer disease (AD). However, the mechanism is not yet fully understood. Here, we observed significant compromise in macroautophagy/autophagy in the brains of mlkl knockout (KO) mice, as evidenced by the downregulation of BECN1/Beclin1 and ULK1 (unc-51 like autophagy activating kinase 1). We identified UBA52 (ubiquitin A-52 residue ribosomal protein fusion product 1) as the binding partner of MLKL under physiological conditions. Loss of Mlkl induced a decrease in ubiquitin levels by preventing UBA52 cleavage. Furthermore, we demonstrated that the deubiquitinase (DUB) USP7 (ubiquitin specific peptidase 7) mediates the processing of UBA52, which is regulated by MLKL. Moreover, our results indicated that the reduction of BECN1 and ULK1 upon Mlkl loss is attributed to a decrease in their lysine 63 (K63)-linked polyubiquitination. Additionally, single-nucleus RNA sequencing revealed that the loss of Mlkl resulted in the disruption of multiple neurodegenerative disease-related pathways, including those associated with AD. These results were consistent with the observation of cognitive impairment in mlkl KO mice and exacerbation of AD pathologies in an AD mouse model with mlkl deletion. Taken together, our findings demonstrate that MLKL-USP7-UBA52 signaling is required for autophagy in brain through maintaining ubiquitin homeostasis, and highlight the contribution of Mlkl loss-induced ubiquitin deficits to the development of neurodegeneration. Thus, the maintenance of adequate levels of ubiquitin may provide a novel perspective to protect individuals from multiple neurodegenerative diseases through regulating autophagy.
    Keywords:  Alzheimer disease; BECN1; ULK1; autophagy; cognitive impairment; neurodegeneration
    DOI:  https://doi.org/10.1080/15548627.2024.2395727
  32. Semin Cancer Biol. 2024 Aug 26. pii: S1044-579X(24)00060-9. [Epub ahead of print]106-107 15-27
    AMPK: The energy sensor at the crossroads of aging and cancer.
    Vasudevarao Penugurti, Rajesh Kumar Manne, Ling Bai, Rajni Kant, Hui-Kuan Lin.
      AMP-activated protein kinase (AMPK) is a protein kinase that plays versatile roles in response to a variety of physiological stresses, including glucose deprivation, hypoxia, and ischemia. As a kinase with pleiotropic functions, it plays a complex role in tumor progression, exhibiting both tumor-promoting and tumor-suppressing activities. On one hand, AMPK enhances cancer cell proliferation and survival, promotes cancer metastasis, and impairs anti-tumor immunity. On the other hand, AMPK inhibits cancer cell growth and survival and stimulates immune responses in a context-dependent manner. Apart from these functions, AMPK plays a key role in orchestrating aging and aging-related disorders, including cardiovascular diseases (CVD), Osteoarthritis (OA), and Diabetes. In this review article, we summarized the functions of AMPK pathway based on its oncogenic and tumor-suppressive roles and highlighted the importance of AMPK pathway in regulating cellular aging. We also spotlighted the significant role of various signaling pathways, activators, and inhibitors of AMPK in serving as therapeutic strategies for anti-cancer and anti-aging therapy.
    Keywords:  AICAR; AMP-activated protein Kinase (AMPK); Aging; Autophagy; Longevity; Metformin; Tumorigenesis; mTOR
    DOI:  https://doi.org/10.1016/j.semcancer.2024.08.002
  33. Biomolecules. 2024 Jul 29. pii: 922. [Epub ahead of print]14(8):
    Complex Interplay between DNA Damage and Autophagy in Disease and Therapy.
    Aman Singh, Naresh Ravendranathan, Jefferson C Frisbee, Krishna K Singh.
      Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations.
    Keywords:  BRCA1/2; DNA damage; autophagy; cancer; doxorubicin
    DOI:  https://doi.org/10.3390/biom14080922
  34. J Neurochem. 2024 Aug 23.
    HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.
    Sabrina Montresor, Maria Lucia Pigazzini, Sudarson Baskaran, Mira Sleiman, Govinda Adhikari, Lukas Basilicata, Luca Secker, Natascha Jacob, Yara Ehlert, Anushree Kelkar, Gurleen Kaur Kalsi, Niraj Kulkarni, Paul Spellerberg, Janine Kirstein.
      Chaperones safeguard protein homeostasis by promoting folding and preventing aggregation. HSP110 is a cytosolic chaperone that functions as a nucleotide exchange factor for the HSP70 cycle. Together with HSP70 and a J-domain protein (JDP), HSP110 maintains protein folding and resolubilizes aggregates. Interestingly, HSP110 is vital for the HSP70/110/JDP-mediated disaggregation of amyloidogenic proteins implicated in neurodegenerative diseases (i.e., α-synuclein, HTT, and tau). However, despite its abundance, HSP110 remains still an enigmatic chaperone, and its functional spectrum is not very well understood. Of note, the disaggregation activity of neurodegenerative disease-associated amyloid fibrils showed both beneficial and detrimental outcomes in vivo. To gain a more comprehensive understanding of the chaperone HSP110 in vivo, we analyzed its role in neuronal proteostasis and neurodegeneration in C. elegans. Specifically, we investigated the role of HSP110 in the regulation of amyloid beta peptide (Aβ) aggregation using an established Aβ-C. elegans model that mimics Alzheimer's disease pathology. We generated a novel C. elegans model that over-expresses hsp-110 pan-neuronally, and we also depleted hsp-110 by RNAi-mediated knockdown. We assessed Aβ aggregation in vivo and in situ by fluorescence lifetime imaging. We found that hsp-110 over-expression exacerbated Aβ aggregation and appeared to reduce the conformational variability of the Aβ aggregates, whereas hsp-110 depletion reduced aggregation more significantly in the IL2 neurons, which marked the onset of Aβ aggregation. HSP-110 also plays a central role in growth and fertility as its over-expression compromises nematode physiology. In addition, we found that HSP-110 modulation affects the autophagy pathway. While hsp-110 over-expression impairs the autophagic flux, a depletion enhances it. Thus, HSP-110 regulates multiple nodes of the proteostasis network to control amyloid protein aggregation, disaggregation, and autophagic clearance.
    Keywords:  Abeta; C. elegans; aggregation; chaperones; proteostasis
    DOI:  https://doi.org/10.1111/jnc.16214
  35. Cells. 2024 Aug 14. pii: 1354. [Epub ahead of print]13(16):
    Autophagy and Female Fertility: Mechanisms, Clinical Implications, and Emerging Therapies.
    Abdel Halim Harrath, Md Ataur Rahman, Sujay Kumar Bhajan, Anup Kumar Bishwas, M D Hasanur Rahman, Saleh Alwasel, Maroua Jalouli, Sojin Kang, Moon Nyeo Park, Bonglee Kim.
      Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, and infertility. Existing research emphasizes the crucial significance of autophagy in embryo implantation, specifically in the endometrium, highlighting its necessity in ensuring proper fetal development. Although some knowledge has been gained, there is still a lack of research on the specific molecular impacts of autophagy on the quality of oocytes, the growth of follicles, and general reproductive health. Autophagy plays a role in the maturation, quality, and development of oocytes. It is also involved in reproductive aging, contributing to reductions in reproductive function that occur with age. This review explores the physiological functions of autophagy in the female reproductive system, its participation in reproductive toxicity, and its important connections with the endometrium and embryo. In addition, this study investigates the possibility of emerging treatment approaches that aim to modify autophagy, using both natural substances and synthetic molecules, to improve female fertility and reproductive outcomes. Additionally, this review intends to inspire future exploration into the intricate role of autophagy in female reproductive health by reviewing recent studies and pinpointing areas where current knowledge is lacking. Subsequent investigations should prioritize the conversion of these discoveries into practical uses in the medical field, which could potentially result in groundbreaking therapies for infertility and other difficulties related to reproduction. Therefore, gaining a comprehensive understanding of the many effects of autophagy on female fertility would not only further the field of reproductive biology but also open new possibilities for diagnostic and treatment methods.
    Keywords:  autophagy; female fertility; follicular development; oocyte quality; reproductive aging; therapeutic interventions
    DOI:  https://doi.org/10.3390/cells13161354
  36. J Fungi (Basel). 2024 Aug 16. pii: 579. [Epub ahead of print]10(8):
    The Mitochondrial Distribution and Morphology Family 33 Gene FgMDM33 Is Involved in Autophagy and Pathogenesis in Fusarium graminearum.
    Wuyun Lv, Yiyi Tu, Ting Xu, You Zhang, Junjie Chen, Nan Yang, Yuchun Wang.
      The mitochondrial distribution and morphology family 33 gene (MDM33) regulates mitochondrial homeostasis by mediating the mitochondrial fission process in yeast. The wheat head blight Fusarium graminearum contains an FgMdm33 protein that is orthologous to Saccharomyces cerevisiae Mdm33, albeit its function remains unknown. We have reported here the roles of FgMdm33 in regulating fungal morphogenesis, mitochondrial morphology, autophagy, apoptosis, and fungal pathogenicity. The ΔFgmdm33 mutants generated through a homologous recombination strategy in this study exhibited defects in terms of mycelial growth, conidia production, and virulence. Hyphal cells lacking FgMDM33 displayed elongated mitochondria and a dispensable respiratory-deficient growth phenotype, indicating the possible involvement of FgMDM33 in mitochondrial fission. The ΔFgmdm33 mutants displayed a remarkable reduction in the proteolysis of GFP-FgAtg8, whereas the formation of autophagic bodies in the hyphal cells of mutants was recorded under the induction of mitophagy. In addition, the transcriptional expression of the apoptosis-inducing factor 1 gene (FgAIF1) was significantly upregulated in the ΔFgmdm33 mutants. Cumulatively, these results indicate that FgMDM33 is involved in mitochondrial fission, non-selective macroautophagy, and apoptosis and that it regulates fungal growth, conidiation, and pathogenicity of the head blight pathogen.
    Keywords:  Fusarium graminearum; MDM33; apoptosis; autophagy; mitochondrial fission; pathogenesis
    DOI:  https://doi.org/10.3390/jof10080579
  37. Cell Mol Life Sci. 2024 Aug 23. 81(1): 368
    HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B.
    Julia Kapr, Ilka Scharkin, Haribaskar Ramachandran, Philipp Westhoff, Marius Pollet, Selina Dangeleit, Gabriele Brockerhoff, Andrea Rossi, Katharina Koch, Jean Krutmann, Ellen Fritsche.
      Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly; (ii) altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.
    Keywords:  Autophagy; Brain development; Disease modeling; GABA; HDAC; In vitro; MEA; Migration; Oligodendrocytes; Personalized
    DOI:  https://doi.org/10.1007/s00018-024-05406-w
  38. J Pharmacol Sci. 2024 Oct;pii: S1347-8613(24)00053-7. [Epub ahead of print]156(2): 102-114
    Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors.
    Sora Nozaki, Masanori Hijioka, Xiaopeng Wen, Natsumi Iwashita, Junya Namba, Yoshiaki Nomura, Aoi Nakanishi, Soichiro Kitazawa, Ryo Honda, Yuji O Kamatari, Ryo Kitahara, Kenji Suzuki, Masatoshi Inden, Yoshihisa Kitamura.
      Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders characterized by the aberrant accumulation of α-synuclein (α-syn). Although no treatment is effective for synucleinopathies, the suppression of α-syn aggregation may contribute to the development of numerous novel therapeutic targets. Recent research revealed that nicotinic acetylcholine (nACh) receptor activation has neuroprotective effects and promotes the degradation of amyloid protein by activating autophagy. In an in vitro human-derived cell line model, we demonstrated that galantamine, the nAChR allosteric potentiating ligand, significantly reduced the cell number of SH-SY5Y cells with intracellular Lewy body-like aggregates by enhancing the sensitivity of α7-nAChR. In addition, galantamine promoted autophagic flux, and prevented the formation of Lewy body-resembled aggregates. In an in vivo synucleinopathy mouse model, the propagation of α-syn aggregation in the cerebral cortex was inhibited by galantamine administration for 90 days. These results suggest that α7-nAChR is expected to be a novel therapeutic target, and galantamine is a potential agent for synucleinopathies.
    Keywords:  Autophagy; Galantamine; Synucleinopathy; nACh receptors; α-syn aggregation
    DOI:  https://doi.org/10.1016/j.jphs.2024.07.008
  39. Antioxidants (Basel). 2024 Aug 03. pii: 946. [Epub ahead of print]13(8):
    In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke.
    Sara Izquierdo-Bermejo, Beatriz Chamorro, María Dolores Martín-de-Saavedra, Miguel Lobete, Francisco López-Muñoz, José Marco-Contelles, María Jesús Oset-Gasque.
      Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia-reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically.
    Keywords:  autophagy; cerebral ischemia; hypoxia; neuroprotection; nitrones; stroke; therapeutic agents
    DOI:  https://doi.org/10.3390/antiox13080946
  40. Antioxidants (Basel). 2024 Jul 23. pii: 886. [Epub ahead of print]13(8):
    The Impairment of Endothelial Autophagy Accelerates Renal Senescence by Ferroptosis and NLRP3 Inflammasome Signaling Pathways with the Disruption of Endothelial Barrier.
    Jin Won Kim, Sun Ah Nam, Eun-Sil Koh, Hyung Wook Kim, Sua Kim, Jin Ju Woo, Yong Kyun Kim.
      Autophagy is a cellular process that degrades damaged cytoplasmic components and regulates cell death. The homeostasis of endothelial cells (ECs) is crucial for the preservation of glomerular structure and function in aging. Here, we investigated the precise mechanisms of endothelial autophagy in renal aging. The genetic deletion of Atg7 in the ECs of Atg7flox/flox;Tie2-Cre mice accelerated aging-related glomerulopathy and tubulointerstitial fibrosis. The EC-specific Atg7 deletion in aging mice induced the detachment of EC with the disruption of glomerular basement membrane (GBM) assembly and increased podocyte loss resulting in microalbuminuria. A Transwell co-culture system of ECs and kidney organoids showed that the iron and oxidative stress induce the disruption of the endothelial barrier and increase vascular permeability, which was accelerated by the inhibition of autophagy. This resulted in the leakage of iron through the endothelial barrier into kidney organoids and increased oxidative stress, which led to ferroptotic cell death. The ferritin accumulation was increased in the kidneys of the EC-specific Atg7-deficient aging mice and upregulated the NLRP3 inflammasome signaling pathway. The pharmacologic inhibition of ferroptosis with liproxstatin-1 recovered the disrupted endothelial barrier and reversed the decreased expression of GPX4, as well as NLRP3 and IL-1β, in endothelial autophagy-deficient aged mice, which attenuated aging-related renal injury including the apoptosis of renal cells, abnormal structures of GBM, and tubulointerstitial fibrosis. Our data showed that endothelial autophagy is essential for the maintenance of the endothelial barrier during renal aging and the impairment of endothelial autophagy accelerates renal senescence by ferroptosis and NLRP3 inflammasome signaling pathways. These processes may be attractive therapeutic targets to reduce cellular injury from renal aging.
    Keywords:  aging; autophagy; kidney; liproxstatin-1
    DOI:  https://doi.org/10.3390/antiox13080886
  41. Brain Res. 2024 Aug 27. pii: S0006-8993(24)00458-X. [Epub ahead of print]1845 149204
    The crucial role of VPS35 and SHH in Parkinson's disease: Understanding the mechanisms behind the neurodegenerative disorder.
    Kritika Bhardwaj, Akanksha Jha, Abhishek Roy, Hemant Kumar.
      Parkinson's disease (PD) is indeed a complex neurodegenerative disorder recognized by the progressive depletion of dopaminergic neurons in the brain, particularly in the substantia nigra region, leading to motor impairments and other symptoms. But at the molecular level, the study about PD still lacks. As the number of cases worldwide continues to increase, it is critical to focus on the cellular and molecular mechanisms of the disease's presentation and neurodegeneration to develop novel therapeutic approaches. At the molecular level, the complexity is more due to the involvement of vacuolar protein sorting 35 (VPS35) and sonic hedgehog (SHH) signaling in PD (directly or indirectly), leading to one of the most prominent hallmarks of the disease, which is an accumulation of α-synuclein. This elevated pathogenesis may result from impaired autophagy due to mutation in the case of VPS35 and impairment in SHH signaling at the molecular level. The traditional understanding of PD is marked by the disruption of dopaminergic neurons and dopaminergic signaling, which exacerbates symptoms of motor function deficits. However, the changes at the molecular level that are being disregarded also impact the overall health of the dopaminergic system. Gaining insight into these two unique mechanisms is essential to determine whether they give neuroprotection or have no effect on the health of neurons. Hence, here we tried to simplify the understanding of the role of VPS35 and SHH signaling to comprehend it in one direction.
    Keywords:  Autophagy; Lysosome; Retromer; Sonic hedgehog; Vacuolar protein sorting 35
    DOI:  https://doi.org/10.1016/j.brainres.2024.149204
  42. Curr Issues Mol Biol. 2024 Jul 27. 46(8): 8088-8103
    Hypomyelination Leukodystrophy 16 (HLD16)-Associated Mutation p.Asp252Asn of TMEM106B Blunts Cell Morphological Differentiation.
    Sui Sawaguchi, Miki Ishida, Yuki Miyamoto, Junji Yamauchi.
      Transmembrane protein 106B (TMEM106B), which is a type II transmembrane protein, is believed to be involved in intracellular dynamics and morphogenesis in the lysosome. TMEM106B is known to be a risk factor for frontotemporal lobar degeneration and has been recently identified as the receptor needed for the entry of SARS-CoV-2, independently of angiotensin-converting enzyme 2 (ACE2). A missense mutation, p.Asp252Asn, of TMEM106B is associated with hypomyelinating leukodystrophy 16 (HLD16), which is an oligodendroglial cell-related white matter disorder causing thin myelin sheaths or myelin deficiency in the central nervous system (CNS). However, it remains to be elucidated how the mutated TMEM106B affects oligodendroglial cells. Here, we show that the TMEM106B mutant protein fails to exhibit lysosome distribution in the FBD-102b cell line, an oligodendroglial precursor cell line undergoing differentiation. In contrast, wild-type TMEM106B was indeed localized in the lysosome. Cells harboring wild-type TMEM106B differentiated into ones with widespread membranes, whereas cells harboring mutated TMEM106B failed to differentiate. It is of note that the output of signaling through the lysosome-resident mechanistic target of rapamycin (mTOR) was greatly decreased in cells harboring mutated TMEM106B. Furthermore, treatment with hesperetin, a citrus flavonoid known as an activator of mTOR signaling, restored the molecular and cellular phenotypes induced by the TMEM106B mutant protein. These findings suggest the potential pathological mechanisms underlying HLD16 and their amelioration.
    Keywords:  TMEM106B; differentiation; hesperetin; mTOR; oligodendrocyte
    DOI:  https://doi.org/10.3390/cimb46080478
  43. Cells. 2024 Aug 13. pii: 1340. [Epub ahead of print]13(16):
    A LAT1-Like Amino Acid Transporter Regulates Neuronal Activity in the Drosophila Mushroom Bodies.
    Julie Delescluse, Mégane M Simonnet, Anna B Ziegler, Kévin Piffaretti, Georges Alves, Yael Grosjean, Gérard Manière.
      The proper functioning of neural circuits that integrate sensory signals is essential for individual adaptation to an ever-changing environment. Many molecules can modulate neuronal activity, including neurotransmitters, receptors, and even amino acids. Here, we ask whether amino acid transporters expressed by neurons can influence neuronal activity. We found that minidiscs (mnd), which encodes a light chain of a heterodimeric amino acid transporter, is expressed in different cell types of the adult Drosophila brain: in mushroom body neurons (MBs) and in glial cells. Using live calcium imaging, we found that MND expressed in α/β MB neurons is essential for sensitivity to the L-amino acids: Leu, Ile, Asp, Glu, Lys, Thr, and Arg. We found that the Target Of Rapamycin (TOR) pathway but not the Glutamate Dehydrogenase (GDH) pathway is involved in the Leucine-dependent response of α/β MB neurons. This study strongly supports the key role of MND in regulating MB activity in response to amino acids.
    Keywords:  Drosophila; LAT-1; SLC; amino acids; mushroom bodies; solute carrier
    DOI:  https://doi.org/10.3390/cells13161340
  44. Inflammation. 2024 Aug 26.
    Metformin as a Modulator of Autophagy and Hypoxia Responses in the Enhancement of Wound Healing in Diabetic Rats.
    Fatma Kubra Tombulturk, Tugba Soydas, Gönül Kanigur-Sultuybek.
      The molecular mechanisms underlying delayed wound repair in diabetes involve dysregulation of key cellular processes, including autophagy and hypoxia response pathways. Herein, we investigated the role of topical metformin, an established anti-diabetic drug with potential autophagy-inducing properties, in improving wound healing outcomes under hypoxic conditions. Full-thickness skin wounds were created in streptozotocin-induced diabetic rats, and tissue samples were collected at regular intervals for molecular and histological analysis. The expression levels of autophagy markers LC3B and Beclin-1 were evaluated via immunohistochemistry and qRT-PCR, while the amount of AMP-activated protein kinase (AMPK) and hypoxia-inducible factor-1α (HIF-1α) were determined via ELISA. Our results demonstrated that metformin administration resulted in the upregulation of LC3B and Beclin-1 in the wound bed, suggesting induction of autophagy in response to the treatment. Mechanistically, metformin treatment also led to the increased amount of AMPK, a critical regulator of cellular energy homeostasis, and a subsequent reduction in HIF-1α amount under hypoxic conditions. In conclusion, our findings demonstrate that metformin promotes wound healing in diabetes mellitus by enhancing autophagy through AMPK activation and modulating HIF-1α amount in a hypoxic microenvironment. This study offers a new therapeutic approach by shedding light on the potential benefits of metformin as adjunctive therapy in diabetic wound management.
    Keywords:  AMPK; Autophagy; Diabetes mellitus; Hypoxia; Metformin; Wound healing
    DOI:  https://doi.org/10.1007/s10753-024-02129-9
  45. Biochem Biophys Res Commun. 2024 Aug 22. pii: S0006-291X(24)01123-9. [Epub ahead of print]739 150587
    Taurine rescues intervertebral disc degeneration by activating mitophagy through the PINK1/Parkin pathway.
    Shengyuan Lin, Tao Li, Bin Zhang, Peng Wang.
      Intervertebral disc degeneration (IDD) is a common cause of low back pain and disability. Recent studies have highlighted the critical role of mitochondrial dysfunction in the progression of IDD. In this study, we investigated the therapeutic potential of taurine in delaying IDD through the activation of mitophagy via the PINK1/Parkin pathway. Our in vitro and in vivo experiments demonstrate that taurine treatment significantly enhances mitophagy, reduces oxidative stress, delays cell senescence, and promotes the removal of damaged mitochondria in nucleus pulposus cells (NPC). Additionally, taurine-mediated activation of the PINK1/Parkin pathway leads to improved mitochondrial homeostasis and slows the progression of disc degeneration. These findings provide new insights into the protective effects of taurine and highlight its potential as a therapeutic agent for IDD.
    Keywords:  Intervertebral disc degeneration; Mitophagy; PINK1/Parkin pathway; Taurine
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150587
  46. Ren Fail. 2024 Dec;46(2): 2393262
    Mitochondrial dysfunction in acute kidney injury.
    Congcong Yao, Ziwei Li, Keke Sun, Yan Zhang, Songtao Shou, Heng Jin.
      Acute kidney injury (AKI) is a systemic clinical syndrome increasing morbidity and mortality worldwide in recent years. Renal tubular epithelial cells (TECs) death caused by mitochondrial dysfunction is one of the pathogeneses. The imbalance of mitochondrial quality control is the main cause of mitochondrial dysfunction. Mitochondrial quality control plays a crucial role in AKI. Mitochondrial quality control mechanisms are involved in regulating mitochondrial integrity and function, including antioxidant defense, mitochondrial quality control, mitochondrial DNA (mtDNA) repair, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Currently, many studies have used mitochondrial dysfunction as a targeted therapeutic strategy for AKI. Therefore, this review aims to present the latest research advancements on mitochondrial dysfunction in AKI, providing a valuable reference and theoretical foundation for clinical prevention and treatment of this condition, ultimately enhancing patient prognosis.
    Keywords:  Acute kidney injury; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1080/0886022X.2024.2393262
  47. Int J Mol Sci. 2024 Aug 13. pii: 8795. [Epub ahead of print]25(16):
    Regulation of TIR-1/SARM-1 by miR-71 Protects Dopaminergic Neurons in a C. elegans Model of LRRK2-Induced Parkinson's Disease.
    Devin Naidoo, Alexandre de Lencastre.
      Parkinson's disease (PD) is a common neurodegenerative disorder characterized by symptoms such as bradykinesia, resting tremor, and rigidity, primarily driven by the degradation of dopaminergic (DA) neurons in the substantia nigra. A significant contributor to familial autosomal dominant PD cases is mutations in the LRRK2 gene, making it a primary therapeutic target. This study explores the role of microRNAs (miRNAs) in regulating the proteomic stress responses associated with neurodegeneration in PD using C. elegans models. Our focus is on miR-71, a miRNA known to affect stress resistance and act as a pro-longevity factor in C. elegans. We investigated miR-71's function in C. elegans models of PD, where mutant LRRK2 expression correlates with dopaminergic neuronal death. Our findings reveal that miR-71 overexpression rescues motility defects and slows dopaminergic neurodegeneration in these models, suggesting its critical role in mitigating the proteotoxic effects of mutant LRRK2. Conversely, miR-71 knockout exacerbates neuronal death caused by mutant LRRK2. Additionally, our data indicate that miR-71's neuroprotective effect involves downregulating the toll receptor domain protein tir-1, implicating miR-71 repression of tir-1 as vital in the response to LRRK2-induced proteotoxicity. These insights into miR-71's role in C. elegans models of PD not only enhance our understanding of molecular mechanisms in neurodegeneration but also pave the way for potential research into human neurodegenerative diseases, leveraging the conservation of miRNAs and their targets across species.
    Keywords:  Parkinson; aging; elegans; miRNA; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms25168795
  48. Biomedicines. 2024 Aug 08. pii: 1802. [Epub ahead of print]12(8):
    mTOR Dysregulation, Insulin Resistance, and Hypertension.
    Silviu Marcel Stanciu, Mariana Jinga, Daniela Miricescu, Constantin Stefani, Remus Iulian Nica, Iulia-Ioana Stanescu-Spinu, Ileana Adela Vacaroiu, Maria Greabu, Silvia Nica.
      Worldwide, diabetes mellitus (DM) and cardiovascular diseases (CVDs) represent serious health problems associated with unhealthy diet and sedentarism. Metabolic syndrome (MetS) is characterized by obesity, dyslipidemia, hyperglycemia, insulin resistance (IR) and hypertension. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase with key roles in glucose and lipid metabolism, cell growth, survival and proliferation. mTOR hyperactivation disturbs glucose metabolism, leading to hyperglycemia and further to IR, with a higher incidence in the Western population. Metformin is one of the most used hypoglycemic drugs, with anti-inflammatory, antioxidant and antitumoral properties, having also the capacity to inhibit mTOR. mTOR inhibitors such as rapamycin and its analogs everolimus and temsirolimus block mTOR activity, decrease the levels of glucose and triglycerides, and reduce body weight. The link between mTOR dysregulation, IR, hypertension and mTOR inhibitors has not been fully described. Therefore, the main aim of this narrative review is to present the mechanism by which nutrients, proinflammatory cytokines, increased salt intake and renin-angiotensin-aldosterone system (RAAS) dysregulation induce mTOR overactivation, associated further with IR and hypertension development, and also mTOR inhibitors with higher potential to block the activity of this protein kinase.
    Keywords:  inhibitors; insulin resistance; mTOR dysregulation; metformin; obesity; protein kinases; sedentarism
    DOI:  https://doi.org/10.3390/biomedicines12081802
  49. Acta Pharmacol Sin. 2024 Aug 23.
    BNIP3-mediated mitophagy attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis through P62-KEAP1-NRF2 pathway activation to maintain iron and redox homeostasis.
    Xin-Xin Wang, Mei Li, Xiao-Wen Xu, Wen-Bin Zhao, Yi-Ming Jin, Li-Li Li, Zheng-Hong Qin, Rui Sheng, Hong Ni.
      As a major contributor to neonatal death and neurological sequelae, hypoxic-ischemic encephalopathy (HIE) lacks a viable medication for treatment. Oxidative stress induced by hypoxic-ischemic brain damage (HIBD) predisposes neurons to ferroptosis due to the fact that neonates accumulate high levels of polyunsaturated fatty acids for their brain developmental needs but their antioxidant capacity is immature. Ferroptosis is a form of cell death caused by excessive accumulation of iron-dependent lipid peroxidation and is closely associated with mitochondria. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. In this study we employed mitophagy agonists and inhibitors to explore the mechanisms by which mitophagy exerted ferroptosis resistance in a neonatal rat HIE model. Seven-days-old neonatal rats were subjected to ligation of the right common carotid artery, followed by exposure to hypoxia for 2 h. The neonatal rats were treated with a mitophagy activator Tat-SPK2 peptide (0.5, 1 mg/kg, i.p.) 1 h before hypoxia, or in combination with mitochondrial division inhibitor-1 (Mdivi-1, 20 mg/kg, i.p.), and ferroptosis inhibitor Ferrostatin-1 (Fer-1) (2 mg/kg, i.p.) at the end of the hypoxia period. The regulation of ferroptosis by mitophagy was also investigated in primary cortical neurons or PC12 cells in vitro subjected to 4 or 6 h of OGD followed by 24 h of reperfusion. We showed that HIBD induced mitochondrial damage, ROS overproduction, intracellular iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by the pretreatment with Tat-SPK2 peptide, and aggravated by the treatment with Mdivi-1 or BNIP3 knockdown. Ferroptosis inhibitors Fer-1 and deferoxamine B (DFO) reversed the accumulation of iron and lipid peroxides caused by Mdivi-1, hence reducing ferroptosis triggered by HI. We demonstrated that Tat-SPK2 peptide-activated BNIP3-mediated mitophagy did not alleviate neuronal ferroptosis through the GPX4-GSH pathway. BNIP3-mediated mitophagy drove the P62-KEAP1-NRF2 pathway, which conferred ferroptosis resistance by maintaining iron and redox homeostasis via the regulation of FTH1, HO-1, and DHODH/FSP1-CoQ10-NADH. This study may provide a new perspective and a therapeutic drug for the treatment of neonatal HIE.
    Keywords:  P62-KEAP1-NRF2 pathway; Tat-SPK2 peptide; ferroptosis; hypoxic-ischemic brain damage; mitophagy
    DOI:  https://doi.org/10.1038/s41401-024-01365-x
  50. J Biol Chem. 2024 Aug 21. pii: S0021-9258(24)02207-5. [Epub ahead of print] 107706
    Structure of a truncated human GlcNAc-1-phosphotransferase variant reveals the basis for its hyperactivity.
    Hua Li, Balraj Doray, Benjamin C Jennings, Wang-Sik Lee, Lin Liu, Stuart Kornfeld, Huilin Li.
      Mutations that cause loss of function of GlcNAc-1-phosphotransferase (PTase) lead to the lysosomal storage disorder mucolipidosis II. PTase is the key enzyme of the mannose 6-phosphate (M6P) targeting system that is responsible for tagging lysosomal hydrolases with the M6P moiety for their delivery to the lysosome. We had previously generated a truncated hyperactive form of PTase termed S1S3 which was shown to notably increase the phosphorylation level of secreted lysosomal enzymes and enhance their uptake by cells. Here, we report the 3.4 Å cryo-EM structure of soluble S1S3 lacking both transmembrane domains and cytosolic tails. The structure reveals a high degree of conservation of the catalytic core to full-length PTase. In this dimeric structure, the EF hand of one protomer is observed interacting with the conserved region 4 of the other. In addition, we present a high-quality EM 3D map of the UDP-GlcNAc bound form of the full-length soluble protein showing the key molecular interactions between the nucleotide sugar donor and side chain amino acids of the protein. Finally, although the domain organization of S1S3 is very similar to that of the Drosophila melanogaster (fruit fly) PTase homolog, we establish that the latter does not act on lysosomal hydrolases.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107706
  51. Autophagy. 2024 Aug 28.
    Macrophage autophagy protects against acute kidney injury by inhibiting renal inflammation through the degradation of TARM1.
    Xiao-Rong Huang, Lin Ye, Ning An, Chun-Yu Wu, Hong-Luan Wu, Hui-Yuan Li, Yan-Heng Huang, Qiao-Ru Ye, Ming-Dong Liu, La-Wei Yang, Jian-Xing Liu, Ji-Xin Tang, Qing-Jun Pan, Peng Wang, Lin Sun, Yin Xia, Hui-Yao Lan, Chen Yang, Hua-Feng Liu.
      Macroautophagy/autophagy activation in renal tubular epithelial cells protects against acute kidney injury (AKI). However, the role of immune cell autophagy, such as that involving macrophages, in AKI remains unclear. In this study, we discovered that macrophage autophagy was an adaptive response during AKI as mice with macrophage-specific autophagy deficiency (atg5-/-) exhibited higher serum creatinine, more severe renal tubule injury, increased infiltration of ADGRE1/F4/80+ macrophages, and elevated expression of inflammatory factors compared to WT mice during AKI induced by either LPS or unilateral ischemia-reperfusion. This was further supported by adoptive transfer of atg5-/- macrophages, but not WT macrophages, to cause more severe AKI in clodronate liposomes-induced macrophage depletion mice. Similar results were also obtained in vitro that bone marrow-derived macrophages (BMDMs) lacking Atg5 largely increased pro-inflammatory cytokine expression in response to LPS and IFNG. Mechanistically, we uncovered that atg5 deletion significantly upregulated the protein expression of TARM1 (T cell-interacting, activating receptor on myeloid cells 1), whereas inhibition of TARM1 suppressed LPS- and IFNG-induced inflammatory responses in atg5-/- RAW 264.7 macrophages. The E3 ubiquitin ligases MARCHF1 and MARCHF8 ubiquitinated TARM1 and promoted its degradation in an autophagy-dependent manner, whereas silencing or mutation of the functional domains of MARCHF1 and MARCHF8 abolished TARM1 degradation. Furthermore, we found that ubiquitinated TARM1 was internalized from plasma membrane into endosomes, and then recruited by the ubiquitin-binding autophagy receptors TAX1BP1 and SQSTM1 into the autophagy-lysosome pathway for degradation. In conclusion, macrophage autophagy protects against AKI by inhibiting renal inflammation through the MARCHF1- and MARCHF8-mediated degradation of TARM1.
    Keywords:  Adoptive transfer; Atg5; bone marrow-derived macrophages; inflammation; ischemia-reperfusion; tubular epithelial cells
    DOI:  https://doi.org/10.1080/15548627.2024.2393926
  52. Nat Cardiovasc Res. 2023 Aug;2(8): 778-792
    MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease.
    Meng Lin, Huifang Xian, Zhanghua Chen, Shang Wang, Ming Liu, Weiwei Liang, Qin Tang, Yao Liu, Wanming Huang, Di Che, Caiqin Guo, Elina Idiiatullina, Rongli Fang, Mahmoud Al-Azab, Jingjie Chang, Rongze Wang, Xiaojun Li, Xiaoyu Zuo, Yan Zhang, Jincun Zhao, Yaping Tang, Shouheng Jin, Zhengjie He, Du Feng, Liwei Lu, Kang Zhang, Yan Wu, Fan Bai, Andrew M Lew, Jun Cui, Yuzhang Wu, Xiaoqiong Gu, Yuxia Zhang.
      Mitophagy is a major quality control pathway that removes unwanted or dysfunctional mitochondria and plays an essential role in vascular health. Here we show that MCM8 expression is significantly decreased in children with Kawasaki disease (KD) who developed coronary artery aneurysms. Mechanistically, we discovered that nitric oxide signaling promotes TRIM21-mediated MCM8 ubiquitination, which disrupts its interaction with MCM9 and promotes its cytosolic export. In the cytosol, MCM8 relocates to the mitochondria pore-forming proteins and promotes their ubiquitination by TRIM21. In addition, MCM8 directly recruits LC3 via its LC3-interacting region (LIR) motif and initiates mitophagy. This suppresses mitochondrial DNA-mediated activation of type I interferon via cGAS and STING. Mice that are deficient in Mcm8, Trim21 and Nos2 or reconstituted with the East-Asian-specific MCM8-P276 variant develop more severe coronary artery vasculopathy in the Lactobacillus casei extract-induced KD model. Collectively, the data suggest that MCM8 protects vascular health in the KD setting.
    DOI:  https://doi.org/10.1038/s44161-023-00314-x
  53. Biomolecules. 2024 Jul 24. pii: 893. [Epub ahead of print]14(8):
    The Autophagic Activator GHF-201 Can Alleviate Pathology in a Mouse Model and in Patient Fibroblasts of Type III Glycogenosis.
    Kumudesh Mishra, Sahar Sweetat, Saja Baraghithy, Uri Sprecher, Monzer Marisat, Sultan Bastu, Hava Glickstein, Joseph Tam, Hanna Rosenmann, Miguel Weil, Edoardo Malfatti, Or Kakhlon.
      Glycogen storage disease type III (GSDIII) is a hereditary glycogenosis caused by deficiency of the glycogen debranching enzyme (GDE), an enzyme, encoded by Agl, enabling glycogen degradation by catalyzing alpha-1,4-oligosaccharide side chain transfer and alpha-1,6-glucose cleavage. GDE deficiency causes accumulation of phosphorylase-limited dextrin, leading to liver disorder followed by fatal myopathy. Here, we tested the capacity of the new autophagosomal activator GHF-201 to alleviate disease burden by clearing pathogenic glycogen surcharge in the GSDIII mouse model Agl-/-. We used open field, grip strength, and rotarod tests for evaluating GHF-201's effects on locomotion, a biochemistry panel to quantify hematological biomarkers, indirect calorimetry to quantify in vivo metabolism, transmission electron microscopy to quantify glycogen in muscle, and fibroblast image analysis to determine cellular features affected by GHF-201. GHF-201 was able to improve all locomotion parameters and partially reversed hypoglycemia, hyperlipidemia and liver and muscle malfunction in Agl-/- mice. Treated mice burnt carbohydrates more efficiently and showed significant improvement of aberrant ultrastructural muscle features. In GSDIII patient fibroblasts, GHF-201 restored mitochondrial membrane polarization and corrected lysosomal swelling. In conclusion, GHF-201 is a viable candidate for treating GSDIII as it recovered a wide range of its pathologies in vivo, in vitro, and ex vivo.
    Keywords:  glycogen; glycogen storage disease type III; pharmacotherapy
    DOI:  https://doi.org/10.3390/biom14080893
  54. Immun Inflamm Dis. 2024 Aug;12(8): e1336
    The preventive and therapeutic role of Lactobacillus spp. in in vitro model of inflammation via affecting autophagy signaling pathway.
    Fatemeh Haririzadeh Jouriani, Mahnaz Torfeh, Mahdi Torkamaneh, Amin Sepehr, Mahdi Rohani, Shadi Aghamohammad.
       BACKGROUND: Intestinal inflammation has various causes and leads to some inflammatory diseases, of which autophagy pathway dysfunction could be considered as one of them. Probiotics could have a positive effect on reducing inflammation by activating the autophagy pathway. To evaluate the precise effects of probiotics as preventive and therapeutic agents to control the symptoms of inflammatory diseases, we aimed to investigate the efficacy of Lactobacillus spp. in regulating the autophagy signaling pathway.
    METHODS: A quantitative real-time polymerase chain reaction assay was used to analyze the expression of autophagy genes involved in the formation of phagophores, autophagosomes, and autolysosomes after exposing the HT-29 cell line to sonicated pathogens and adding Lactobacillus spp. before, after, and simultaneously with inflammation. A cytokine assay was also accomplished to evaluate the interleukin (IL)-6 and IL-1β level following the probiotic treatment.
    RESULTS: Lactobacillus spp. generally increased autophagy gene expression and consumption of Lactobacillus spp. before, simultaneously, and after inflammation, ultimately leading to activate autophagy pathways. The proinflammatory cytokines including IL-6 and IL-1β decreased after probiotic treatment.
    CONCLUSIONS: Our native probiotic Lactobacillus spp. showed beneficial effects on HT-29 cells by increasing autophagy gene expression and decreasing the proinflammatory cytokines production in all treatments. Therefore, this novel probiotic cocktail Lactobacillus spp. can prevent and treat inflammation-related diseases.
    Keywords:  Lactobacillus spp.; autophagy; gut microbiome; inflammation
    DOI:  https://doi.org/10.1002/iid3.1336
  55. Pharmacol Res. 2024 Aug 22. pii: S1043-6618(24)00300-1. [Epub ahead of print]208 107355
    ATF family members as therapeutic targets in cancer: From mechanisms to pharmacological interventions.
    Xueyao Zhang, Zhijia Li, Xiaochun Zhang, Ziyue Yuan, Lan Zhang, Peng Miao.
      The activating transcription factor (ATF)/ cAMP-response element binding protein (CREB) family represents a large group of basic zone leucine zip (bZIP) transcription factors (TFs) with a variety of physiological functions, such as endoplasmic reticulum (ER) stress, amino acid stress, heat stress, oxidative stress, integrated stress response (ISR) and thus inducing cell survival or apoptosis. Interestingly, ATF family has been increasingly implicated in autophagy and ferroptosis in recent years. Thus, the ATF family is important for homeostasis and its dysregulation may promote disease progression including cancer. Current therapeutic approaches to modulate the ATF family include direct modulators, upstream modulators, post-translational modifications (PTMs) modulators. This review summarizes the structural domain and the PTMs feature of the ATF/CREB family and comprehensively explores the molecular regulatory mechanisms. On this basis, their pathways affecting proliferation, metastasis, and drug resistance in various types of cancer cells are sorted out and discussed. We then systematically summarize the status of the therapeutic applications of existing ATF family modulators and finally look forward to the future prospect of clinical applications in the treatment of tumors by modulating the ATF family.
    Keywords:  ATF family; Apoptosis; Autophagy; Cancer; Ferroptosis; Modulators; Stress; Transcription factor
    DOI:  https://doi.org/10.1016/j.phrs.2024.107355
  56. Biomedicines. 2024 Jul 30. pii: 1693. [Epub ahead of print]12(8):
    KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons.
    Mingri Zhao, Junling Wang, Miao Liu, Yaoyao Xu, Jiali Huang, Yiti Zhang, Jianfeng He, Ao Gu, Mujun Liu, Xionghao Liu.
      Mutations in the C-terminal of KIF1A (Kinesin family member 1A) may lead to amyotrophic lateral sclerosis (ALS) through unknown mechanisms that are not yet understood. Using iPSC reprogramming technology and motor neuron differentiation techniques, we generated iPSCs from a healthy donor and two ALS patients with KIF1A mutations (R1457Q and P1688L) and differentiated them into spinal motor neurons (iPSC-MN) to investigate KIF1A-related ALS pathology. Our in vitro iPSC-iMN model faithfully recapitulated specific aspects of the disease, such as neurite fragmentation. Through this model, we observed that these mutations led to KIF1A aggregation at the proximal axon of motor neurons and abnormal accumulation of its transport cargo, LAMP1, resulting in autophagy dysfunction and cell death. RNAseq analysis also indicated that the functions of the extracellular matrix, structure, and cell adhesion were significantly disturbed. Notably, using rapamycin during motor neuron differentiation can effectively prevent motor neuron death.
    Keywords:  ALS; KIF1A; iPSC; motor neuron
    DOI:  https://doi.org/10.3390/biomedicines12081693
  57. Cell Death Discov. 2024 Aug 26. 10(1): 379
    Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1.
    Sven König, Florian Strassheimer, Nadja I Brandner, Jan-Hendrik Schröder, Hans Urban, Leander F Harwart, Stephanie Hehlgans, Joachim P Steinbach, Michael W Ronellenfitsch, Anna-Luisa Luger.
      In glioblastoma (GB) cells oxidative stress is induced by both, conditions of the tumor microenvironment as well as by therapeutic interventions. Upregulation of superoxide dismutase 1 (SOD1), a key enzyme for oxidative defense and downstream target of mammalian target of rapamycin complex 1 (mTORC1) is a candidate mechanism to sustain survival and proliferation of tumor cells. SOD1 was inhibited by shRNA mediated gene suppression, CRISPR/Cas9 knockout and pharmacological inhibition in human (primary) GB cells. SOD1 activity was determined by SOD1/2 activity assay. ROS levels, cell death and the NADPH/NADP-ratio were measured under normal and starvation conditions. To study the mTORC1-SOD1 axis, mTORC1 activated TSC2 knockdown cells (TSC2sh) were analyzed. Genetic and pharmacological inhibition of SOD1 correlated with decreased SOD1 activity, increased ROS and enhanced the sensitivity of glioma cells towards starvation- and hypoxia-induced cell death. This was accompanied by a decreased NADPH/NADP-ratio. Furthermore, combination therapy of SOD1 and mTORC1 inhibition partially rescued the protective effect of mTORC1 inhibitor monotherapy. SOD1 mediates adaptation of GB cells to stress conditions in the tumor microenvironment in a mTORC1-dependent manner. Moreover, SOD1 activation contributes to the cell death resistance conferred by mTORC1 inhibitors under hypoxic conditions.
    DOI:  https://doi.org/10.1038/s41420-024-02145-6
  58. Cell Death Dis. 2024 Aug 26. 15(8): 620
    NLRP4 renders pancreatic cancer resistant to olaparib through promotion of the DNA damage response and ROS-induced autophagy.
    Mingming Xiao, Jing Yang, Mingwei Dong, Xiaoqi Mao, Haoqi Pan, Yalan Lei, Xuhui Tong, Xiaoning Yu, Xianjun Yu, Si Shi.
      Olaparib has been approved as a therapeutic option for metastatic pancreatic ductal adenocarcinoma patients with BRCA1/2 mutations. However, a significant majority of pancreatic cancer patients have inherent resistance or develop tolerance to olaparib. It is crucial to comprehend the molecular mechanism underlying olaparib resistance to facilitate the development of targeted therapies for pancreatic cancer. In this study, we conducted an analysis of the DepMap database to investigate gene expression variations associated with olaparib sensitivity. Our findings revealed that NLRP4 upregulation contributes to increased resistance to olaparib in pancreatic cancer cells, both in vitro and in vivo. RNA sequencing and Co-IP MS analysis revealed that NLRP4 is involved in the DNA damage response and autophagy pathway. Our findings confirmed that NLRP4 enhances the capacity for DNA repair and induces the production of significant levels of reactive oxygen species (ROS) and autophagy in response to treatment with olaparib. Specifically, NLRP4-generated mitochondrial ROS promote autophagy in pancreatic cancer cells upon exposure to olaparib. However, NLRP4-induced ROS do not affect DNA damage. The inhibition of mitochondrial ROS using MitoQ and autophagy using chloroquine (CQ) may render cells more susceptible to the effects of olaparib. Taken together, our findings highlight the significant roles played by NLRP4 in the processes of autophagy and DNA repair when pancreatic cancer cells are treated with olaparib, thereby suggesting the potential therapeutic utility of olaparib in pancreatic cancer patients with low NLRP4 expression.
    DOI:  https://doi.org/10.1038/s41419-024-06984-0
  59. BMC Musculoskelet Disord. 2024 Aug 24. 25(1): 665
    Loss of BACH1 improves osteogenic differentiation in glucocorticoid-induced hBMSCs through restoring autophagy.
    ShuYing Xiao, GuoJuan Li, MeiHua Tan, Wen Liu, WenJin Li.
       BACKGROUND: Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis. Recently, autophagy has been found to be related with the development of various diseases, including osteoporosis and osteoblast differentiation regulations. BTB and CNC homology 1 (BACH1) was a previously confirmed regulator for osteoblast differentiation, but whether it's could involve in glucocorticoid-induced human bone mesenchymal stem cells (hBMSCs) differentiation and autophagy regulation remain not been elucidated.
    METHODS: hBMSCs were identified by flow cytometry method, and its differentiation ability were measured by ARS staining, oil O red, and Alcian blue staining assays. Gene and proteins were quantified via qRT-PCR and western blot assays, respectively. Autophagy activity was determined using immunofluorescence. ChIP and dual luciferase assay validated the molecular interactions.
    RESULTS: The data revealed that isolated hBMSCs exhibited positive of CD29/CD44 and negative CD45/CD34. Moreover, BACH1 was abated gradually during osteoblast differentiation of hBMSCs, while dexamethasone (Dex) treatment led to BACH1 upregulation. Loss of BACH1 improved osteoblast differentiation and activated autophagy activity in Dex-challenged hBMSCs. Autophagy-related proteins (ATG3, ATG4, ATG5, ATG7, ATG12) were repressed after Dex treatment, while ATG3, ATG7 and BECN1 could be elevated by BACH1 knockdown, especially ATG7. Moreover, BACH1 could interact ATG7 promoter region to inhibit its transcription. Co-inhibition of ATG7 greatly overturned the protective roles of BACH1 loss on osteoblast differentiation and autophagy in Dex-induced hBMSCs.
    CONCLUSION: Taken together, our results demonstrated that silencing of BACH1 mitigated Dex-triggered osteogenic differentiation inhibition by transcriptionally activating ATG7-mediated autophagy, suggesting that BACH1 may be a therapeutic target for GIOP treatment.
    Keywords:  ATG7; Autophagy; BACH1; Glucocorticoid-induced osteoporosis; Osteoblast differentiation
    DOI:  https://doi.org/10.1186/s12891-024-07761-y
  60. Exp Gerontol. 2024 Aug 23. pii: S0531-5565(24)00205-5. [Epub ahead of print] 112559
    Role of fibroblast autophagy and proliferation in skin anti-aging.
    Yantong Lu, Guangjuan Pan, Zhiying Wei, Yaohua Li, Xiaojiao Pan.
      Skin, as the outermost protective barrier of the body, becomes damaged with age and exposure to external stimuli. Dermal fibroblasts age and undergo apoptosis, which decreases collagen, collagen fibers, elastic fibers, hyaluronic acid, etc., leading skin to loss of elasticity and appearance of wrinkles. Skin aging is complex, involving several biological reactions，and various treatment methods are used to treat it. This review focuses on the importance of autophagy and cell proliferation in skin anti-aging, summarizes research progress on skin anti-aging by regulating autophagy and promoting the proliferation of dermal fibroblasts, and discusses future directions on skin anti-aging research.
    Keywords:  Autophagy; Cell proliferation; Dermis; Fibroblasts; Skin anti-aging
    DOI:  https://doi.org/10.1016/j.exger.2024.112559
  61. Andrology. 2024 Aug 28.
    Trehalose attenuates testicular aging by activating autophagy and improving mitochondrial quality.
    Huaming Xi, Wenjing Shan, Minghui Li, Ziqian Wang, Yuan Li.
       BACKGROUND: Reproductive aging can adversely affect male fertility and the health of offspring. The aging process is accompanied by impaired autophagy. Recent studies have shown that Trehalose plays an important role in the prevention of various diseases by regulating autophagy. However, the roles of Trehalose in testicular aging and reproductive decline remain to be clarified.
    OBJECTIVE: The present study aimed to evaluate the protective effects of Trehalose on testes in an aging mouse model.
    MATERIALS AND METHODS: In this study, an in vivo aging model in mice by administering D-galactose was established to explore the protective effect of Trehalose on testicular aging. We examined histological changes and related indicators of apoptosis, autophagy, mitochondrial biogenesis, and sperm quality.
    RESULTS: D-galactose treatment induced oxidative stress, apoptosis, and impairment of autophagy of testicular cells in mouse testes. Trehalose administration significantly reduced germ cell apoptosis and DNA damage caused by D-galactose-induced oxidative stress. Notably, Trehalose activated autophagy activity and improved mitochondrial function in testicular cells. Furthermore, Trehalose treatment increased the expression level of the tight junction protein ZO-1, and accelerated clearance of damaged mitochondria in Sertoli cells, indicating that Trehalose ameliorated Sertoli cell function in D-galactose-induced aging testes.
    DISCUSSION AND CONCLUSION: These findings suggest that Trehalose administration activated the autophagy activity in testicular cells and improved mitochondrial function, thereby effectively preventing testicular aging. Trehalose and its activated autophagy are crucial for preventing testicular aging, thus restoring autophagy activity by administering Trehalose could be a promising means to delay aging.
    Keywords:  autophagy; mitochondria; oxidative stress; testicular aging; trehalose
    DOI:  https://doi.org/10.1111/andr.13746
  62. Arch Biochem Biophys. 2024 Aug 23. pii: S0003-9861(24)00257-1. [Epub ahead of print]760 110135
    Docosahexaenoic acid enhances the treatment efficacy for castration-resistant prostate cancer by inhibiting autophagy through Atg4B inhibition.
    Yudai Kudo, Kana Nakamura, Honoka Tsuzuki, Kotaro Hirota, Mina Kawai, Daisuke Takaya, Kaori Fukuzawa, Teruki Honma, Yuta Yoshino, Mitsuhiro Nakamura, Masaki Shiota, Naohiro Fujimoto, Akira Ikari, Satoshi Endo.
      Autophagy induction in cancer is involved in cancer progression and the acquisition of resistance to anticancer agents. Therefore, autophagy is considered a potential therapeutic target in cancer therapy. In this study, we found that long-chain fatty acids (LCFAs) have inhibitory effects on Atg4B, which is essential for autophagosome formation, through screening based on the pharmacophore of 21f, a recently developed Atg4B inhibitor. Among these fatty acids, docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibited the most potent Atg4B inhibitory activity. DHA inhibited autophagy induced by androgen receptor signaling inhibitors (ARSI) in LNCaP and 22Rv1 prostate cancer cells and significantly increased apoptotic cell death. Furthermore, we investigated the effect of DHA on resistance to ARSI by establishing darolutamide-resistant prostate cancer 22Rv1 (22Rv1/Dar) cells, which had developed resistance to darolutamide, a novel ARSI. At baseline, 22Rv1/Dar cells showed a higher autophagy level than parental 22Rv1 cells. DHA significantly suppressed Dar-induced autophagy and sensitized 22Rv1/Dar cells by inducing apoptotic cell death through mitochondrial dysfunction. These results suggest that DHA supplementation may improve prostate cancer therapy with ARSI.
    Keywords:  Atg4B; Autophagy; Darolutamide resistance; Docosahexaenoic acid; Long-chain fatty acids; Prostate cancer cells
    DOI:  https://doi.org/10.1016/j.abb.2024.110135
  63. Pathol Res Pract. 2024 Aug 22. pii: S0344-0338(24)00464-3. [Epub ahead of print]262 155553
    Ferritinophagy: Molecular mechanisms and role in disease.
    Qi Zhu, Jianan Zhai, Zhengguo Chen, Zhifang Guo, Ningning Wang, Cong Zhang, Haoyuan Deng, Shaopeng Wang, Guang Yang.
      Ferritinophagy is a regulatory pathway of iron homeostasis. It is a process in which nuclear receptor coactivator 4 (NCOA4) carries ferritin to autophagolysosomes for degradation. After ferritin is degraded by autophagy, iron ions are released, which promotes the labile iron pool (LIP) to drive the Fenton reaction to cause lipid peroxidation. Furthermore, ferroptosis promoted by the accumulation of lipid reactive oxygen species (ROS) induced by ferritinophagy can cause a variety of systemic diseases. In clinical studies, targeting the genes regulating ferritinophagy can prevent and treat such diseases. This article describes the key regulatory factors of ferritinophagy and the mechanism of ferritinophagy involved in ferroptosis. It also reviews the damage of ferritinophagy to the body, providing a theoretical basis for further finding clinical treatment methods.
    Keywords:  Autophagy; Disease; Ferritin; Ferritinophagy; Ferroptosis; NCOA4
    DOI:  https://doi.org/10.1016/j.prp.2024.155553
  64. bioRxiv. 2024 Aug 15. pii: 2024.08.14.607425. [Epub ahead of print]
    Structural Analyses of a GABARAP~ATG3 Conjugate Uncover a Novel Non-covalent Ubl-E2 Backside Interaction.
    Kazuto Ohashi, Takanori Otomo.
      Members of the ATG8 family of ubiquitin-like proteins (Ubls) are conjugated to phosphatidylethanolamine (PE) in the autophagosomal membrane, where they recruit degradation substrates and facilitate membrane biogenesis. Despite this well-characterized function, the mechanisms underlying the lipidation process, including the action of the E2 enzyme ATG3, remain incompletely understood. Here, we report the crystal structure of human ATG3 conjugated to the mammalian ATG8 protein GABARAP via an isopeptide bond, mimicking the Ubl~E2 thioester intermediate. In this structure, the GABARAP~ATG3 conjugate adopts an open configuration with minimal contacts between the two proteins. Notably, the crystal lattice reveals non-covalent contacts between GABARAP and the backside of ATG3's E2 catalytic center, resulting in the formation of a helical filament of the GABARAP~ATG3 conjugate. While similar filament formations have been observed with canonical Ub~E2 conjugates, the E2 backside-binding interface of GABARAP is distinct from those of Ub/Ubl proteins and overlaps with the binding site for LC3 interacting region (LIR) peptides. NMR analysis confirms the presence of this non-covalent interaction in solution, and mutagenesis experiments demonstrate the involvement of the E2 backside in PE conjugation. These findings highlight the critical role of the E2 backside in the lipidation process and suggest evolutionary adaptations in the unique E2 enzyme ATG3.
    DOI:  https://doi.org/10.1101/2024.08.14.607425
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