bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2024–10–27
forty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. USP9X-mediated deubiquitination of Raptor contributes to autophagy impairment and memory deficits in P301S mice.
  2. Recruitment of autophagy initiator TAX1BP1 advances aggrephagy from cargo collection to sequestration.
  3. Fluorescent Reporters, Imaging, and Artificial Intelligence Toolkits to Monitor and Quantify Autophagy, Heterophagy, and Lysosomal Trafficking Fluxes.
  4. Lysosomal activity depends on TRPML1-mediated Ca2+ release coupled to incoming vesicle fusions.
  5. Pancreatic β-Cells, Diabetes and Autophagy.
  6. TFEB signaling promotes autophagic degradation of NLRP3 to attenuate neuroinflammation in diabetic encephalopathy.
  7. Golgiphagy: a novel selective autophagy to the fore.
  8. Autophagy and autophagic cell death in sepsis: friend or foe?
  9. Multiplex Genomic Tagging of Mammalian ATG8s to Study Autophagy.
  10. Modulation of autophagy by melatonin and its receptors: implications in brain disorders.
  11. Autophagy: A New Avenue and Biochemical Mechanisms to Mitigate the Climate Change.
  12. Macrophages and autophagy: partners in crime.
  13. Lysosomal Ca2+ release-facilitated TFEB nuclear translocation alleviates ischemic brain injury by attenuating autophagic/lysosomal dysfunction in neurons.
  14. Dynamic control of mTORC1 facilitates bone healing in mice.
  15. Nuclear proteasomes as a backup for autophagy: interconnected proteostasis pathways.
  16. The role of polo-like kinases 2 in the proteasomal and lysosomal degradation of alpha-synuclein in neurons.
  17. PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system.
  18. Reconstitution of Rab11-FIP4 Expression Rescues Cellular Homeostasis in Cystinosis.
  19. Natural products that alleviate depression: The putative role of autophagy.
  20. Multiple roles of mitochondrial autophagy receptor FUNDC1 in mitochondrial events and kidney disease.
  21. IL-17A's role in exacerbating radiation-induced lung injury: Autophagy impairment via the PP2A-mTOR pathway.
  22. Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells.
  23. Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response.
  24. Autophagy activation ameliorates the fibrosis of trabecular meshwork cells induced by TGFβ2 through the promotion of fibrotic proteins degradation.
  25. TMEM175 Plays a Crucial Role in Osteoblast Differentiation by Regulating Lysosomal Function and Autophagy.
  26. Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.
  27. Autophagy-Mediated Cellular Remodeling during Terminal Differentiation of Keratinocytes in the Epidermis and Skin Appendages.
  28. DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity.
  29. Promising and challenging phytochemicals targeting LC3 mediated autophagy signaling in cancer therapy.
  30. Optineurin regulates motor and learning behaviors by affecting dopaminergic neuron survival in mice.
  31. Mechanisms of drug resistance in nutrient-depleted colorectal cancer cells: insights into lysosomal and mitochondrial drug sequestration.
  32. Senolytics Enhance the Longevity of Caenorhabditis elegans by Altering Betaine Metabolism.
  33. Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
  34. Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages.
  35. Novel prospects in targeting neurodegenerative disorders via autophagy.
  36. Role of autophagy in myocardial remodeling after myocardial infarction.
  37. Identification of KW-2449 as a dual inhibitor of ferroptosis and necroptosis reveals that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis.
  38. Lysosome toxicities induced by nanoparticle exposure and related mechanisms.
  39. Mitochondrial pathways and sarcopenia in the geroscience era.
  40. Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.
  41. Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.
  42. Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.
  43. Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
  44. Intrinsically disordered region amplifies membrane remodeling to augment selective ER-phagy.
  45. Mitostasis in age-associated neurodegeneration.
  46. The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux.
  47. AMBRA1 controls the translation of immune-specific genes in T lymphocytes.
  48. LC3-associated phagocytosis and human diseases: Insights from mechanisms to therapeutic potential.
  49. Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.
  1. Cell Commun Signal. 2024 Oct 24. 22(1): 516
    USP9X-mediated deubiquitination of Raptor contributes to autophagy impairment and memory deficits in P301S mice.
    Siyi Zheng, Jiahui Zhu, Cailin Wang, Yanqing Wu, Shangqi Sun, Hongxiu Guo, Yanmin Chang, Rong Ma, Gang Li.
       BACKGROUND: Tauopathies, including Alzheimer's disease, are characterized by the pathological aggregation of tau protein, which is strongly linked to dysregulation of the autophagy-lysosomal degradation pathway. However, therapeutic strategies targeting this pathway remain limited.
    METHODS: We used both in vitro and in vivo models to investigate the role of Raptor in tau pathology. Knockdown of Raptor was performed to assess its impact on mTORC1 activation, autophagy, and tau accumulation. The relationship between USP9X and Raptor was also examined. Pharmacological inhibition of USP9X with WP1130 was employed to further confirm the involvement of the USP9X-Raptor-mTORC1 axis in tau degradation.
    RESULTS: Elevated Raptor levels in the hippocampus of P301S mice led to hyperactivation of mTORC1, impairing autophagy flux. Knockdown of Raptor effectively suppressed mTORC1 activation, promoted autophagy, and mitigated the accumulation of tau and its phosphorylated isoforms. This reduction in tau pathology was accompanied by decreased neuronal loss in the hippocampus, amelioration of synaptic damage, and improvement in cognitive function. The increased Raptor protein observed in the hippocampus of P301S mice was likely attributable to elevated USP9X content, which enhanced Raptor deubiquitination and protected it from proteasomal degradation. Pharmacological inhibition of USP9X with WP1130 in vitro effectively suppressed Raptor, promoted autophagy, and accelerated the degradation of tau and phosphorylated tau.
    CONCLUSIONS: Our findings highlight Raptor and USP9X as promising molecular targets for therapeutic intervention in tauopathies. Targeting the USP9X-Raptor-mTORC1 axis may provide a novel strategy for promoting autophagy and mitigating tau pathology in Alzheimer's disease and other tauopathies.
    Keywords:  Alzheimer’s disease; Autophagy; Raptor; Tau; USP9X
    DOI:  https://doi.org/10.1186/s12964-024-01872-8
  2. EMBO J. 2024 Oct 24.
    Recruitment of autophagy initiator TAX1BP1 advances aggrephagy from cargo collection to sequestration.
    Bernd Bauer, Jonas Idinger, Martina Schuschnig, Luca Ferrari, Sascha Martens.
      Autophagy mediates the degradation of harmful material within lysosomes. In aggrephagy, the pathway mediating the degradation of aggregated, ubiquitinated proteins, this cargo material is collected in larger condensates prior to its sequestration by autophagosomes. In this process, the autophagic cargo receptors SQSTM1/p62 and NBR1 drive cargo condensation, while TAX1BP1, which binds to NBR1, recruits the autophagy machinery to facilitate autophagosome biogenesis at the condensates. The mechanistic basis for the TAX1BP1-mediated switch from cargo collection to its sequestration is unclear. Here we show that TAX1BP1 is not a constitutive component of the condensates. Its recruitment correlates with the induction of autophagosome biogenesis. TAX1BP1 is sufficient to recruit the TBK1 kinase via the SINTBAD adapter. We define the NBR1-TAX1BP1-binding site, which is adjacent to the GABARAP/LC3 interaction site, and demonstrate that the recruitment of TAX1BP1 to cargo mimetics can be enhanced by an increased ubiquitin load. Our study suggests that autophagosome biogenesis is initiated once sufficient cargo is collected in the condensates.
    Keywords:  Aggrephagy p62; NBR1; Quality Control; Selective Autophagy; TAX1BP1
    DOI:  https://doi.org/10.1038/s44318-024-00280-5
  3. Traffic. 2024 Oct;25(10): e12957
    Fluorescent Reporters, Imaging, and Artificial Intelligence Toolkits to Monitor and Quantify Autophagy, Heterophagy, and Lysosomal Trafficking Fluxes.
    Mikhail Rudinskiy, Diego Morone, Maurizio Molinari.
      Lysosomal compartments control the clearance of cell-own material (autophagy) or of material that cells endocytose from the external environment (heterophagy) to warrant supply of nutrients, to eliminate macromolecules or parts of organelles present in excess, aged, or containing toxic material. Inherited or sporadic mutations in lysosomal proteins and enzymes may hamper their folding in the endoplasmic reticulum (ER) and their lysosomal transport via the Golgi compartment, resulting in lysosomal dysfunction and storage disorders. Defective cargo delivery to lysosomal compartments is harmful to cells and organs since it causes accumulation of toxic compounds and defective organellar homeostasis. Assessment of resident proteins and cargo fluxes to the lysosomal compartments is crucial for the mechanistic dissection of intracellular transport and catabolic events. It might be combined with high-throughput screenings to identify cellular, chemical, or pharmacological modulators of these events that may find therapeutic use for autophagy-related and lysosomal storage disorders. Here, discuss qualitative, quantitative and chronologic monitoring of autophagic, heterophagic and lysosomal protein trafficking in fixed and live cells, which relies on fluorescent single and tandem reporters used in combination with biochemical, flow cytometry, light and electron microscopy approaches implemented by artificial intelligence-based technology.
    Keywords:  ER‐phagy; ER‐to‐lysosome‐associated degradation (ERLAD); artificial intelligence; autophagy; autophagy flux; endolysosomes (EL); heterophagy; lysosomal storage disorders (LSD); lysosomes; tandem fluorescent reporters
    DOI:  https://doi.org/10.1111/tra.12957
  4. J Biol Chem. 2024 Oct 19. pii: S0021-9258(24)02413-X. [Epub ahead of print] 107911
    Lysosomal activity depends on TRPML1-mediated Ca2+ release coupled to incoming vesicle fusions.
    Arindam Bhattacharjee, Hussein Abuammar, Gábor Juhász.
      The lysosomal cation channel TRPML1/MCOLN1 facilitates autophagic degradation during amino acid starvation based on studies involving long-term TRMPL1 modulation. Here we show that lysosomal activation (more acidic pH and higher hydrolase activity) depends on incoming vesicle fusions. We identify an immediate, calcium-dependent role of TRPML1 in lysosomal activation through promoting autophagosome-lysosome fusions and lysosome acidification within 10-20 minutes of its pharmacological activation. Lysosomes also become more fusion competent upon TRPML1 activation via increased transport of lysosomal SNARE proteins syntaxin 7 and VAMP7 by SNARE carrier vesicles. We find that incoming vesicle fusion is a prerequisite for lysosomal Ca2+ efflux that leads to acidification and hydrolytic enzyme activation. Physiologically, the first vesicle fusions likely trigger generation of the phospholipid PI(3,5)P2 that activates TRPML1, and allosteric TRPML1 activation in the absence of PI(3,5)P2 restores autophagosome-lysosome fusion and rescues abnormal SNARE sequestration within lysosomes. We thus identify a prompt role of TRPML1-mediated calcium signaling in lysosomal fusions, activation, and SNARE trafficking.
    Keywords:  SNARE proteins; autophagy; ion channel; lysosomal acidification; membrane fusion
    DOI:  https://doi.org/10.1016/j.jbc.2024.107911
  5. Endocr Res. 2024 Oct 21. 1-16
    Pancreatic β-Cells, Diabetes and Autophagy.
    Yang Ou, Yan-Li Zhao, Heng Su.
       PURPOSE: Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis.
    METHODS: We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management.
    RESULTS: Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression.
    CONCLUSION: Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.
    Keywords:  Autophagy; diabetes; insulin homeostasis; mitophagy; pancreatic β-cells
    DOI:  https://doi.org/10.1080/07435800.2024.2413064
  6. Am J Physiol Cell Physiol. 2024 Oct 22.
    TFEB signaling promotes autophagic degradation of NLRP3 to attenuate neuroinflammation in diabetic encephalopathy.
    Yijia Lin, Lizhen Cheng, Yixin Chen, Wei Li, Qihao Guo, Ya Miao.
      Diabetic encephalopathy (DE), a neurological complication of diabetes mellitus, has an unclear etiology. Shreds of evidence show that the Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome-induced neuroinflammation and transcription factor EB (TFEB)-mediated autophagy impairment may take part in DE development. The crosstalk between these two pathways and their contribution to DE remains to be explored. A mouse model of type 2 diabetes mellitus (T2DM) exhibiting cognitive dysfunction was created, along with high glucose (HG) cultured BV2 cells. Following, 3-methyladenine (3-MA) and rapamycin were utilized to modulate autophagy. To evaluate the potential therapeutic benefits of TFEB in DE, we overexpressed and knocked down TFEB in both mice and cells. Autophagy impairment and NLRP3 inflammasome activation were noticed in T2DM mice and HG-cultured BV2 cells. The inflammatory response caused by NLRP3 inflammasome activation was decreased by rapamycin-induced autophagy enhancement, while 3-MA treatment further deteriorated it. Nuclear translocation and expression of TFEB were hampered in HG-cultured BV2 cells and T2DM mice. Exogenous TFEB overexpression boosted NLRP3 degradation via autophagy, which in turn alleviated microglial activation as well as ameliorated cognitive deficits and neuronal damage. Additionally, TFEB knockdown exacerbated neuroinflammation by decreasing autophagy-mediated NLRP3 degradation. Our findings have unraveled the pathogenesis of a previously underappreciated disease, implying that the activation of NLRP3 inflammasome and impairment of autophagy in microglia are significant etiological factors in the DE. The TFEB-mediated autophagy pathway can reduce neuroinflammation by enhancing NLRP3 degradation. This could potentially serve as a viable and innovative treatment approach for DE.
    Keywords:  Autophagy; Diabetic encephalopathy; Microglia; NLRP3; TFEB
    DOI:  https://doi.org/10.1152/ajpcell.00322.2024
  7. Cell Biosci. 2024 Oct 22. 14(1): 130
    Golgiphagy: a novel selective autophagy to the fore.
    Yifei Chen, Yihui Wu, Xianyan Tian, Genbao Shao, Qiong Lin, Aiqin Sun.
      The Golgi apparatus is the central hub of the cellular endocrine pathway and plays a crucial role in processing, transporting, and sorting proteins and lipids. Simultaneously, it is a highly dynamic organelle susceptible to degradation or fragmentation under various physiological or pathological conditions, potentially contributing to the development of numerous human diseases. Autophagy serves as a vital pathway for eukaryotes to manage intracellular and extracellular stress and maintain homeostasis by targeting damaged or redundant organelles for removal. Recent research has revealed that autophagy mechanisms can specifically degrade Golgi components, known as Golgiphagy. This review summarizes recent findings on Golgiphagy while also addressing unanswered questions regarding its mechanisms and regulation, aiming to advance our understanding of the role of Golgiphagy in human disease.
    Keywords:  Autophagy; Golgi apparatus; Golgi fragmentation; Golgiphagy; Receptor
    DOI:  https://doi.org/10.1186/s13578-024-01311-8
  8. J Intensive Care. 2024 Oct 25. 12(1): 41
    Autophagy and autophagic cell death in sepsis: friend or foe?
    Toshiaki Iba, Julie Helms, Cheryl L Maier, Ricard Ferrer, Jerrold H Levy.
      In sepsis, inflammation, and nutrient deficiencies endanger cellular homeostasis and survival. Autophagy is primarily a mechanism of cellular survival under fasting conditions. However, autophagy-dependent cell death, known as autophagic cell death, is proinflammatory and can exacerbate sepsis. Autophagy also regulates various types of non-inflammatory and inflammatory cell deaths. Non-inflammatory apoptosis tends to suppress inflammation, however, inflammatory necroptosis, pyroptosis, ferroptosis, and autophagic cell death lead to the release of inflammatory cytokines and damage-associated molecular patterns (DAMPs) and amplify inflammation. The selection of cell death mechanisms is complex and often involves a mixture of various styles. Similarly, protective autophagy and lethal autophagy may be triggered simultaneously in cells. How cells balance the regulatory mechanisms of these processes is an area of interest that is still under investigation. Therapies aimed at modulating autophagy are considered promising. Enhancing autophagy helps clear and recycle damaged organelles and reduce the burden of inflammatory processes while inhibiting excessive autophagy, which could prevent autophagic cell death. In this review, we introduce recent advances in research and the complex regulatory system of autophagy in sepsis.
    Keywords:  Apoptosis; Autophagy; Mitochondria; Mitophagy; Necrosis; Sepsis
    DOI:  https://doi.org/10.1186/s40560-024-00754-y
  9. J Biol Chem. 2024 Oct 19. pii: S0021-9258(24)02410-4. [Epub ahead of print] 107908
    Multiplex Genomic Tagging of Mammalian ATG8s to Study Autophagy.
    Korina Goldin-Azulay, Milana Fraiberg, Olena Trofimyuk, Yishai Levin, Nina Reuven, Ekaterina Kopitman, Zvulun Elazar.
      Atg8 proteins play a crucial role in autophagy. There is a single Atg8 isoform in yeast, while mammals have up to seven homologs categorized into LC3s and GABARAPs. The GABARAP subfamily consists of GABARAP, GABARAPL1, and GABARAPL2/GATE16, implicated in various stages along the pathway. However, the intricacies among GABARAP proteins are complex and require a more precise delineation. Here, we introduce a new cellular platform to study autophagy using CRISPR/Cas9-mediated tagging of endogenous genes of the GABARAP subfamily with different fluorescent proteins. This platform allows robust examination of autophagy by flow cytometry of cell populations and monitoring of GABARAP homologs at single-cell resolution using fluorescence microscopy. Strikingly, the simultaneous labeling of the different endogenous GABARAPs allows the identification and isolation of autophagosomes differentially marked by these proteins. Using this system, we found that the different GABARAPs are associated with different autophagosomes. We argue that this new cellular platform will be crucial in studying the unique roles of individual GABARAP proteins in autophagy and other putative cellular processes.
    Keywords:  CRISPR/Cas; autophagy; degradation; gene knockout; proteomics; starvation
    DOI:  https://doi.org/10.1016/j.jbc.2024.107908
  10. Acta Pharmacol Sin. 2024 Oct 24.
    Modulation of autophagy by melatonin and its receptors: implications in brain disorders.
    Chen-Ze Zhu, Gui-Zhi Li, Hai-Feng Lyu, Yang-Yang Lu, Yue Li, Xiang-Nan Zhang.
      Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.
    Keywords:  autophagy; brain disorders; melatonin; melatonin receptor; neuron
    DOI:  https://doi.org/10.1038/s41401-024-01398-2
  11. Scientifica (Cairo). 2024 ;2024 9908323
    Autophagy: A New Avenue and Biochemical Mechanisms to Mitigate the Climate Change.
    Muhammad Abubakkar Azmat, Malaika Zaheer, Muhammad Shaban, Saman Arshad, Muhammad Hasan, Alyan Ashraf, Muhammad Naeem, Aftab Ahmad, Nayla Munawar.
      Autophagy is a preserved process in eukaryotes that allows large material degeneration and nutrient recovery via vacuoles or lysosomes in cytoplasm. Autophagy starts from the moment of induction during the formation of a phagophore. Degradation may occur in the autophagosomes even without fusion with lysosome or vacuole, particularly in microautophagosomes. This process is arbitrated by the conserved machinery of basic autophagy-related genes (ATGs). In selective autophagy, specific materials are recruited by autophagosomes via receptors. Selective autophagy targets a vast variety of cellular components for degradation, i.e., old or damaged organelles, aggregates, and inactive or misfolded proteins. In optimal conditions, autophagy in plants ensures cellular homeostasis, proper plant growth, and fitness. Moreover, autophagy is essential during stress responses in plants and aids in survival of plants. Several biotic and abiotic stresses, i.e., pathogen infection, nutrient deficiency, plant senescence, heat stress, drought, osmotic stress, and hypoxia induce autophagy in plants. Cell death is not a stress, which induces autophagy but in contrast, sometimes it is a consequence of autophagy. In this way, autophagy plays a vital role in plant survival during harsh environmental conditions by maintaining nutrient concentration through elimination of useless cellular components. This review discussed the recent advances regarding regulatory functions of autophagy under normal and stressful conditions in plants and suggests future prospects in mitigating climate change. Autophagy in plants offers a viable way to increase plant resilience to climate change by increasing stress tolerance and nutrient usage efficiency.
    Keywords:  ATGs (autophagy-related genes); abiotic stress; autophagosome; autophagy; biotic stress; selective autophagy
    DOI:  https://doi.org/10.1155/2024/9908323
  12. FEBS J. 2024 Oct 22.
    Macrophages and autophagy: partners in crime.
    Alessandra Vitaliti, Alessio Reggio, Alessandro Palma.
      Macrophages and autophagy are intricately linked, both playing vital roles in maintaining homeostasis and responding to disease. Macrophages, known for their 'eating' function, rely on a sophisticated digestion system to process a variety of targets, from apoptotic cells to pathogens. The connection between macrophages and autophagy is established early in their development, influencing both differentiation and mature functions. Autophagy regulates essential immune functions, such as inflammation control, pathogen clearance, and antigen presentation, linking innate and adaptive immunity. Moreover, it modulates cytokine production, ensuring a balanced inflammatory response that prevents excessive tissue damage. Autophagy also plays a critical role in macrophage polarization, influencing their shift between pro-inflammatory and anti-inflammatory states. This review explores the role of autophagy in macrophages, emphasizing its impact across various tissues and pathological conditions, and detailing the cellular and molecular mechanisms by which autophagy shapes macrophage function.
    Keywords:  autophagy; immunity; lysosome; macrophages; phagocytes
    DOI:  https://doi.org/10.1111/febs.17305
  13. Sci Rep. 2024 10 22. 14(1): 24836
    Lysosomal Ca2+ release-facilitated TFEB nuclear translocation alleviates ischemic brain injury by attenuating autophagic/lysosomal dysfunction in neurons.
    Qian Lei, Xuemei Chen, Yajie Xiong, Shangdan Li, Jiaqian Wang, Hongyun He, Yihao Deng.
      Neuronal death was frequently driven by autophagic/lysosomal dysfunction after ischemic stroke, whereas how to restore the impaired autophagic flux remained elusive. Autophagic/lysosomal signaling could be augmented after transcription factor EB (TFEB) nuclear translocation, which was facilitated by its dephosphorylation. A key TFEB dephosphorylase was calcineurin (CaN), whose activity was drastically regulated by cytosolic calcium ion concentration ([Ca2+]) controlled by lysosomal Ca2+ channel-like protein of TRPML1. Our research shows that ML-SA1, an agonist of the TRPML1 channel, significantly enhanced the lysosomal Ca2+ release and the CaN expression in penumbric neurons, subsequently promoted TFEB nuclear translocation, and greatly reversed autophagy/lysosome dysfunction. Moreover, ML-SA1 treatment significantly reduced neuronal loss, infarct size, and neurological deficits. By contrast, ML-SI3, an inhibitor of TRPML1, inhibited the lysosomal Ca2+ release conversely, aggravated the impairment of autophagic flux and consequentially exacerbated brain stroke lesion. These studies suggest that TRPML1 elevation alleviates ischemic brain injury by restoring autophagic/lysosomal dysfunction via Lysosomal Ca2+ release-facilitated TFEB nuclear translocation in neurons.
    Keywords:  Autophagic/lysosomal dysfunction; Ischemic stroke; Lysosomal Ca2+ ; Neuroprotection; TFEB; TRPML1
    DOI:  https://doi.org/10.1038/s41598-024-75802-6
  14. Bone. 2024 Oct 17. pii: S8756-3282(24)00274-6. [Epub ahead of print] 117285
    Dynamic control of mTORC1 facilitates bone healing in mice.
    Delong Li, Daozhang Cai, Denghui Xie, Liang Wang, Yan Zhang, Guangfeng Ruan, Qun Zhang, Bo Yan, Haiyan Zhang, Pinglin Lai, Zhengquan Liao, Yu Jiang, Dianbo Yu, Changhai Ding, Chengliang Yang.
      Bone healing requires well-orchestrated sequential actions of osteoblasts and osteoclasts. Previous studies have demonstrated that the mechanistic target of rapamycin complex 1 (mTORC1) plays a critical role in the metabolism of osteoblasts and osteoclasts. However, the role of mTORC1 in bone healing remains unclear. Here, we showed that a dynamic change in mTORC1 activity during the process was essential for proper healing and can be harnessed therapeutically for treatment of bone fractures. Low mTORC1 activity induced by osteoblastic Raptor knockout or rapamycin treatment promoted osteoblast-mediated osteogenesis, thus leading to better bone formation and shorter bone union time. Rapamycin treatment in vitro also revealed that low mTORC1 activity enhanced osteoblast differentiation and maturation. However, rapamycin treatment affected the recruitment of osteoclasts to new bone sites, thus resulting in delayed callus absorption in bone marrow cavity. Mechanistically, decreased mTORC1 activity inhibited the recruitment of osteoclast progenitor cells to healing sites through a decrease in osteoblastic expression of monocyte chemoattractant protein-1, thus inhibiting osteoclast-mediated remodeling. Therefore, normal mTORC1 activity was necessary for bone remodeling stage. Furthermore, through the use of sustained-release materials at the bone defect, we confirmed that localized application of rapamycin in early stages accelerated bone healing without affecting bone remodeling. Together, these findings revealed that the activity of mTORC1 continually changed during bone healing, and staged rapamycin treatment could be used to promote bone healing.
    Keywords:  Bone healing; Bone remodeling; MCP-1; Rapamycin; mTORC1
    DOI:  https://doi.org/10.1016/j.bone.2024.117285
  15. Autophagy. 2024 Oct 20. 1-2
    Nuclear proteasomes as a backup for autophagy: interconnected proteostasis pathways.
    Meiyan Jin, Daniel J Klionsky.
      Protein homeostasis (proteostasis) refers to the balance of the cellular protein environment, tightly regulated by pathways governing protein synthesis, folding, trafficking, and degradation. Growing evidence supports the interconnection of these pathways to ensure the robustness of the proteo-stasis network. A recent study by Park et al. showed that, in macroautophagy/autophagy-deficient cells, the loss of proteasome or nuclear pore components causes synthetic lethality, as cytoplasmic proteins that accumulate under impaired autophagy are transported to the nucleus and degraded by nuclear proteasomes. The authors illustrated the mechanistic basis for why cells with conditions such as Huntington disease, where both autophagy and cytoplasm-to-nuclear shuttling are compromised, are more vulnerable to proteostasis perturbation.Abbreviation: UPR: unfolded protein response; UPS: ubiquitin-proteasome system.
    Keywords:  Autophagy; nuclear pore complex; nuclear proteasome; proteasome; proteostasis
    DOI:  https://doi.org/10.1080/15548627.2024.2416261
  16. FASEB J. 2024 Oct;38(20): e70121
    The role of polo-like kinases 2 in the proteasomal and lysosomal degradation of alpha-synuclein in neurons.
    Chun Chau Sung, Wai Yun Lam, Kenny K K Chung.
      Parkinson's disease (PD) is a neurodegenerative disorder caused by the degeneration of dopaminergic neurons in the brain stem. PD is mostly sporadic, but familial PD (FPD) cases are recorded in different studies. The first gene mutation that is linked to FPD is α-synuclein (α-syn). It was then found that α-syn is also accumulated in Lewy body (LB), a classical pathological hallmark in PD patients. Different studies have shown that α-syn accumulation and aggregation can be a crucial factor contributing to the degeneration of dopaminergic neurons in PD. α-syn has been found to be degraded by the ubiquitin proteasomal system (UPS) and autophagy-lysosomal pathway (ALP). In this study, we initially explored how α-syn phosphorylation by GRK6, PLK2 and CK2α would facilitate its degradation in relation to the UPS or ALP. Unexpectedly, we found that the degradation of α-syn through PLK2 phosphorylation could be modulated by UPS and ALP in a novel mechanism. Specially, attenuation of UPS could increase the amount of PLK2 and then could facilitate the phosphorylation and degradation of α-syn through ALP. To test this further in vivo, we attenuate the proteasomal activity in a well-established A53T α-syn transgenic PD mouse model. We found that attenuation of proteasomal activity in the A53T α-syn transgenic mice could reduce the accumulation of α-syn in the striatum and midbrain. Based on our results, this study provides a new insight into how α-syn is degraded through the UPS and ALP.
    Keywords:  autophagy–lysosomal pathway; phosphorylation; protein degradation; ubiquitin‐proteasomal system; α‐synuclein
    DOI:  https://doi.org/10.1096/fj.202401035R
  17. FEBS J. 2024 Oct 21.
    PGC-1α regulation by FBXW7 through a novel mechanism linking chaperone-mediated autophagy and the ubiquitin-proteasome system.
    Simona Eleuteri, Bao Wang, Gianni Cutillo, Tracy Shi Zhang Fang, Kai Tao, Yan Qu, Qian Yang, Wenyi Wei, David K Simon.
      Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and antioxidative defenses, and it may play a critical role in Parkinson's disease (PD). F-box/WD repeat domain-containing protein (FBXW7), an E3 protein ligase, promotes the degradation of substrate proteins through the ubiquitin-proteasome system (UPS) and leads to the clearance of PGC-1α. Here, we elucidate a novel post-translational mechanism for regulating PGC-1α levels in neurons. We show that enhancing chaperone-mediated autophagy (CMA) activity promotes the CMA-mediated degradation of FBXW7 and consequently increases PGC-1α. We confirm the relevance of this pathway in vivo by showing decreased FBXW7 and increased PGC-1α as a result of boosting CMA selectively in dopaminergic (DA) neurons by overexpressing lysosomal-associated membrane protein 2A (LAMP2A) in TH-Cre-LAMP2-loxp conditional mice. We further demonstrate that these mice are protected against MPTP-induced oxidative stress and neurodegeneration. These results highlight a novel regulatory pathway for PGC-1α in DA neurons and suggest targeted increasing of CMA or decreasing FBXW7 in DA neurons as potential neuroprotective strategies in PD.
    Keywords:  CMA; Fbxw7; PGC‐1α; Parkinson's disease
    DOI:  https://doi.org/10.1111/febs.17276
  18. Mol Cell Biol. 2024 Oct 22. 1-13
    Reconstitution of Rab11-FIP4 Expression Rescues Cellular Homeostasis in Cystinosis.
    Farhana Rahman, Jennifer L Johnson, Mouad Ait Kbaich, Elsa Meneses-Salas, Aparna Shukla, Danni Chen, William B Kiosses, Evripidis Gavathiotis, Ana Maria Cuervo, Stephanie Cherqui, Sergio D Catz.
      Rab11 family interacting protein 4 (Rab11-FIP4) regulates endocytic trafficking. A possible role for Rab11-FIP4 in the regulation of lysosomal function has been proposed, but its precise function in the regulation of cellular homeostasis is unknown. By mRNA array and protein analysis, we found that Rab11-FIP4 is downregulated in the lysosomal storage disease cystinosis, which is caused by genetic defects in the lysosomal cystine transporter, cystinosin. Rescue of Rab11-FIP4 expression in Ctns-/- fibroblasts re-established normal autophagosome levels and decreased LC3B-II expression in cystinotic cells. Furthermore, Rab11-FIP4 reconstitution increased the localization of the chaperone-mediated autophagy receptor LAMP2A at the lysosomal membrane. Treatment with genistein, a phytoestrogen that upregulates macroautophagy, or the CMA activator QX77 (CA77) restored Rab11-FIP4 expression levels in cystinotic cells supporting a cross-regulation between two independent autophagic mechanisms, lysosomal function and Rab11-FIP4. Improved cellular homeostasis in cystinotic cells rescued by Rab11-FIP4 expression correlated with decreased endoplasmic reticulum stress, an effect that was potentiated by Rab11 and partially blocked by expression of a dominant negative Rab11. Restoring Rab11-FIP4 expression in cystinotic proximal tubule cells increased the localization of the endocytic receptor megalin at the plasma membrane, suggesting that Rab11-FIP4 reconstitution has the potential to improve cellular homeostasis and function in cystinosis.
    Keywords:  ATF4; Arf6; ER stress; Lysosomal disease; Rab GTPases; Rab11; Rab11-FIP4; autophagy; chaperone-mediated autophagy; trafficking
    DOI:  https://doi.org/10.1080/10985549.2024.2410814
  19. Pharmacol Ther. 2024 Oct 17. pii: S0163-7258(24)00151-7. [Epub ahead of print] 108731
    Natural products that alleviate depression: The putative role of autophagy.
    Yunfeng Zhou, Fengwei Nan, Qianwen Zhang, Wangjun Xu, Shaojie Fang, Ke Liu, Bingxin Zhao, Hao Han, Xinmei Xie, Changjiang Qin, Xiaobin Pang.
      Major depressive disorder (MDD) is a common mental disorder that severely disrupts psychosocial function and decreases the quality of life. Although the pathophysiological mechanism underlying MDD is complex and remains unclear, emerging evidence suggests that autophagy dysfunction plays a role in MDD occurrence and progression. Natural products serve as a major source of drug discovery and exert tremendous potential in developing antidepressants. Recently published reports are paying more attention on the autophagy regulatory effect of antidepressant natural products. In this review, we comprehensively discuss the abnormal changes occurred in multiple autophagy stages in MDD patients, and animal and cell models of depression. Importantly, we emphasize the regulatory mechanism of antidepressant natural products on disturbed autophagy, including monomeric compounds, bioactive components, crude extracts, and traditional Chinese medicine formulae. Our comprehensive review suggests that enhancing autophagy might be a novel approach for MDD treatment, and natural products restore autophagy homeostasis to facilitate the renovation of mitochondria, impede neuroinflammation, and enhance neuroplasticity, thereby alleviating depression.
    Keywords:  Autophagy; Depression; Natural products; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.pharmthera.2024.108731
  20. Front Cell Dev Biol. 2024 ;12 1453365
    Multiple roles of mitochondrial autophagy receptor FUNDC1 in mitochondrial events and kidney disease.
    Kaiqing Li, Xue Xia, Ying Tong.
      This article reviews the latest research progress on the role of mitochondrial autophagy receptor FUN14 domain containing 1 (FUNDC1) in mitochondrial events and kidney disease. FUNDC1 is a protein located in the outer membrane of mitochondria, which maintains the function and quality of mitochondria by regulating mitochondrial autophagy, that is, the selective degradation process of mitochondria. The structural characteristics of FUNDC1 enable it to respond to intracellular signal changes and regulate the activity of mitochondrial autophagy through phosphorylation and dephosphorylation. During phosphorylation, unc-51-like kinase 1 (ULK1) promotes the activation of mitophagy by phosphorylating Ser17 of FUNDC1. In contrast, Src and CK2 kinases inhibit the interaction between FUNDC1 and LC3 by phosphorylating Tyr18 and Ser13, thereby inhibiting mitophagy. During dephosphorylation, PGAM5 phosphatase enhances the interaction between FUNDC1 and LC3 by dephosphorylating Ser13, thereby activating mitophagy. BCL2L1 inhibits the activity of PGAM5 by interacting with PGAM5, thereby preventing the dephosphorylation of FUNDC1 and inhibiting mitophagy. FUNDC1 plays an important role in mitochondrial events, participating in mitochondrial fission, maintaining the homeostasis of iron and proteins in mitochondrial matrix, and mediating crosstalk between mitochondria, endoplasmic reticulum and lysosomes, which have important effects on cell energy metabolism and programmed death. In the aspect of kidney disease, the abnormal function of FUNDC1 is closely related to the occurrence and development of many diseases. In acute kidney injury (AKI), cardiorenal syndrome (CRS), diabetic nephropathy (DN), chronic kidney disease (CKD) ,renal fibrosis (RF) and renal anemia, FUNDC1-mediated imbalance of mitophagy may be one of the key factors in disease progression. Therefore, in-depth study of the regulatory mechanism and function of FUNDC1 is of great significance for understanding the pathogenesis of renal disease and developing new treatment strategies.
    Keywords:  FUNDC1; dephosphorylation; kidney disease; mitochondrial autophagy; phosphorylation
    DOI:  https://doi.org/10.3389/fcell.2024.1453365
  21. Biochim Biophys Acta Mol Cell Res. 2024 Oct 20. pii: S0167-4889(24)00207-6. [Epub ahead of print]1872(1): 119864
    IL-17A's role in exacerbating radiation-induced lung injury: Autophagy impairment via the PP2A-mTOR pathway.
    Liangzhong Liu, GuangMing Yi, Xiaohong Li, Cai Chen, Kehong Chen, Hengqiu He, Jinjin Li, Fanghao Cai, Yuan Peng, Zhenzhou Yang, Xiaoyue Zhang.
       OBJECTIVE: Radiation-induced lung injury (RILI) is a serious complication of radiotherapy, and the role of IL-17A in this process is not well understood. While IL-17A has been shown to modulate autophagy, conflicting reports exist regarding its activation or inhibition of autophagy. This study investigates the role of IL-17A in RILI and its effects on autophagy via the PP2A-mTOR pathway, with a focus on the PP2A B56α subunit.
    METHODS: C57BL/6J mice and human lung epithelial cells (BEAS-2B) were exposed to radiation with or without recombinant IL-17A. Autophagy markers were analyzed using Western blotting, immunofluorescence, and autophagy flux assays. PP2A activity, specifically the B56α subunit, was measured. A PP2A agonist (DT-061) was used to verify its role in reversing IL-17A-mediated autophagy inhibition.
    RESULTS: IL-17A inhibited autophagy in lung epithelial cells exposed to radiation by suppressing PP2A activity, particularly through downregulation of the B56α subunit, leading to mTOR activation and reduced autophagosome formation. Treatment with DT-061 restored autophagic activity and improved cell viability. These findings align with reports suggesting that IL-17A inhibits autophagy in certain contexts, while other studies have shown opposing effects.
    CONCLUSION: IL-17A inhibits autophagy in RILI through the PP2A B56α-mTOR pathway, exacerbating lung damage. Further research is needed to clarify the role of IL-17A in different cell types and conditions. Targeting the IL-17A-PP2A B56α-mTOR axis may offer new therapeutic strategies for RILI management.
    Keywords:  Autophagy; IL-17A; PP2A B56α; Radiation-induced lung injury; mTOR
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119864
  22. Sci Signal. 2024 Oct 22. 17(859): eadi8753
    Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells.
    Teresa Rosenlehner, Stefanie Pennavaria, Batuhan Akçabozan, Shiva Jahani, Thomas J O'Neill, Daniel Krappmann, Tobias Straub, Jan Kranich, Reinhard Obst.
      Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.
    DOI:  https://doi.org/10.1126/scisignal.adi8753
  23. Open Biol. 2024 Oct;14(10): 240194
    Zebrafish reveal new roles for Fam83f in hatching and the DNA damage-mediated autophagic response.
    Rebecca A Jones, Fay Cooper, Gavin Kelly, David Barry, Matthew J Renshaw, Gopal Sapkota, James C Smith.
      The FAM83 (Family with sequence similarity 83) family is highly conserved in vertebrates, but little is known of the functions of these proteins beyond their association with oncogenesis. Of the family, FAM83F is of particular interest because it is the only membrane-targeted FAM83 protein. When overexpressed, FAM83F activates the canonical Wnt signalling pathway and binds to and stabilizes p53; it therefore interacts with two pathways often dysregulated in disease. Insights into gene function can often be gained by studying the roles they play during development, and here we report the generation of fam83f knock-out (KO) zebrafish, which we have used to study the role of Fam83f in vivo. We show that endogenous fam83f is most strongly expressed in the hatching gland of developing zebrafish embryos, and that fam83f KO embryos hatch earlier than their wild-type (WT) counterparts, despite developing at a comparable rate. We also demonstrate that fam83f KO embryos are more sensitive to ionizing radiation than WT embryos-an unexpected finding, bearing in mind the previously reported ability of FAM83F to stabilize p53. Transcriptomic analysis shows that loss of fam83f leads to downregulation of phosphatidylinositol-3-phosphate (PI(3)P) binding proteins and impairment of cellular degradation pathways, particularly autophagy, a crucial component of the DNA damage response. Finally, we show that Fam83f protein is itself targeted to the lysosome when overexpressed in HEK293T cells, and that this localization is dependent upon a C' terminal signal sequence. The zebrafish lines we have generated suggest that Fam83f plays an important role in autophagic/lysosomal processes, resulting in dysregulated hatching and increased sensitivity to genotoxic stress in vivo.
    Keywords:  DNA damage; Fam83f; autophagy; development; hatching; zebrafish
    DOI:  https://doi.org/10.1098/rsob.240194
  24. Hum Cell. 2024 Oct 22. 38(1): 4
    Autophagy activation ameliorates the fibrosis of trabecular meshwork cells induced by TGFβ2 through the promotion of fibrotic proteins degradation.
    Gang Wang, Rumeng Zhao, Zhenyang Guo, Huiling Cui, Di Wang, Jing Ren, Shichao Zhu, Ke Zhang, Bo Tang, Jingyi Zhang, Peng Li, Shichao Duan, Haijun Li.
      The level of transforming growth factor-beta2 (TGFβ2) is elevated in aqueous humor of partial glaucoma patients, and induced trabecular meshwork (TM) fibrosis, which could cause TM cells dysfunction and lead to intraocular pressure (IOP) elevation. Autophagy is a dynamic process of bulk degradation of organelles and proteins under stress condition, while its functions in fibrotic development remain controversial. Meanwhile, it is still unclear if activation of autophagy could ameliorate TGFβ2-induced fibrosis in TM cells. In this study, we demonstrated that autophagy activation with Rapamycin or Everolimus could ameliorate TM fibrosis induced by TGFβ2. We also proved that activation of autophagy may decrease TM cells fibrosis and reduce elevated IOP induced by TGFβ2 in vivo, while Rapamycin or Everolimus has no effect on TGFβ/Smad3 pathway activity and fibrotic genes expression. However, when Chloroquine phosphate blocks autophagy-lysosome pathway, the protective effect of Rapamycin or Everolimus on fibrosis was weakened. We established that autophagy activation ameliorates TM fibrosis through promoting fibrotic proteins degradation.
    Keywords:  Autophagy; Fibrosis; Rapamycin; Smad3; TGFβ2; Trabecular meshwork cells
    DOI:  https://doi.org/10.1007/s13577-024-01141-3
  25. Mol Cells. 2024 Oct 17. pii: S1016-8478(24)00152-3. [Epub ahead of print] 100127
    TMEM175 Plays a Crucial Role in Osteoblast Differentiation by Regulating Lysosomal Function and Autophagy.
    Seung Hye Lee, Ji Sun Jang, Shenzheng Mo, Hong-Hee Kim.
      Bone provides structural support, enables movement, protects internal organs, regulates calcium and phosphorus levels, and contains bone marrow essential for hematopoiesis. Osteoblasts are specialized cells responsible for bone formation through the secretion of extracellular matrix components. Transmembrane protein 175 (TMEM175), which functions as an endosomal/lysosomal K+ channel and a lysosomal H+ channel, regulates lysosomal function and autophagy. Despite the recognized importance of lysosomes and autophagy in osteoblast differentiation, the specific role of TMEM175 in osteoblast differentiation has not been revealed. In this study, we investigated whether TMEM175 is associated with human bone mineral density (BMD) and fracture, and examined the role of TMEM175 in osteoblast differentiation. In analyses of single nucleotide polymorphisms (SNPs) of pore ion channel genes using the mouse2human database, a significant correlation between TMEM175 SNPs and human BMD and fracture was identified. TMEM175 expression levels were found to increase during osteoblast differentiation from bone chip-derived mesenchymal stem cells (BMSCs). Knockdown of TMEM175 in BMSCs suppressed osteoblast differentiation, as evidenced by decreased matrix mineralization and lower expression levels of osteoblast marker genes. Further analysis indicated that TMEM175 deficiency leads to lysosomal dysfunction and partially impairs autophagic clearance during osteoblast differentiation. Moreover, the TMEM175 inhibitor 4-aminopyridine (4-AP) decreased osteoblast differentiation of BMSCs. Taken together, this study reveals that TMEM175 plays an important role for osteoblast differentiation by regulating lysosomal function and autophagic clearance.
    Keywords:  Autophagy; Lysosome; Osteoblast differentiation; Transmembrane protein 175
    DOI:  https://doi.org/10.1016/j.mocell.2024.100127
  26. Commun Biol. 2024 Oct 22. 7(1): 1373
    Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.
    Seda Yasa, Elisabeth S Butz, Alessio Colombo, Uma Chandrachud, Luca Montore, Sarah Tschirner, Matthias Prestel, Steven D Sheridan, Stephan A Müller, Janos Groh, Stefan F Lichtenthaler, Sabina Tahirovic, Susan L Cotman.
      Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic signatures are indicative of defects in lysosomal function and abnormal lipid metabolism. Consistent with these findings, CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Accordingly, we also observe impaired myelin integrity in aged Cln3∆ex7/8 mouse brain. Autophagy inducers and cholesterol-lowering drugs correct the observed microglial phenotypes. Taken together, these data implicate a cell-autonomous defect in CLN3-deficient microglia that impacts their ability to support neuronal cell health, suggesting microglial targeted therapies should be considered for CLN3 disease.
    DOI:  https://doi.org/10.1038/s42003-024-07057-w
  27. Cells. 2024 Oct 10. pii: 1675. [Epub ahead of print]13(20):
    Autophagy-Mediated Cellular Remodeling during Terminal Differentiation of Keratinocytes in the Epidermis and Skin Appendages.
    Leopold Eckhart, Florian Gruber, Supawadee Sukseree.
      The epidermis of the skin and skin appendages, such as nails, hair and sebaceous glands, depend on a balance of cell proliferation and terminal differentiation in order to fulfill their functions at the interface of the body and the environment. The differentiation of epithelial cells of the skin, commonly referred to as keratinocytes, involves major remodeling processes that generate metabolically inactive cell remnants serving as building blocks of the epidermal stratum corneum, nail plates and hair shafts. Only sebaceous gland differentiation results in cell disintegration and holocrine secretion. A series of studies performed in the past decade have revealed that the lysosome-dependent intracellular degradation mechanism of autophagy is active during keratinocyte differentiation, and the blockade of autophagy significantly alters the properties of the differentiation products. Here, we present a model for the autophagy-mediated degradation of organelles and cytosolic proteins as an important contributor to cellular remodeling in keratinocyte differentiation. The roles of autophagy are discussed in comparison to alternative intracellular degradation mechanisms and in the context of programmed cell death as an integral end point of epithelial differentiation.
    Keywords:  apoptosis; autophagy; cornification; hair; keratin; keratinocytes; nail; protease; sebaceous; skin barrier
    DOI:  https://doi.org/10.3390/cells13201675
  28. Elife. 2024 Oct 22. pii: RP88318. [Epub ahead of print]12
    DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity.
    Pinhua Wang, Sunayana Sarkar, Menghuan Zhang, Tingting Xiao, Fenhua Kong, Zhe Zhang, Deepa Balasubramanian, Nandan Jayaram, Sayantan Datta, Ruyu He, Ping Wu, Peng Chao, Ying Zhang, Michael Washburn, Laurence A Florens, Sonal Nagarkar-Jaiswal, Manish Jaiswal, Man Mohan.
      DYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A, is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.
    Keywords:  D. melanogaster; DYRK1A; Drosophila melanogaster; biochemistry; cell biology; cell growth; chemical biology; microcephaly
    DOI:  https://doi.org/10.7554/eLife.88318
  29. Immun Inflamm Dis. 2024 Oct;12(10): e70041
    Promising and challenging phytochemicals targeting LC3 mediated autophagy signaling in cancer therapy.
    Peramaiyan Rajendran, Kaviyarasi Renu, Enas M Ali, Marwa Azmy M Genena, Vishnupriya Veeraraghavan, Ramya Sekar, Ashok Kumar Sekar, Sujatha Tejavat, Parthasarathi Barik, Basem M Abdallah.
       BACKGROUND: Phytochemicals possess a wide range of anti-tumor properties, including the modulation of autophagy and regulation of programmed cell death. Autophagy is a critical process in cellular homeostasis and its dysregulation is associated with several pathological conditions, such as cancer, neurodegenerative diseases, and diabetes. In cancer, autophagy plays a dual role by either promoting tumor growth or suppressing it, depending on the cellular context. During autophagy, autophagosomes engulf cytoplasmic components such as proteins and organelles. LC3-II (microtubule-associated protein 1 light chain 3-II) is an established marker of autophagosome formation, making it central to autophagy monitoring in mammals.
    OBJECTIVE: To explore the regulatory role of phytochemicals in LC3-mediated autophagy and their potential therapeutic impact on cancer. The review emphasizes the involvement of autophagy in tumor promotion and suppression, particularly focusing on autophagy-related signaling pathways like oxidative stress through the NRF2 pathway, and its implications for genomic stability in cancer development.
    METHODS: The review focuses on a comprehensive analysis of bioactive compounds including Curcumin, Celastrol, Resveratrol, Kaempferol, Naringenin, Carvacrol, Farnesol, and Piperine. Literature on these compounds was examined to assess their influence on autophagy, LC3 expression, and tumor-related signaling pathways. A systematic literature search was conducted across databases including PubMed, Scopus, and Web of Science from inception to 2023. Studies were selected from prominent databases, focusing on their roles in cancer diagnosis and therapeutic interventions, particularly in relation to LC3-mediated mechanisms.
    RESULTS: Phytochemicals have been shown to modulate autophagy through the regulation of LC3-II levels and autophagic flux in cancer cells. The interaction between autophagy and other cellular pathways such as oxidative stress, inflammation, and epigenetic modulation highlights the complex role of autophagy in tumor biology. For instance, Curcumin and Resveratrol have been reported to either induce or inhibit autophagy depending on cancer type, influencing tumor progression and therapeutic responses.
    CONCLUSION: Targeting autophagy through LC3 modulation presents a promising strategy for cancer therapy. The dual role of autophagy in tumor suppression and promotion, however, necessitates careful consideration of the context in which autophagy is induced or inhibited. Future research should aim to delineate these context-specific roles and explore how phytochemicals can be optimized for therapeutic efficacy. Novel therapeutic strategies should focus on the use of bioactive compounds to fine-tune autophagy, thereby maximizing tumor suppression and inducing programmed cell death in cancer cells.
    Keywords:  autophagy; cancer; celastrol; kaempferol; naringenin; piperine; resveratrol
    DOI:  https://doi.org/10.1002/iid3.70041
  30. Exp Neurol. 2024 Oct 18. pii: S0014-4886(24)00333-9. [Epub ahead of print]383 115007
    Optineurin regulates motor and learning behaviors by affecting dopaminergic neuron survival in mice.
    Xianfei Yang, Ruoling Zheng, Hongyao Zhang, Zixian Ou, Sha Wan, Dongfeng Lin, Jianguo Yan, Mingyue Jin, Jie Tan.
      Optineurin (OPTN) is an autophagy receptor that participates in the degradation of damaged mitochondria, protein aggregates, and invading pathogens. OPTN is closely related to various types of neurodegenerative diseases. However, the role of OPTN in the central nervous system is unclear. Here, we found that OPTN dysregulation in the compact part of substantia nigra (SNc) led to motor and learning deficits in animal models. Knockdown of OPTN increased total and phosphorylated α-synuclein levels which induced microglial activation and dopaminergic neuronal loss in the SNc. Overexpression of OPTN can't reverse the motor and learning phenotypes. Mechanistic analysis revealed that upregulation of OPTN increased α-synuclein phosphorylation independent of its autophagy receptor activity, which further resulted in microglial activation and dopaminergic neuronal loss similar to OPTN downregulation. Our study uncovers the crucial role of OPTN in maintaining dopaminergic neuron survival and motor and learning functions which are disrupted in PD patients.
    Keywords:  Autophagy; Dopaminergic neurons; Neurodegenerative diseases; OPTN
    DOI:  https://doi.org/10.1016/j.expneurol.2024.115007
  31. Biol Open. 2024 Jul 15. pii: bio060448. [Epub ahead of print]13(10):
    Mechanisms of drug resistance in nutrient-depleted colorectal cancer cells: insights into lysosomal and mitochondrial drug sequestration.
    Serra Gülse Köse, Aliye Ezgi Güleç Taşkıran.
      This Review delves into the mechanisms behind drug resistance in colorectal cancer (CRC), particularly examining the role of nutrient depletion and its contribution to multidrug resistance (MDR). The study highlights metabolic adaptations of cancer cells as well as metabolic adaptations of cancer cells under low nutrient availability, including shifts in glycolysis and lipid metabolism. It emphasizes the significance of MDR1 and its encoded efflux transporter, P-glycoprotein (P-gp/B1), in mediating drug resistance and how pathways such as HIF1α, AKT, and mTOR influence the expression of P-gp/B1 under limited nutrient availability. Additionally, the Review explores the dual roles of autophagy in drug sensitivity and resistance under nutrient limited conditions. It further investigates the involvement of lysosomes and mitochondria, focusing on their roles in drug sequestration and the challenges posed by lysosomal entrapment facilitated by non-enzymatic processes and ABC transporters like P-gp/B1. Finally, the Review underscores the importance of understanding the interplay between drug sequestration, lysosomal functions, nutrient depletion, and MDR1 gene modulation. It suggests innovative strategies, including structural modifications and nanotechnology, as promising approaches to overcoming drug resistance in cancer therapy.
    Keywords:  Autophagy; Colorectal cancer (CRC); Lysosomal drug sequestration; Mitochondrial drug sequestration; P-glycoprotein (P-gp/B1)
    DOI:  https://doi.org/10.1242/bio.060448
  32. J Gerontol A Biol Sci Med Sci. 2024 Nov 01. pii: glae221. [Epub ahead of print]79(11):
    Senolytics Enhance the Longevity of Caenorhabditis elegans by Altering Betaine Metabolism.
    Wenning Lan, Xiaolian Xiao, Jingjing Nian, Ziran Wang, Xiaojing Zhang, Yajiao Wu, Dongcheng Zhang, Junkun Chen, Wenqiang Bao, Chutao Li, Yun Zhang, An Zhu, Fangrong Zhang.
      Aging triggers physiological changes in organisms that are tightly linked to metabolic changes. Senolytics targeting many fundamental aging processes are currently being developed. However, the host metabolic response to natural senescence and the molecular mechanism underlying the antiaging benefits of senolytics remain poorly understood. In this study, we investigated metabolic changes during natural senescence based on the Caenorhabditis elegans model and pinpointed potential biomarkers linked to the benefits of senolytics. These results suggest that age-dependent metabolic changes during natural aging occur in C elegans. Betaine was identified as a crucial metabolite in the natural aging process. We explored the metabolic effects of aging interventions by administering 3 antiaging drugs-metformin, quercetin, and minocycline-to nematodes. Notably, betaine expression significantly increased under the 3 antiaging drug treatments. Our findings demonstrated that betaine supplementation extends lifespan, primarily through pathways associated with the forkhead box transcription factor (FoxO) signaling pathway, the p38-mitogen-activated protein kinase (MAPK) signaling pathway, autophagy, the longevity regulating pathway, and the target of rapamycin (mTOR) signaling pathway. In addition, autophagy and free radicals are altered in betaine-treated nematodes. Overall, we found that betaine is a critical metabolite during natural aging and that senolytics extend the lifespan of nematodes by increasing betaine levels and promoting autophagy and antioxidant activity. This finding suggests that betaine could be a novel therapeutic target for promoting longevity.
    Keywords:  Autophagy; Biomarker; Metabolism; Oxidative stress
    DOI:  https://doi.org/10.1093/gerona/glae221
  33. Ageing Res Rev. 2024 Oct 19. pii: S1568-1637(24)00367-2. [Epub ahead of print]102 102549
    Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
    Luigi Ferrucci, Flora Guerra, Cecilia Bucci, Emanuele Marzetti, Anna Picca.
      Mitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the endosomal-lysosomal system has revealed additional mechanisms of mitophagy and mitochondrial quality control that operate via the production of mitochondria-derived vesicles (MDVs). Circulating MDVs can be isolated and characterized to provide an unprecedented opportunity to study this type of mitochondrial recycling in vivo and to relate it to human physiology and pathology. Defining the role of MDVs in human physiology, pathology, and aging is hampered by the lack of standardized methods to isolate, validate, and characterize these vesicles. Hence, some basic questions about MDVs remain unanswered. While MDVs are generated directly through the extrusion of mitochondrial membranes within the cell, a set of circulating extracellular vesicles leaking from the endosomal-lysosomal system and containing mitochondrial portions have also been identified and warrant investigation. Preliminary research indicates that MDV generation serves multiple biological roles and contributes to restoring cell homeostasis. However, studies have shown that MDVs may also be involved in pathological conditions. Therefore, further research is warranted to establish when/whether MDVs are supporting disease progression and/or are extracting damaged mitochondrial components to alleviate cellular oxidative burden and restore redox homeoastasis. This information will be relevant for exploiting these vesicles for therapeutic purpose. Herein, we provide an overview of preclinical and clinical studies on MDVs in aging and associated conditions and discuss the interplay between MDVs and some of the hallmarks of aging (mitophagy, inflammation, and proteostasis). We also outline open questions on MDV research that should be prioritized by future investigations.
    Keywords:  Exosomes; Extracellular vesicles; Inflammaging; Mitochondrial DNA; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.arr.2024.102549
  34. Cell Mol Immunol. 2024 Oct 23.
    Ubiquitin regulatory X (UBX) domain-containing protein 6 is essential for autophagy induction and inflammation control in macrophages.
    Young Jae Kim, Sung-Gwon Lee, So Young Park, Sang Min Jeon, Soo In Kim, Kyung Tae Kim, Taylor Roh, Sang-Hee Lee, Min Joung Lee, Jinyoung Lee, Hyeon Ji Kim, So Eui Lee, Jin Kyung Kim, Jun Young Heo, In Soo Kim, Chungoo Park, Seungwha Paik, Eun-Kyeong Jo.
      Ubiquitin regulatory X (UBX) domain-containing protein 6 (UBXN6) is an essential cofactor for the activity of the valosin-containing protein p97, an adenosine triphosphatase associated with diverse cellular activities. Nonetheless, its role in cells of the innate immune system remains largely unexplored. In this study, we report that UBXN6 is upregulated in humans with sepsis and may serve as a pivotal regulator of inflammatory responses via the activation of autophagy. Notably, the upregulation of UBXN6 in sepsis patients was negatively correlated with inflammatory gene profiles but positively correlated with the expression of Forkhead box O3, an autophagy-driving transcription factor. Compared with those of control mice, the macrophages of mice subjected to myeloid cell-specific UBXN6 depletion exhibited exacerbated inflammation, increased mitochondrial oxidative stress, and greater impairment of autophagy and endoplasmic reticulum-associated degradation pathways. UBXN6-deficient macrophages also exhibited immunometabolic remodeling, characterized by a shift to aerobic glycolysis and elevated levels of branched-chain amino acids. These metabolic shifts amplify mammalian target of rapamycin pathway signaling, in turn reducing the nuclear translocation of the transcription factor EB and impairing lysosomal biogenesis. Together, these data reveal that UBXN6 serves as an activator of autophagy and regulates inflammation to maintain immune system suppression during human sepsis.
    Keywords:  Autophagy; Immunosuppression; Inflammation; Sepsis; UBXN6
    DOI:  https://doi.org/10.1038/s41423-024-01222-1
  35. Eur J Pharmacol. 2024 Oct 18. pii: S0014-2999(24)00750-7. [Epub ahead of print]984 177060
    Novel prospects in targeting neurodegenerative disorders via autophagy.
    Shumayila Khan, Saurabh Upadhyay, Md Imtaiyaz Hassan.
      Protein aggregation occurs as a consequence of dysfunction in the normal cellular proteostasis, which leads to the accumulation of toxic fibrillar aggregates of certain proteins in the cell. Enhancing the activity of proteolytic pathways may serve as a way of clearing these aggregates in a cell, and consequently, autophagy has surfaced as a promising target for the treatment of neurodegenerative disorders. Several strategies involving small molecule compounds that stimulate autophagic pathway of cell have been discovered. However, despite many compounds having demonstrated favorable outcomes in experimental disease models, the translation of these findings into clinical benefits for patient's remains limited. Consequently, alternative strategies are actively being explored to effectively target neurodegeneration via autophagy modulation. Recently, newer approaches such as modulation of expression of autophagic genes have emerged as novel and interesting areas of research in this field, which hold promising potential in neuroprotection. Similarly, as discussed for the first time in this review, the use of autophagy-inducing nanoparticles by utilizing their physicochemical properties to stimulate the autophagic process, rather than relying on their role as drug carriers, offers a completely fresh avenue for targeting neurodegeneration without the risk of drug-associated adverse effects. This review provides fresh perspectives on developing autophagy-targeted therapies for neurodegenerative disorders. Additionally, it discusses the challenges and impediments of implementing these strategies to alleviate the pathogenesis of neurodegenerative disorders in clinical settings and highlights the prospects and directions of future research in this context.
    Keywords:  Alzheimer's disease; Autophagy; Huntington's disease; Neurodegeneration; Neuroprotection; Neurotherapeutics; Parkinson's disease; Protein aggregation
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177060
  36. J Cardiovasc Pharmacol. 2024 Oct 25.
    Role of autophagy in myocardial remodeling after myocardial infarction.
    Run-Ze Tian, Dong-Lin Zhuang, Chi Teng Vong, Xuyu He, Qing Ouyang, Jing-Hua Liang, Yan-Ping Guo, Yu-Hong Wang, Shuang Zhao, Haiyun Yuan, Moussa Ide Nasser, Ge Li, Ping Zhu.
      Autophagy is the process of reusing the body's senescent and damaged cell components, which can be regarded as the cellular circulatory system. There are three distinct forms of autophagy: macro-autophagy, micro-autophagy, and chaperone-mediated autophagy. In the heart, autophagy is regulated mainly through mitophagy due to the metabolic changes of cardiomyocytes caused by ischemia and hypoxia. Myocardial remodeling is characterized by gradual heart enlargement, cardiac dysfunction, and extraordinary molecular changes. Cardiac remodeling after myocardial infarction is almost inevitable, which is the leading cause of heart failure. Autophagy has a protective effect on myocardial remodeling improvement. Autophagy can minimize cardiac remodeling by preventing misfolded protein accumulation and oxidative stress. This review summarizes the nestest molecular mechanisms of autophagy and myocardial remodeling, the protective effects, and the new target of autophagy medicine in cardiac remodeling. The future development and challenges of autophagy in heart disease are also summarized.
    DOI:  https://doi.org/10.1097/FJC.0000000000001646
  37. Cell Death Dis. 2024 Oct 21. 15(10): 764
    Identification of KW-2449 as a dual inhibitor of ferroptosis and necroptosis reveals that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis.
    Yaxing Zhao, Qingsong Wang, Jing Zhu, Jin Cai, Xiaona Feng, Qianqian Song, Hui Jiang, Wenqing Ren, Yuan He, Ping Wang, Du Feng, Jianqiang Yu, Yue Liu, Qihui Wu, Jitkaew Siriporn, Zhenyu Cai.
      Necroptosis and ferroptosis are two distinct forms of necrotic-like cell death in terms of their morphological features and regulatory mechanisms. These two types of cell death can coexist in disease and contribute to pathological processes. Inhibition of both necroptosis and ferroptosis has been shown to enhance therapeutic effects in treating complex necrosis-related diseases. However, targeting both necroptosis and ferroptosis by a single compound can be challenging, as these two forms of cell death involve distinct molecular pathways. In this study, we discovered that KW-2449, a previously described necroptosis inhibitor, also prevented ferroptosis both in vitro and in vivo. Mechanistically, KW-2449 inhibited ferroptosis by targeting the autophagy pathway. We further identified that KW-2449 functioned as a ULK1 (Unc-51-like kinase 1) inhibitor to block ULK1 kinase activity in autophagy. Remarkably, we found that Necrostatin-1, a classic necroptosis inhibitor that has been shown to prevent ferroptosis, also targets the autophagy pathway to suppress ferroptosis. This study provides the first understanding of how necroptosis inhibitors can prevent ferroptosis and suggests that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis. Therefore, the identification and design of pharmaceutical molecules that target the autophagy pathway from necroptosis inhibitors is a promising strategy to develop dual inhibitors of necroptosis and ferroptosis in clinical application.
    DOI:  https://doi.org/10.1038/s41419-024-07157-9
  38. Ecotoxicol Environ Saf. 2024 Oct 19. pii: S0147-6513(24)01291-0. [Epub ahead of print]286 117215
    Lysosome toxicities induced by nanoparticle exposure and related mechanisms.
    Yawen Feng, Hongying Fu, Xing Zhang, Suqin Liu, Xiaoran Wei.
      Nanoparticles (NPs) have achieved extensive utilization across diverse domains, highlighting their unavoidable impact on health. The internalization of NPs carries the potential to trigger inflammation and instigate ailments by selectively targeting lysosomes, thereby posing significant public health concern. Lysosomes, essential organelles responsible for the degradation of biological macromolecules within cells, are crucial for cellular homeostasis and participate in key biological processes, including inter-organelle communication, signal transduction, plasma membrane repair, and immune responses. Consequently, a thorough understanding of lysosomal function is essential for elucidating the mechanisms underlying NPs-mediated toxicity. NPs-induced lysosomal dysfunction primarily involves disruptions in the acidic microenvironment of lysosomes, lysosomal membrane rupture, and membrane permeabilization. Additionally, potential molecular mechanisms contributing to the increased risk of lysosomal damage caused by NPs have been described, particularly concerning ion channel proteins such as V-ATPase, TRPM2, CLC-7, and LAMPs. This review aims to detail the alterations in lysosomal functionality induced by NPs and their associated mechanisms. By providing a theoretical framework, this review aims to support the potential application of NPs in biomedical fields.
    Keywords:  Lysosomal acidity; Lysosomal membrane permeability; Lysosomal membrane rupture; Lysosomal toxicity; Nanoparticles
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117215
  39. J Nutr Health Aging. 2024 Oct 19. pii: S1279-7707(24)00485-8. [Epub ahead of print]28(12): 100397
    Mitochondrial pathways and sarcopenia in the geroscience era.
    Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Anna Picca.
      Sarcopenia is associated with structural, ultrastructural, and molecular abnormalities of skeletal muscle. Mitochondrial dysfunction is a pivotal factor involved in muscle aging and sarcopenia. Mitochondrial bioenergetics are significantly reduced in muscles of older adults which is associated with whole-body aerobic capacity, muscle strength, and physical performance. Transcriptional profiling of muscle samples from older adults also revealed inverse correlations between gene expression patterns of autophagy and mitophagy and muscle volume and physical performance. This is in line with the proposition that mitochondrial quality control (MQC) processes are key to organellar and tissue health. MQC encompasses mitochondrial biogenesis, dynamics, and mitophagy. The latter has recently been included among the hallmarks of aging and alterations in MQC have been associated with chronic sterile inflammation as well as muscle atrophy and dysfunction. Several biomarkers spanning MQC, inflammation, metabolism, intercellular communication, and gut microbiota have been linked to sarcopenia. Findings from these initial studies hold promise to inform geroscience-based research in the field of sarcopenia by offering a plausible biological framework for developing gerotherapeutics and monitoring their effects.
    Keywords:  Biology of aging; Extracellular vesicles; Inflammaging; Mitochondrial quality control; Multi-Marker; Omics
    DOI:  https://doi.org/10.1016/j.jnha.2024.100397
  40. Free Radic Biol Med. 2024 Oct 22. pii: S0891-5849(24)00997-3. [Epub ahead of print]
    Calorie restriction modulates mitochondrial dynamics and autophagy in leukocytes of patients with obesity.
    Zaida Abad-Jiménez, Sandra López-Domènech, María Pelechá, Laura Perea-Galera, Susana Rovira-Llopis, Celia Bañuls, Ana Blas-García, Nadezda Apostolova, Carlos Morillas, Víctor Manuel Víctor, Milagros Rocha.
       BACKGROUND: Although it is established that caloric restriction offers metabolic and clinical benefits, the molecular mechanisms underlying these effects remain unclear. Thus, this study aimed to investigate whether caloric restriction can modulate mitochondrial function and remodelling and stimulate autophagic flux in the PBMCs of patients with obesity.
    METHODS: This was an interventional study of 38 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical variables, mitochondrial function parameters (by fluorescence imaging of mitochondrial ROS and membrane potential), and protein expression of markers of mitochondrial dynamics (MNF1, MFN2, OPA, DRP1 and FIS1) and autophagy (LC3, Beclin, BCL2 and NBR1) by western blot.
    RESULTS: Caloric restriction induced an improvement in metabolic outcomes that was accompanied by an increase in AMPK expression, a decrease of mitochondrial ROS and mitochondrial membrane potential, which was associated with increased markers of mitochondrial dynamics (MFN2, DRP1 and FIS1) and activation of autophagy as evidenced by augmented LC3 II/I, Beclin1 and NBR1, and a decrease in BCL2.
    CONCLUSION: These findings shed light on the specific molecular mechanisms by which caloric restriction facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis and cell recovery, including mitochondrial function and dynamics and autophagy.
    Keywords:  Obesity; PBMCs; VLCD; autophagy; mitochondrial quality control; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.295
  41. Cell Metab. 2024 Oct 18. pii: S1550-4131(24)00395-4. [Epub ahead of print]
    Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.
    Chenxi Zhao, Tingting Zhang, Si-Tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, Ke Li.
      Obesity is a major risk factor for poor breast cancer outcomes, but the impact of obesity-induced tumor microenvironment (TME) metabolites on breast cancer growth and metastasis remains unclear. Here, we performed TME metabolomic analysis in high-fat diet (HFD) mouse models and found that glutathione (GSH) levels were elevated in the TME of obesity-accelerated breast cancer. The deletion of glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme in GSH biosynthesis, in adipocytes but not tumor cells reduced obesity-related tumor progression. Mechanistically, we identified that GSH entered tumor cells and directly bound to lysosomal integral membrane protein-2 (scavenger receptor class B, member 2 [SCARB2]), interfering with the interaction between its N and C termini. This, in turn, recruited mTORC1 to lysosomes through ARF1, leading to the activation of mTOR signaling. Overall, we demonstrated that GSH links obesity and breast cancer progression by acting as an activator of mTOR signaling. Targeting the GSH/SCARB2/mTOR axis could benefit breast cancer patients with obesity.
    Keywords:  ARF1; GSH; SCARB2; adipocyte; breast cancer; glutathione; lysosomal integral membrane protein-2; mTORC1; mammalian target of rapamycin complex 1; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.013
  42. Mol Metab. 2024 Oct 20. pii: S2212-8778(24)00181-9. [Epub ahead of print] 102050
    Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.
    Katie C Coate, Chunhua Dai, Ajay Singh, Jade Stanley, Brittney A Covington, Amber Bradley, Favour Oladipupo, Yulong Gong, Scott Wisniewski, Katelyn Sellick, Erick Spears, Greg Poffenberger, Anna Marie R Schornack, Alexandria Bustabad, Tyler Rodgers, Nandita Dey, Leonard D Shultz, Dale L Greiner, Hai Yan, Alvin C Powers, Wenbiao Chen, E Danielle Dean.
       OBJECTIVE: Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context.
    METHODS: We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth.
    RESULTS: Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice.
    CONCLUSIONS: Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.
    Keywords:  Beta cell; Delta cell; Glucagon receptor; Pancreatic islet; Proliferation; mTOR
    DOI:  https://doi.org/10.1016/j.molmet.2024.102050
  43. Nat Commun. 2024 Oct 24. 15(1): 9181
    Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
    Leighton H Daigh, Debarya Saha, David L Rosenthal, Katherine R Ferrick, Tobias Meyer.
      DNA damage is a primary trigger for cellular senescence, which in turn causes organismal aging and is a promising target of anti-aging therapies. Most DNA damage occurs when DNA is fragile during DNA replication in S phase, but senescent cells maintain DNA damage long-after DNA replication has stopped. How senescent cells induce DNA damage and why senescent cells fail to repair damaged DNA remain open questions. Here, we combine reversible expression of the senescence-inducing CDK4/6 inhibitory protein p16INK4 (p16) with live single-cell analysis and show that sustained mTORC1 signaling triggers senescence in non-proliferating cells by increasing transcriptional DNA damage and inflammation signaling that persists after p16 is degraded. Strikingly, we show that activation of E2F transcriptional program, which is regulated by CDK4/6 activity and promotes expression of DNA repair proteins, repairs transcriptionally damaged DNA without requiring DNA replication. Together, our study suggests that senescence can be maintained by ongoing mTORC1-induced transcriptional DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
    DOI:  https://doi.org/10.1038/s41467-024-52820-6
  44. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2408071121
    Intrinsically disordered region amplifies membrane remodeling to augment selective ER-phagy.
    Sergio Alejandro Poveda-Cuevas, Kateryna Lohachova, Borna Markusic, Ivan Dikic, Gerhard Hummer, Ramachandra M Bhaskara.
      Intrinsically disordered regions (IDRs) play a pivotal role in organellar remodeling. They transduce signals across membranes, scaffold signaling complexes, and mediate vesicular traffic. Their functions are regulated by constraining conformational ensembles through specific intra- and intermolecular interactions, physical tethering, and posttranslational modifications. The endoplasmic reticulum (ER)-phagy receptor FAM134B/RETREG1, known for its reticulon homology domain (RHD), includes a substantial C-terminal IDR housing the LC3 interacting motif. Beyond engaging the autophagic machinery, the function of the FAM134B-IDR is unclear. Here, we investigate the characteristics of the FAM134B-IDR by extensive modeling and molecular dynamics simulations. We present detailed structural models for the IDR, mapping its conformational landscape in solution and membrane-anchored configurations. Our analysis reveals that depending on the membrane anchor, the IDRs collapse onto the membrane and induce positive membrane curvature to varying degrees. The charge patterns underlying this Janus-like behavior are conserved across other ER-phagy receptors. We found that IDRs alone are sufficient to sense curvature. When combined with RHDs, they intensify membrane remodeling and drive efficient protein clustering, leading to faster budding, thereby amplifying RHD remodeling functions. Our simulations provide a perspective on IDRs of FAM134B, their Janus-like membrane interactions, and the resulting modulatory functions during large-scale ER remodeling.
    Keywords:  ER remodeling; IDRs; conformational entropy; curvature induction; structural ensemble
    DOI:  https://doi.org/10.1073/pnas.2408071121
  45. Biochim Biophys Acta Mol Basis Dis. 2024 Oct 20. pii: S0925-4439(24)00541-6. [Epub ahead of print] 167547
    Mitostasis in age-associated neurodegeneration.
    Mrutyunjaya Panda, Maria Markaki, Nektarios Tavernarakis.
      Mitochondria are essential organelles that play crucial roles in various metabolic and signalling pathways. Proper neuronal function is highly dependent on the health of these organelles. Of note, the intricate structure of neurons poses a critical challenge for the transport and distribution of mitochondria to specific energy-intensive domains, such as synapses and dendritic appendages. When faced with chronic metabolic challenges and bioenergetic deficits, neurons undergo degeneration. Unsurprisingly, disruption of mitostasis, the process of maintaining cellular mitochondrial content and function within physiological limits, has been implicated in the pathogenesis of several age-associated neurodegenerative disorders. Indeed, compromised integrity and metabolic activity of mitochondria is a principal hallmark of neurodegeneration. In this review, we survey recent findings elucidating the role of impaired mitochondrial homeostasis and metabolism in the onset and progression of age-related neurodegenerative disorders. We also discuss the importance of neuronal mitostasis, with an emphasis on the major mitochondrial homeostatic and metabolic pathways that contribute to the proper functioning of neurons. A comprehensive delineation of these pathways is crucial for the development of early diagnostic and intervention approaches against neurodegeneration.
    Keywords:  Age-associated neurodegenerative disorders; Metabolism; Mitochondria; Mitostasis; Neurodegeneration; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167547
  46. FEBS J. 2024 Oct 21.
    The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux.
    Linghuan Li, Yuanhai Sun, Lingqin Li, Wanfang Zheng, Weiwei Zha, Tengjiao Zhao, Guangyao Zhu, Hanbing Li.
      Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic lipid deposition is a key factor in the development of NAFLD. N6-methyladenosine (m6A) modification, the most prevalent mRNA modification in eukaryotic cells, plays an important role in regulating hepatic lipid metabolism. However, its potential role in hepatic lipid deposition remains poorly understood. Histological and immunohistochemistry studies were used to investigate lipid deposition in free fatty acids (FFAs)-incubated LO2 cells, high-fat diet-fed mice models and clinical samples. Stable overexpression and knockdown of AlkB homolog 5 (ALKBH5) was manipulated to investigate the effects of ALKBH5 on m6A methylation and lipid metabolism in hepatocytes. RNA-sequencing transcriptome analysis and methylated RNA immunoprecipitation-quantitative-PCR analysis were used to reveal the potential downstream molecular targets of ALKBH5. ALKBH5 was down-regulated in fatty liver compared to normal liver in both humans and mice. Overexpression of ALKBH5 significantly improved FFA-induced lipid accumulation and promoted autophagosome-lysosome fusion in hepatocytes. Meanwhile, knockdown of ALKBH5 significantly increased the expression of microtubule-associated protein 1A/1B-light chain 3B and Sequestosome 1, leading to impaired autophagic flux and further lipid deposition in hepatocytes under FFA incubation. Overexpression of vacuolar protein sorting 11 (VPS11) reversed FFA-induced lipid accumulation in ALKBH5-silenced hepatocytes. Mechanistically, ALKBH5 alleviated hepatic lipid deposition and impaired autophagic flux by removing the m6A modification on VPS11 mRNA to promote its translation. Collectively, our findings revealed an epigenetic mechanism by which ALKBH5 alleviates hepatic lipid deposition by restoring VPS11-dependent autophagic flux, providing a potential target to counteract NAFLD.
    Keywords:  ALKBH5; N6‐methyladenosine; NAFLD; VPS11; autophagy
    DOI:  https://doi.org/10.1111/febs.17299
  47. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2416722121
    AMBRA1 controls the translation of immune-specific genes in T lymphocytes.
    Simone Gottlieb, Wanjing Shang, Deji Ye, Satoshi Kubo, Ping Du Jiang, Samantha Shafer, Leilei Xu, Lixin Zheng, Ann Y Park, Jian Song, Waipan Chan, Zhiqin Zeng, Tingyan He, Benjamin Schwarz, Björn Häupl, Thomas Oellerich, Michael J Lenardo, Yikun Yao.
      T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cell cycle regulation, and cell death. The molecular regulation of mRNA translation in these processes is poorly understood. Using a whole-genome CRISPR screen for regulators of CD95 (FAS/APO-1)-mediated T cell death, we identified AMBRA1, a protein previously studied for its roles in autophagy, E3 ubiquitin ligase activity, and cyclin regulation. T cells lacking AMBRA1 resisted FAS-mediated cell death by down-regulating FAS expression at the translational level. We show that AMBRA1 is a vital regulator of ribosome protein biosynthesis and ribosome loading on select mRNAs, whereby it plays a key role in balancing TCR signaling with cell cycle regulation pathways. We also found that AMBRA1 itself is translationally controlled by TCR stimulation via the CD28-PI3K-mTORC1-EIF4F pathway. Together, these findings shed light on the molecular control of translation after T cell activation and implicate AMBRA1 as a translational regulator governing TCR signaling, cell cycle progression, and T cell death.
    Keywords:  AMBRA1; FAS signaling pathway; T cell activation; T cell death; protein translation
    DOI:  https://doi.org/10.1073/pnas.2416722121
  48. FASEB J. 2024 Oct 31. 38(20): e70130
    LC3-associated phagocytosis and human diseases: Insights from mechanisms to therapeutic potential.
    Xu Chen, Qi Su, Ruize Gong, Xing Ling, Runxiao Xu, Qijia Feng, Jialiang Ke, Meng Liu, Gulipiyanmu Kahaerjiang, Yuhang Liu, Yanyan Yang, Zhihong Jiang, Hongmei Wu, Yitao Qi.
      LC3-associated phagocytosis (LAP) is a distinct type of autophagy that involves the sequestration of extracellular material by phagocytes. Beyond the removal of dead cells and cellular debris from eukaryotic cells, LAP is also involved in the removal of a variety of pathogens, including bacteria, fungi, and viruses. These events are integral to multiple physiological and pathological processes, such as host defense, inflammation, and tissue homeostasis. Dysregulation of LAP has been associated with the pathogenesis of several human diseases, including infectious diseases, autoimmune diseases, and neurodegenerative diseases. Thus, understanding the molecular mechanisms underlying LAP and its involvement in human diseases may provide new insights into the development of novel therapeutic strategies for these conditions. In this review, we summarize and highlight the current consensus on the role of LAP and its biological functions in disease progression to propose new therapeutic strategies. Further studies are needed to illustrate the precise role of LAP in human disease and to determine new therapeutic targets for LAP-associated pathologies.
    Keywords:  LAP‐associated pathology; LC3‐associated phagocytosis; molecular mechanism; therapeutic strategy
    DOI:  https://doi.org/10.1096/fj.202402126R
  49. Mol Neurobiol. 2024 Oct 23.
    Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.
    Weiwei Yu, Yunong Li, Yao Li, Jun Hu, Jun Wu, Xuhui Chen, Yining Huang, Xin Shi.
      The perturbed structure and function of mitochondria-associated membranes (MAM), instead of the amyloid cascade, have been gradually proposed to play a basic role in the pathogenesis of Alzheimer's disease (AD). Notably, autophagy inhibition is one of the main mechanisms of MAM dysfunction and plays an important role in neuronal injury. However, the upstream molecular mechanism underlying the MAM dysfunctions remains elusive. Here, we defined an unexpected and critical role of connexin43 (Cx43) in regulating the MAM structure. The expression levels of Cx43 and mitofusin-2 (MFN2, the MAM biomarker) increase significantly in 9-month-old APPswe/PS1dE9 double-transgenic AD model mice, and there is an obvious colocalization relationship. Moreover, both AD mice and cells lacking Cx43 exhibit an evident reduction in the MAM contact sites, which subsequently promotes the conversion from microtubule-associated protein 1 light-chain 3B I (LC3B-I) to LC3B-II via inhibition mTOR-dependent pathway and then initiates the generation of autophagosomes. Autophagosome formation ultimately promotes β-amyloid (Aβ) clearance and attenuates Aβ-associated pathological changes in AD, mainly including astrogliosis and neuronal apoptosis. Our findings not only reveal a previously unrecognized effect of Cx43 on MAM upregulation but also highlight the major player of MAM-induced autophagy inhibition in Cx43-facilitated AD pathogenesis, providing a novel insight into the alternative therapeutic strategies for the early treatment of AD.
    Keywords:  Alzheimer’s disease; Autophagy; Connexin43; Mitochondria-associated membranes; β-Amyloid
    DOI:  https://doi.org/10.1007/s12035-024-04536-3
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:11.