bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023‒10‒15
fifty-nine papers selected by
Viktor Korolchuk, Newcastle University
  1. Orchestration of autophagosome fusion by STRIPAK complex components in muscle tissue.
  2. AMPK Regulates Phagophore-to-Autophagosome Maturation.
  3. Vault-phagy: a phase-separation-mediated selective autophagy of vault, a non-membranous organelle.
  4. The Molecular Mechanism and Therapeutic Application of Autophagy for Urological Disease.
  5. Exonuclease Xrn1 regulates TORC1 signaling in response to SAM availability.
  6. Lysosomes in senescence and aging.
  7. The Combined Inhibition of Autophagy and Diacylglycerol Acyltransferase-Mediated Lipid Droplet Biogenesis Induces Cancer Cell Death during Acute Amino Acid Starvation.
  8. A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion.
  9. HOOKLESS1 acetylates AUTOPHAGY-RELATED PROTEIN18a to promote autophagy during nutrient starvation in Arabidopsis.
  10. Autophagy protects mitochondrial health in heart failure.
  11. Ferroptosis, autophagy, tumor and immunity.
  12. The intricate dance: host autophagy and Coxiella burnetii infection.
  13. Integrated Multi-Omics Analyses Reveal That Autophagy-Mediated Cellular Metabolism Is Required for the Initiation of Pollen Germination.
  14. Extracellular release in the quality control of the mammalian mitochondria.
  15. SIRT1 is a regulator of autophagy: implications for the progression and treatment of myocardial ischemia-reperfusion.
  16. Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN.
  17. Fluorescent reporter of  Caenorhabditis elegans Parkin: Regulators of its abundance and role in autophagy-lysosomal dynamics.
  18. Visualization of Lysosomal Dynamics during Autophagy by Fluorescent Probe.
  19. C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy.
  20. Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
  21. The endolysosomal pathway and ALS/FTD.
  22. Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?
  23. Live while the DNA lasts. The role of autophagy in DNA loss and survival of diploid yeast cells during chronological aging.
  24. Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans.
  25. The Cytoprotective Role of Autophagy in Response to BRAF-Targeted Therapies.
  26. Ancient genomic linkage couples metabolism with erythroid development.
  27. ATNC: Versatile Nanobody Chimeras for Autophagic Degradation of Intracellular Unligandable and Undruggable Proteins.
  28. Exploration of SUMO2/3 Expression Levels and Autophagy Process in Fragile X-Associated Tremor/Ataxia Syndrome: Addressing Study Limitations and Insights for Future Research.
  29. Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.
  30. Impaired mitophagosome-lysosome fusion mediates olanzapine-induced aging.
  31. The Crosstalk Between Autophagy and MicroRNAs in Esophageal Carcinoma:.
  32. Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment.
  33. Stimulator of Interferon Genes (STING) Triggers Adipocyte Autophagy.
  34. Targeted Protein Degradation Mediated by Genetically Engineered Lysosome-Targeting Exosomes.
  35. Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
  36. Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids.
  37. ZEA mediates autophagy through the ROS-AMPK-m-TOR pathway to enhance the susceptibility of mastitis induced by Staphylococcus aureus in mice.
  38. The role of autophagy in the treatment of type II diabetes and its complications: a review.
  39. PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
  40. Scoparone induces autophagic cell death via the PAK1/AKT axis in colorectal cancer.
  41. PSAT1 promotes autophagy to resist insufficient autophagy caused by cigarette smoke extract in human airway epithelial cells.
  42. An Overview of the Role of Furin in Type 2 Diabetes.
  43. The autophagy protein Def8 is altered in Alzheimer's disease and Aβ42-expressing Drosophila brains.
  44. Axonal Transport of Lysosomes Is Unaffected in Glucocerebrosidase-Inhibited iPSC-Derived Forebrain Neurons.
  45. Exosomes derived from cardiac fibroblasts with angiotensin II stimulation provoke hypertrophy and autophagy inhibition in cardiomyocytes.
  46. PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models.
  47. Autophagy as a Target for Non-Immune Intrinsic Functions of Programmed Cell Death-Ligand 1 in Cancer.
  48. Bioorthogonal Aptamer-ATTEC Conjugates for Degradation of Alpha-Synuclein via Autophagy-Lysosomal Pathway.
  49. Autophagy facilitates intracellular survival of pathogenic rickettsiae in macrophages via evasion of autophagosomal maturation and reduction of microbicidal pro-inflammatory IL-1 cytokine responses.
  50. LILAR, a novel long noncoding RNA regulating autophagy in the liver tissues of endotoxemic mice through a competing endogenous RNA mechanism.
  51. SERPINB1 promotes Senecavirus A replication by degrading IKBKE and regulating the IFN pathway via autophagy.
  52. Ethanolic Extract of Propolis Modulates Autophagy-Related microRNAs in Osteoarthritic Chondrocytes.
  53. Protein condensates as flexible platforms for membrane traffic.
  54. Actionable autophagy checkpoints in cardiovascular ageing.
  55. Ambra1 in exosomes secreted by HK-2 cells damaged by supersaturated oxalate induce mitophagy and autophagy-ferroptosis in normal HK-2 cells to participate in the occurrence of kidney stones.
  56. DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy.
  57. Lysosomal cystine controls ferroptosis in cancer.
  58. Lysosomal Therapies and Drug Delivery Strategies: An Overview.
  59. Metabolic support by macrophages sustains colonic epithelial homeostasis.
  1. Autophagy Rep. 2023 ;pii: 2260670. [Epub ahead of print]2(1):
    Orchestration of autophagosome fusion by STRIPAK complex components in muscle tissue.
    Yungui Guo, Erika R Geisbrecht.
      Autophagy is a central process responsible for the disposal of normal as well as damaged cellular proteins and organelles. Proper regulation of multiple steps - including initiation and the fusion between autophagosomes and lysosomes - is essential for the completion of cargo disposal. While the function of many proteins that mediate canonical autophagy has been characterized, the identification of new autophagy regulators may shed light on differences between tissues and/or responses to cellular stresses. In this punctum, we discuss our recent findings about how the Striatin-Interacting Phosphatase and Kinase (STRIPAK)-NUAK-Starvin (Stv) complex coordinately regulates autophagy in the muscle tissue of Drosophila melanogaster.
    Keywords:  Autophagy; Drosophila; NUAK; STRIPAK; Strip; muscle
    DOI:  https://doi.org/10.1080/27694127.2023.2260670
  2. bioRxiv. 2023 Sep 30. pii: 2023.09.28.559981. [Epub ahead of print]
    AMPK Regulates Phagophore-to-Autophagosome Maturation.
    Carlo Barnaba, David G Broadbent, Gloria I Perez, Jens C Schmidt.
      Autophagy is an important metabolic pathway that can non-selectively recycle cellular material or lead to targeted degradation of protein aggregates or damaged organelles. Autophagosome formation starts with autophagy factors accumulating on lipid vesicles containing ATG9. These phagophores attach to donor membranes, expand via ATG2-mediated lipid transfer, capture cargo, and mature into autophagosomes, ultimately fusing with lysosomes for their degradation. Autophagy can be activated by nutrient stress, for example by a reduction in the cellular levels of amino acids. In contrast, how autophagy is regulated by low cellular ATP levels via the AMP-activated protein kinase (AMPK), an important therapeutic target, is less clear. Using live-cell imaging and an automated image analysis pipeline, we systematically dissect how nutrient starvation regulates autophagosome biogenesis. We demonstrate that glucose starvation downregulates autophagosome maturation by AMPK mediated inhibition of phagophores tethering to donor membranes. Our results clarify AMPK's regulatory role in autophagy and highlight its potential as a therapeutic target to reduce autophagy.
    DOI:  https://doi.org/10.1101/2023.09.28.559981
  3. Autophagy. 2023 Oct 10. 1-2
    Vault-phagy: a phase-separation-mediated selective autophagy of vault, a non-membranous organelle.
    Reo Kurusu, Hideaki Morishita, Masaaki Komatsu.
      SQSTM1/p62 bodies are phase-separated condensates that play a fundamental role in intracellular quality control and stress responses. Despite extensive studies investigating the mechanism of formation and degradation of SQSTM1/p62 bodies, the constituents of SQSTM1/p62 bodies remain elusive. We recently developed a purification method for intracellular SQSTM1/p62 bodies using a cell sorter and identified their constituents by mass spectrometry. Combined with mass spectrometry of tissues from selective autophagy-deficient mice, we identified vault, a ubiquitous non-membranous organelle composed of proteins and non-coding RNA, as a novel substrate for selective autophagy. Vault directly binds to NBR1, an SQSTM1/p62 binding partner recruited to SQSTM1/p62 bodies, and is subsequently degraded by selective autophagy dependent on the phase separation of SQSTM1/p62. We named this process "vault-phagy" and found that defects in vault-phagy are related to nonalcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma. Our method for purifying SQSTM1/p62 bodies will contribute to elucidating the mechanisms of several stress responses and diseases mediated by SQSTM1/p62 bodies.
    Keywords:  Fluorescence-activated particle sorting; Mallory-Denk bodies; NBR1; liquid-liquid phase separation; nonalcoholic steatohepatitis; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2266996
  4. Int J Mol Sci. 2023 Oct 04. pii: 14887. [Epub ahead of print]24(19):
    The Molecular Mechanism and Therapeutic Application of Autophagy for Urological Disease.
    Kuang-Shun Chueh, Jian-He Lu, Tai-Jui Juan, Shu-Mien Chuang, Yung-Shun Juan.
      Autophagy is a lysosomal degradation process known as autophagic flux, involving the engulfment of damaged proteins and organelles by double-membrane autophagosomes. It comprises microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy. Macroautophagy consists of three stages: induction, autophagosome formation, and autolysosome formation. Atg8-family proteins are valuable for tracking autophagic structures and have been widely utilized for monitoring autophagy. The conversion of LC3 to its lipidated form, LC3-II, served as an indicator of autophagy. Autophagy is implicated in human pathophysiology, such as neurodegeneration, cancer, and immune disorders. Moreover, autophagy impacts urological diseases, such as interstitial cystitis /bladder pain syndrome (IC/BPS), ketamine-induced ulcerative cystitis (KIC), chemotherapy-induced cystitis (CIC), radiation cystitis (RC), erectile dysfunction (ED), bladder outlet obstruction (BOO), prostate cancer, bladder cancer, renal cancer, testicular cancer, and penile cancer. Autophagy plays a dual role in the management of urologic diseases, and the identification of potential biomarkers associated with autophagy is a crucial step towards a deeper understanding of its role in these diseases. Methods for monitoring autophagy include TEM, Western blot, immunofluorescence, flow cytometry, and genetic tools. Autophagosome and autolysosome structures are discerned via TEM. Western blot, immunofluorescence, northern blot, and RT-PCR assess protein/mRNA levels. Luciferase assay tracks flux; GFP-LC3 transgenic mice aid study. Knockdown methods (miRNA and RNAi) offer insights. This article extensively examines autophagy's molecular mechanism, pharmacological regulation, and therapeutic application involvement in urological diseases.
    Keywords:  autophagy; pathophysiological processes; urological disease
    DOI:  https://doi.org/10.3390/ijms241914887
  5. bioRxiv. 2023 Sep 28. pii: 2023.09.28.559955. [Epub ahead of print]
    Exonuclease Xrn1 regulates TORC1 signaling in response to SAM availability.
    Madeline M McGinnis, Benjamin M Sutter, Samira Jahangiri, Benjamin P Tu.
      Autophagy is a conserved process of cellular self-digestion that promotes survival during nutrient stress. In yeast, methionine starvation is sufficient to induce autophagy. One pathway of autophagy induction is governed by the SEACIT complex, which regulates TORC1 activity in response to amino acids through the Rag GTPases Gtr1 and Gtr2. However, the precise mechanism by which SEACIT senses amino acids and regulates TORC1 signaling remains incompletely understood. Here, we identify the conserved 5'-3' RNA exonuclease Xrn1 as a surprising and novel regulator of TORC1 activity in response to methionine starvation. This role of Xrn1 is dependent on its catalytic activity, but not on degradation of any specific class of mRNAs. Instead, Xrn1 modulates the nucleotide-binding state of the Gtr1/2 complex, which is critical for its interaction with and activation of TORC1. This work identifies a critical role for Xrn1 in nutrient sensing and growth control that extends beyond its canonical housekeeping function in RNA degradation and indicates an avenue for RNA metabolism to function in amino acid signaling into TORC1.
    DOI:  https://doi.org/10.1101/2023.09.28.559955
  6. EMBO Rep. 2023 Oct 09. e57265
    Lysosomes in senescence and aging.
    Jay Xiaojun Tan, Toren Finkel.
      Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age-related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age-related diseases and potentially for aging itself.
    Keywords:  LYPAS; age-related disease; autophagy; lysosomal quality control; senescence
    DOI:  https://doi.org/10.15252/embr.202357265
  7. Cancers (Basel). 2023 Oct 05. pii: 4857. [Epub ahead of print]15(19):
    The Combined Inhibition of Autophagy and Diacylglycerol Acyltransferase-Mediated Lipid Droplet Biogenesis Induces Cancer Cell Death during Acute Amino Acid Starvation.
    Maida Jusović, Pia Starič, Eva Jarc Jovičić, Toni Petan.
      Lipid droplets (LDs) are dynamic organelles involved in the management of fatty acid trafficking and metabolism. Recent studies suggest that autophagy and LDs serve complementary roles in the protection against nutrient stress, but the autophagy-LD interplay in cancer cells is not well understood. Here, we examined the relationship between autophagy and LDs in starving HeLa cervical cancer- and MDA-MB-231 breast cancer cells. We found that acute amino acid depletion induces autophagy and promotes diacylglycerol acyltransferase 1 (DGAT1)-mediated LD accumulation in HeLa cells. Inhibition of autophagy via late-stage autophagy inhibitors, or by knocking down autophagy-related 5 (ATG5), reduced LD accumulation in amino acid-starved cancer cells, suggesting that autophagy contributes to LD biogenesis. On the contrary, knockdown of adipose triglyceride lipase (ATGL) increased LD accumulation, suggesting that LD breakdown is mediated by lipolysis under these conditions. Concurrent inhibition of autophagy by silencing ATG5 and of LD biogenesis using DGAT inhibitors was effective in killing starving HeLa cells, whereas cell survival was not compromised by suppression of ATGL-mediated lipolysis. Autophagy-dependent LD biogenesis was also observed in the aggressive triple-negative MDA-MB-231 breast cancer cells deprived of amino acids, but these cells were not sensitized to starvation by the combined inhibition of LD biogenesis and autophagy. These findings reveal that while targeting autophagy-driven and DGAT-mediated LD biogenesis reduces the resilience of HeLa cervical cancer cells to amino acid deprivation, this strategy may not be successful in other cancer cell types.
    Keywords:  autophagy; cancer; cell death; diacylglycerol acyltransferase; lipid droplets; nutrient starvation
    DOI:  https://doi.org/10.3390/cancers15194857
  8. Sci Adv. 2023 Oct 13. 9(41): eadh1134
    A noncanonical function of SKP1 regulates the switch between autophagy and unconventional secretion.
    Jie Li, Gregory J Krause, Qi Gui, Susmita Kaushik, Gergely Rona, Qingyue Zhang, Feng-Xia Liang, Avantika Dhabaria, Carlos Anerillas, Jennifer L Martindale, Nikita Vasilyev, Manor Askenazi, Beatrix Ueberheide, Evgeny Nudler, Myriam Gorospe, Ana Maria Cuervo, Michele Pagano.
      Intracellular degradation of proteins and organelles by the autophagy-lysosome system is essential for cellular quality control and energy homeostasis. Besides degradation, endolysosomal organelles can fuse with the plasma membrane and contribute to unconventional secretion. Here, we identify a function for mammalian SKP1 in endolysosomes that is independent of its established role as an essential component of the family of SCF/CRL1 ubiquitin ligases. We found that, under nutrient-poor conditions, SKP1 is phosphorylated on Thr131, allowing its interaction with V1 subunits of the vacuolar ATPase (V-ATPase). This event, in turn, promotes V-ATPase assembly to acidify late endosomes and enhance endolysosomal degradation. Under nutrient-rich conditions, SUMOylation of phosphorylated SKP1 allows its binding to and dephosphorylation by the PPM1B phosphatase. Dephosphorylated SKP1 interacts with SEC22B to promote unconventional secretion of the content of less acidified hybrid endosomal/autophagic compartments. Collectively, our study implicates SKP1 phosphorylation as a switch between autophagy and unconventional secretion in a manner dependent on cellular nutrient status.
    DOI:  https://doi.org/10.1126/sciadv.adh1134
  9. Plant Cell. 2023 Oct 12. pii: koad252. [Epub ahead of print]
    HOOKLESS1 acetylates AUTOPHAGY-RELATED PROTEIN18a to promote autophagy during nutrient starvation in Arabidopsis.
    Li Huang, Xing Wen, Lian Jin, Huihui Han, Hongwei Guo.
      Acetylation is an important post-translational modification (PTM) that regulates almost all core processes of autophagy in yeast and mammals. However, the role of protein acetylation in plant autophagy and the underlying regulatory mechanisms remain unclear. Here, we show the essential role of the putative acetyltransferase HOOKLESS1 (HLS1) in acetylation of the autophagy-related protein ATG18a, a key autophagy component that regulates autophagosome formation in Arabidopsis (Arabidopsis thaliana). Loss of HLS1 function suppressed starvation-induced autophagy and increased plant susceptibility to nutrient deprivation. We discovered that HLS1 physically interacts with and directly acetylates ATG18a both in vitro and in vivo. By contrast, mutating putative active sites in HLS1 inhibited ATG18a acetylation and suppressed autophagy upon nutrient deprivation. Accordingly, overexpression of ATG18a mutant variants with lower acetylation levels inhibited the binding activity of ATG18a to PtdIns(3)P and autophagosome formation under starvation conditions. Moreover, HLS1-modulated autophagy was uncoupled from its function in hook development. Taken together, these findings shed light on a key regulator of autophagy and further elucidate the importance of PTMs in modulating autophagy in plants.
    DOI:  https://doi.org/10.1093/plcell/koad252
  10. Heart Fail Rev. 2023 Oct 12.
    Autophagy protects mitochondrial health in heart failure.
    Yating Tang, Wenlong Xu, Yu Liu, Jiajun Zhou, Kai Cui, Yanmei Chen.
      The progression of heart failure is reported to be strongly associated with homeostatic imbalance, such as mitochondrial dysfunction and abnormal autophagy, in the cardiomyocytes. Mitochondrial dysfunction triggers autophagic and cardiac dysfunction. In turn, abnormal autophagy impairs mitochondrial function and leads to apoptosis or autophagic cell death under certain circumstances. These events often occur concomitantly, forming a vicious cycle that exacerbates heart failure. However, the role of the crosstalk between mitochondrial dysfunction and abnormal autophagy in the development of heart failure remains obscure and the underlying mechanisms are mainly elusive. The potential role of the link between mitochondrial dysfunction and abnormal autophagy in heart failure progression has recently garnered attention. This review summarized recent advances of the interactions between mitochondria and autophagy during the development of heart failure.
    Keywords:  Autophagy; Heart failure; Mitochondria health; Mitochondria-targeted therapeutics; Mitochondrial quality control
    DOI:  https://doi.org/10.1007/s10741-023-10354-x
  11. Heliyon. 2023 Sep;9(9): e19799
    Ferroptosis, autophagy, tumor and immunity.
    Yuyan Xie, Yang Zhou, Jiale Wang, Lijuan Du, Yuanyuan Ren, Fang Liu.
      Ferroptosis was first proposed in 2012, a new form of cell death. Autophagy plays a crucial role in cell clearance and maintaining homeostasis. Autophagy is involved in the initial step of ferroptosis under the action of histone elements such as NCOA4, RAB7A, and BECN1. Ferroptosis and autophagy are involved in tumor progression, treatment, and drug resistance in the tumor microenvironment. In this review, we described the mechanisms of ferroptosis, autophagy, and tumor and immunotherapy, respectively, and emphasized the relationship between autophagy-related ferroptosis and tumor.
    Keywords:  Autophagy; Autophagy related ferroptosis; Ferroptosis; Immunity; Tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e19799
  12. Front Microbiol. 2023 ;14 1281303
    The intricate dance: host autophagy and Coxiella burnetii infection.
    Tingting Wang, Chao Wang, Chang Li, Lei Song.
      Q fever is a zoonotic disease caused by Coxiella burnetii, an obligatory intracellular bacterial pathogen. Like other intracellular pathogens, C. burnetii is able to survive and reproduce within host cells by manipulating host cellular processes. In particular, the relationship between C. burnetii infection and host autophagy, a cellular process involved in degradation and recycling, is of great interest due to its intricate nature. Studies have shown that autophagy can recognize and target intracellular pathogens such as Legionella and Salmonella for degradation, limiting their replication and promoting bacterial clearance. However, C. burnetii can actively manipulate the autophagic pathway to create an intracellular niche, known as the Coxiella-containing vacuole (CCV), where it can multiply and evade host immune responses. C. burnetii promotes the fusion of CCVs with lysosomes through mechanisms involving virulence factors such as Cig57 and CvpF. This review summarizes the latest findings on the dynamic interaction between host autophagy and C. burnetii infection, highlighting the complex strategies employed by both the bacterium and the host. A better understanding of these mechanisms could provide important insights into the development of novel therapeutic interventions and vaccine strategies against C. burnetii infections.
    Keywords:  Q fever; autophagosome; effector; lysosome; type IV secretion system
    DOI:  https://doi.org/10.3389/fmicb.2023.1281303
  13. Int J Mol Sci. 2023 Oct 09. pii: 15014. [Epub ahead of print]24(19):
    Integrated Multi-Omics Analyses Reveal That Autophagy-Mediated Cellular Metabolism Is Required for the Initiation of Pollen Germination.
    Xuemei Zhou, Qiuyu Zhang, Yuliang Zhao, Shanshan Ding, Guang-Hui Yu.
      Autophagy is an evolutionarily conserved mechanism for degrading and recycling various cellular components, functioning in both normal development and stress conditions. This process is tightly regulated by a set of autophagy-related (ATG) proteins, including ATG2 in the ATG9 cycling system and ATG5 in the ATG12 conjugation system. Our recent research demonstrated that autophagy-mediated compartmental cytoplasmic deletion is essential for pollen germination. However, the precise mechanisms through which autophagy regulates pollen germination, ensuring its fertility, remain largely unknown. Here, we applied multi-omics analyses, including transcriptomic and metabolomic approaches, to investigate the downstream pathways of autophagy in the process of pollen germination. Although ATG2 and ATG5 play similar roles in regulating pollen germination, high-throughput transcriptomic analysis reveals that silencing ATG5 has a greater impact on the transcriptome than silencing ATG2. Cross-comparisons of transcriptome and proteome analysis reveal that gene expression at the mRNA level and protein level is differentially affected by autophagy. Furthermore, high-throughput metabolomics analysis demonstrates that pathways related to amino acid metabolism and aminoacyl-tRNA biosynthesis were affected by both ATG2 and ATG5 silencing. Collectively, our multi-omics analyses reveal the central role of autophagy in cellular metabolism, which is critical for initiating pollen germination and ensuring pollen fertility.
    Keywords:  autophagy; metabolome; multi-omics analyses; pollen germination; tobacco; transcriptome
    DOI:  https://doi.org/10.3390/ijms241915014
  14. J Biomed Sci. 2023 Oct 08. 30(1): 85
    Extracellular release in the quality control of the mammalian mitochondria.
    Kuei-Hsiang Pan, Hung Chang, Wei Yuan Yang.
      Mammalian cells release a wealth of materials to their surroundings. Emerging data suggest these materials can even be mitochondria with perturbed morphology and aberrant function. These dysfunctional mitochondria are removed by migrating cells through membrane shedding. Neuronal cells, cardiomyocytes, and adipocytes send dysfunctional mitochondria into the extracellular space for nearby cells to degrade. Various studies also indicate that there is an interplay between intracellular mitochondrial degradation pathways and mitochondrial release in handling dysfunctional mitochondria. These observations, in aggregate, suggest that extracellular release plays a role in quality-controlling mammalian mitochondria. Future studies will help delineate the various types of molecular machinery mammalian cells use to release dysfunctional mitochondria. Through the studies, we will better understand how mammalian cells choose between intracellular degradation and extracellular release for the quality control of mitochondria.
    Keywords:  Autophagy; Extracellular vesicles; Mitochondria; Mitophagy; Organelle quality control
    DOI:  https://doi.org/10.1186/s12929-023-00979-3
  15. Pharmacol Res. 2023 Oct 09. pii: S1043-6618(23)00313-4. [Epub ahead of print] 106957
    SIRT1 is a regulator of autophagy: implications for the progression and treatment of myocardial ischemia-reperfusion.
    Xiaoqing Ding, Chenyu Zhu, Wenhong Wang, Mengying Li, Chunwei Ma, Binghong Gao.
      SIRT1 is a highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase. It is involved in the regulation of various pathophysiological processes, including cell proliferation, survival, differentiation, autophagy, and oxidative stress. Therapeutic activation of SIRT1 protects the heart and cardiomyocytes from pathology-related stress, particularly myocardial ischemia/reperfusion (I/R). Autophagy is an important metabolic pathway for cell survival during energy or nutrient deficiency, hypoxia, or oxidative stress. Autophagy is a double-edged sword in myocardial I/R injury. The activation of autophagy during the ischemic phase removes excess metabolic waste and helps ensure cardiomyocyte survival, whereas excessive autophagy during reperfusion depletes the cellular components and leads to autophagic cell death. Increasing research on I/R injury has indicated that SIRT1 is involved in the process of autophagy and regulates myocardial I/R. SIRT1 regulates autophagy through various pathways, such as the deacetylation of FOXOs, ATGs, and LC3. Recent studies have confirmed that SIRT1-mediated autophagy plays different roles at different stages of myocardial I/R injury. By targeting the mechanism of SIRT1-mediated autophagy at different stages of I/R injury, new small-molecule drugs, miRNA activators, or blockers can be developed. For example, resveratrol, sevoflurane, quercetin, and melatonin in the ischemic stage, coptisine, curcumin, berberine, and some miRNAs during reperfusion, were involved in regulating the SIRT1-autophagy axis, exerting a cardioprotective effect. Here, we summarize the possible mechanisms of autophagy regulation by SIRT1 in myocardial I/R injury and the related molecular drug applications to identify strategies for treating myocardial I/R injury.
    Keywords:  SIRT1; autophagy; ischemia–reperfusion; molecular drugs; myocardial; myocardial I/R injury
    DOI:  https://doi.org/10.1016/j.phrs.2023.106957
  16. Int J Mol Sci. 2023 Sep 26. pii: 14576. [Epub ahead of print]24(19):
    Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN.
    Alejandra Suárez-Carrillo, Mónica Álvarez-Córdoba, Ana Romero-González, Marta Talaverón-Rey, Suleva Povea-Cabello, Paula Cilleros-Holgado, Rocío Piñero-Pérez, Diana Reche-López, David Gómez-Fernández, José Manuel Romero-Domínguez, Manuel Munuera-Cabeza, Antonio Díaz, Susana González-Granero, José Manuel García-Verdugo, José A Sánchez-Alcázar.
      Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected.
    Keywords:  BPAN; WDR45; antioxidants; autophagy; iron accumulation
    DOI:  https://doi.org/10.3390/ijms241914576
  17. Open Res Eur. 2022 ;2 23
    Fluorescent reporter of  Caenorhabditis elegans Parkin: Regulators of its abundance and role in autophagy-lysosomal dynamics.
    Roman Vozdek, Bingying Wang, Kathy H Li, Peter P Pramstaller, Andrew A Hicks, Dengke K Ma.
      Background: Parkin, which when mutated leads to early-onset Parkinson's disease, acts as an E3 ubiquitin ligase. How Parkin is regulated for selective protein and organelle targeting is not well understood. Here, we used protein interactor and genetic screens in Caenorhabditis elegans ( C. elegans) to identify new regulators of Parkin abundance and showed their impact on autophagy-lysosomal dynamics and alpha-Synuclein processing. Methods: We generated a transgene encoding mCherry-tagged C. elegans Parkin - Parkinson's Disease Related 1 (PDR-1). We performed protein interactor screen using Co-immunoprecipitation followed by mass spectrometry analysis to identify putative interacting partners of PDR-1. Ribonucleic acid interference (RNAi) screen and an unbiased mutagenesis screen were used to identify genes regulating PDR-1 abundance. Confocal microscopy was used for the identification of the subcellular localization of PDR-1 and alpha-Synuclein processing. Results: We show that the mCherry::pdr-1 transgene rescues the mitochondrial phenotype of pdr-1 mutants and that the expressed PDR-1 reporter is localized in the cytosol with enriched compartmentalization in the autophagy-lysosomal system. We determined that the transgenic overexpression of the PDR-1 reporter, due to inactivated small interfering RNA (siRNA) generation pathway, disrupts autophagy-lysosomal dynamics. From the RNAi screen of putative PDR-1 interactors we found that the inactivated Adenine Nucleotide Translocator ant-1.1/hANT, or hybrid ubiquitin genes ubq-2/h UBA52 and ubl-1/h RPS27A encoding a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively, induced PDR-1 abundance and affected lysosomal dynamics. In addition, we demonstrate that the abundant PDR-1 plays a role in alpha-Synuclein processing. Conclusions: These data show that the abundant reporter of  C. elegans Parkin affects the autophagy-lysosomal system together with alpha-Synuclein processing which can help in understanding the pathology in Parkin-related diseases.
    Keywords:  C. elegans; Parkin; Parkinson’s disease; RNA interference; Synuclein; autophagy; genetic screen
    DOI:  https://doi.org/10.12688/openreseurope.14235.2
  18. Anal Chem. 2023 Oct 10.
    Visualization of Lysosomal Dynamics during Autophagy by Fluorescent Probe.
    Guofang Li, Langdi Zhang, Hua Zheng, Ling Huang, Zihong Li, Wenxiu Li, Weiying Lin.
      Lysosomes are one of the important organelles within cells, and their dynamic movement processes are associated with many biological events. Therefore, real-time monitoring of lysosomal dynamics processes has far-reaching implications. A lysosome-targeted fluorescent probe N(CH2)3-BD-PZ is proposed for real-time monitoring of lysosomal kinetic motility. Using this probe, the dynamic process of lysosomes under starvation induction was successfully explored through fluorescence imaging. Importantly, we observed a new pattern of lysosomal dynamic movement, in which an irregular lysosome was slowly cleaved into two different-sized touching lysosomes and then fused to form a new round lysosome. This research provides a powerful fluorescence tool to understand the dynamic motility of intracellular lysosomes under fluorescence imaging.
    DOI:  https://doi.org/10.1021/acs.analchem.3c03329
  19. Nat Commun. 2023 Oct 11. 14(1): 6360
    C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy.
    Shen Zhang, Mindan Tong, Denghao Zheng, Huiying Huang, Linsen Li, Christian Ungermann, Yi Pan, Hanyan Luo, Ming Lei, Zaiming Tang, Wan Fu, She Chen, Xiaoxia Liu, Qing Zhong.
      The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a "hook-up" model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.
    DOI:  https://doi.org/10.1038/s41467-023-42003-0
  20. J Biomed Sci. 2023 Oct 12. 30(1): 86
    Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
    Lei Liu, Yanjun Li, Guo Chen, Quan Chen.
      Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to cellular energy needs and other cellular and environmental cues. Great strides have been made to uncover key regulators of these complex processes. Emerging evidence has shown that there exists a tight coordination between mitophagy and mitobiogenesis, and their defects may cause many human diseases. In this review, we will first summarize the recent advances made in the discovery of molecular regulations of mitobiogenesis and mitophagy and then focus on the mechanism and signaling pathways involved in the simultaneous regulation of mitobiogenesis and mitophagy in the response of tissue or cultured cells to energy needs, stress, or pathophysiological conditions. Further studies of the crosstalk of these two opposing processes at the molecular level will provide a better understanding of how the cell maintains optimal cellular fitness and function under physiological and pathophysiological conditions, which holds promise for fighting aging and aging-related diseases.
    Keywords:  Aging; Aging-related diseases; Mitochondrial biogenesis; Mitochondrial quality; Mitophagy; Mitophagy receptors
    DOI:  https://doi.org/10.1186/s12929-023-00975-7
  21. Trends Neurosci. 2023 Oct 10. pii: S0166-2236(23)00222-9. [Epub ahead of print]
    The endolysosomal pathway and ALS/FTD.
    Tiffany W Todd, Wei Shao, Yong-Jie Zhang, Leonard Petrucelli.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are considered to be part of a disease spectrum that is associated with causative mutations and risk variants in a wide range of genes. Mounting evidence indicates that several of these genes are linked to the endolysosomal system, highlighting the importance of this pathway in ALS/FTD. Although many studies have focused on how disruption of this pathway impacts on autophagy, recent findings reveal that this may not be the whole picture: specifically, disrupting autophagy may not be sufficient to induce disease, whereas disrupting the endolysosomal system could represent a crucial pathogenic driver. In this review we discuss the connections between ALS/FTD and the endolysosomal system, including a breakdown of how disease-associated genes are implicated in this pathway. We also explore the potential downstream consequences of disrupting endolysosomal activity in the brain, outside of an effect on autophagy.
    Keywords:  C9ORF72; TDP-43; TMEM106B; autophagy; neurodegeneration; proteinopathy
    DOI:  https://doi.org/10.1016/j.tins.2023.09.004
  22. Int J Mol Sci. 2023 Sep 28. pii: 14666. [Epub ahead of print]24(19):
    Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?
    Claudio Ponticelli, Gabriella Moroni, Francesco Reggiani.
      Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either PKD1 or PKD2 genes, responsible for encoding polycystin 1 and polycystin 2, respectively. These proteins are primarily located within the primary cilia. The disease follows an inexorable progression, leading most patients to severe renal failure around the age of 50, and extra-renal complications are frequent. A cure for ADPKD remains elusive, but some measures can be employed to manage symptoms and slow cyst growth. Tolvaptan, a vasopressin V2 receptor antagonist, is the only drug that has been proven to attenuate ADPKD progression. Recently, autophagy, a cellular recycling system that facilitates the breakdown and reuse of aged or damaged cellular components, has emerged as a potential contributor to the pathogenesis of ADPKD. However, the precise role of autophagy in ADPKD remains a subject of investigation, displaying a potentially twofold impact. On the one hand, impaired autophagy may promote cyst formation by inducing apoptosis, while on the other hand, excessive autophagy may lead to fibrosis through epithelial to mesenchymal transition. Promising results of autophagy inducers have been observed in preclinical studies. Clinical trials are warranted to thoroughly assess the long-term safety and efficacy of a combination of autophagy inducers with metabolic and/or aquaferetic drugs. This research aims to shed light on the complex involvement of autophagy in ADPKD, explore the regulation of autophagy in disease progression, and highlight the potential of combination therapies as a promising avenue for future investigations.
    Keywords:  autophagy; autosomal dominant polycystic kidney disease; kidney diseases; polycystins; renal involvement
    DOI:  https://doi.org/10.3390/ijms241914666
  23. Aging (Albany NY). 2023 Oct 09. 15
    Live while the DNA lasts. The role of autophagy in DNA loss and survival of diploid yeast cells during chronological aging.
    Tuguldur Enkhbaatar, Marek Skoneczny, Karolina Stępień, Mateusz Mołoń, Adrianna Skoneczna.
      Aging is inevitable and affects all cell types, thus yeast cells are often used as a model in aging studies. There are two approaches to studying aging in yeast: replicative aging, which describes the proliferative potential of cells, and chronological aging, which is used for studying post-mitotic cells. While analyzing the chronological lifespan (CLS) of diploid Saccharomyces cerevisiae cells, we discovered a remarkable phenomenon: ploidy reduction during aging progression. To uncover the mechanism behind this unusual process we used yeast strains undergoing a CLS assay, looking for various aging parameters. Cell mortality, regrowth ability, autophagy induction and cellular DNA content measurements indicated that during the CLS assay, dying cells lost their DNA, and only diploids survived. We demonstrated that autophagy was responsible for the gradual loss of DNA. The nucleophagy marker activation at the start of the CLS experiment correlated with the significant drop in cell viability. The activation of piecemeal microautophagy of nucleus (PMN) markers appeared to accompany the chronological aging process until the end. Our findings emphasize the significance of maintaining at least one intact copy of the genome for the survival of post-mitotic diploid cells. During chronological aging, cellular components, including DNA, are exposed to increasing stress, leading to DNA damage and fragmentation in aging cells. We propose that PMN-dependent clearance of damaged DNA from the nucleus helps prevent genome rearrangements. However, as long as one copy of the genome can be rebuilt, cells can still survive.
    Keywords:  aging; autophagy; double-strand breaks; genome instability; lifespan
    DOI:  https://doi.org/10.18632/aging.205102
  24. iScience. 2023 Oct 20. 26(10): 107960
    Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan in C. elegans.
    Anita V Kumar, Joslyn Mills, Wesley M Parker, Joshua A Leitão, Diego I Rodriguez, Sandrine E Daigle, Celeste Ng, Rishi Patel, Joseph L Aguilera, Joseph R Johnson, Shi Quan Wong, Louis R Lapierre.
      In several long-lived Caenorhabditis elegans strains, such as insulin/IGF-1 receptor daf-2 mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but their role in longevity is unclear. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we uncovered an important role for lipid droplets in proteostasis and longevity. Using genome-wide RNAi screening, we identified several SQST-1 modulators, including lipid droplets-associated and aggregation-prone proteins. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase gene atgl-1/ATGL enhanced autophagy, and extended lifespan. Notably, a substantial amount of ubiquitinated proteins were found on lipid droplets. Reducing lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised, and significantly reduced the lifespan of long-lived daf-2 animals. Altogether, our study uncovered a key role for lipid droplets in C. elegans as a proteostatic mediator that modulates ubiquitinated protein accumulation, facilitates autophagy, and promotes longevity.
    Keywords:  Biochemistry; Biological sciences
    DOI:  https://doi.org/10.1016/j.isci.2023.107960
  25. Int J Mol Sci. 2023 Sep 30. pii: 14774. [Epub ahead of print]24(19):
    The Cytoprotective Role of Autophagy in Response to BRAF-Targeted Therapies.
    Ahmed M Elshazly, David A Gewirtz.
      BRAF-targeted therapies are widely used for the treatment of melanoma patients with BRAF V600 mutations. Vemurafenib, dabrafenib as well as encorafenib have demonstrated substantial therapeutic activity; however, as is the case with other chemotherapeutic agents, the frequent development of resistance limits their efficacy. Autophagy is one tumor survival mechanism that could contribute to BRAF inhibitor resistance, and multiple studies support an association between vemurafenib-induced and dabrafenib-induced autophagy and tumor cell survival. Clinical trials have also demonstrated a potential benefit from the inclusion of autophagy inhibition as an adjuvant therapy. This review of the scientific literature relating to the role of autophagy that is induced in response to BRAF-inhibitors supports the premise that autophagy targeting or modulation could be an effective adjuvant therapy.
    Keywords:  autophagy; cytoprotective; cytostatic; cytotoxic; dabrafenib; encorafenib; vemurafenib
    DOI:  https://doi.org/10.3390/ijms241914774
  26. bioRxiv. 2023 Sep 25. pii: 2023.09.25.558944. [Epub ahead of print]
    Ancient genomic linkage couples metabolism with erythroid development.
    Alexandra E Preston, Joe N Frost, Mohsin Badat, Megan Teh, Andrew E Armitage, Ruggiero Norfo, Sarah K Wideman, Muhammad Hanifi, Natasha White, Noémi Roy, Bart Ghesquiere, Christian Babbs, Mira Kassouf, James Davies, Jim R Hughes, Rob Beagrie, Douglas R Higgs, Hal Drakesmith.
      Generation of mature cells from progenitors requires tight coupling of differentiation and metabolism. During erythropoiesis, erythroblasts are required to massively upregulate globin synthesis then clear extraneous material and enucleate to produce erythrocytes 1-3 . Nprl3 has remained in synteny with the α-globin genes for >500 million years 4 , and harbours the majority of the α-globin enhancers 5 . Nprl3 is a highly conserved inhibitor of mTORC1, which controls cellular metabolism. However, whether Nprl3 itself serves an erythroid role is unknown. Here, we show that Nprl3 is a key regulator of erythroid metabolism. Using Nprl3-deficient fetal liver and adult competitive bone marrow - fetal liver chimeras, we show that NprI3 is required for sufficient erythropoiesis. Loss of Nprl3 elevates mTORC1 signalling, suppresses autophagy and disrupts erythroblast glycolysis and redox control. Human CD34+ progenitors lacking NPRL3 produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Finally, we show that the α-globin enhancers upregulate NprI3 expression, and that this activity is necessary for optimal erythropoiesis. Therefore, the anciently conserved linkage of NprI3 , α-globin and their associated enhancers has enabled coupling of metabolic and developmental control in erythroid cells. This may enable erythropoiesis to adapt to fluctuating nutritional and environmental conditions.
    DOI:  https://doi.org/10.1101/2023.09.25.558944
  27. J Am Chem Soc. 2023 Oct 12.
    ATNC: Versatile Nanobody Chimeras for Autophagic Degradation of Intracellular Unligandable and Undruggable Proteins.
    Huiping He, Chengjian Zhou, Xi Chen.
      Targeted protein degradation (TPD) through the autophagy pathway displays broad substrate scope and is gaining increasing interest in biology and medicine. However, current approaches using small-molecule degraders have limitations due to the lack of versatility, modularity, and ease of implementation and are restricted to addressing only ligandable proteins. Herein, we report a nonsmall molecule-based autophagy-targeting nanobody chimera (ATNC), or phagobody, for selective degradation of intracellular targets, which overcomes these limitations. The core of an ATNC features a nanobody for recruiting proteins as well as an autophagic pathway-directing module. ATNC turns out to be a general, modular, and versatile degradation platform. We show that ATNC can be versatilely implemented in different ways including expressed ATNC intrabodies for ease of use, chemically induced proximity (CIP)-operated logic-gated conditional and tunable degradation, and cyclic cell-penetrating peptide-tethered cell-permeable phagobodies that selectively degrade the undruggable therapeutically relevant HE4 protein, resulting in effective suppression of ovarian cancer cell proliferation and migration. Overall, ATNC represents a general, modular, and versatile targeted degradation platform that degrades unligandable proteins and offers therapeutic potential.
    DOI:  https://doi.org/10.1021/jacs.3c08843
  28. Cells. 2023 Sep 26. pii: 2364. [Epub ahead of print]12(19):
    Exploration of SUMO2/3 Expression Levels and Autophagy Process in Fragile X-Associated Tremor/Ataxia Syndrome: Addressing Study Limitations and Insights for Future Research.
    Maria Isabel Alvarez-Mora, Glòria Garrabou, Laura Molina-Porcel, Ruben Grillo-Risco, Francisco Garcia-Garcia, Tamara Barcos, Judith Cantó-Santos, Laia Rodriguez-Revenga.
      Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that appears in adult FMR1 premutation carriers. The neuropathological hallmark of FXTAS is an intranuclear inclusion in neurons and astrocytes. Nearly 200 different proteins have been identified in FXTAS inclusions, being the small ubiquitin-related modifier 2 (SUMO2), ubiquitin and p62 the most highly abundant. These proteins are components of the protein degradation machinery. This study aimed to characterize SUMO2/3 expression levels and autophagy process in human postmortem brain samples and skin fibroblast cultures from FXTAS patients. Results revealed that FXTAS postmortem brain samples are positive for SUMO2/3 conjugates and supported the idea that SUMO2/3 accumulation is involved in inclusion formation. Insights from RNA-sequencing data indicated that SUMOylation processes are significantly upregulated in FXTAS samples. In addition, the analysis of the autophagy flux showed the accumulation of p62 protein levels and autophagosomes in skin fibroblasts from FXTAS patients. Similarly, gene set analysis evidenced a significant downregulation in gene ontology terms related to autophagy in FXTAS samples. Overall, this study provides new evidence supporting the role of SUMOylation and autophagic processes in the pathogenic mechanisms underlying FXTAS.
    Keywords:  FMR1 premutation; FXTAS; SUMO2/3; SUMOylation; autophagy; p62
    DOI:  https://doi.org/10.3390/cells12192364
  29. Development. 2023 Oct 12. pii: dev.201930. [Epub ahead of print]
    Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.
    Akane Hatsuda, Junko Kurisu, Kazuto Fujishima, Ayano Kawaguchi, Nobuhiko Ohno, Mineko Kengaku.
      Dendritic outgrowth in immature neurons is enhanced by neuronal activity and is considered one of the mechanisms of neural circuit optimization. It is known that calcium signals affect transcriptional regulation and cytoskeletal remodeling necessary for dendritic outgrowth. Here we demonstrate that activity-dependent calcium signaling also controls mitochondrial homeostasis via AMP-activated protein kinase (AMPK) in growing dendrites of differentiating hippocampal neurons. We found that the inhibition of neuronal activity induces dendritic hypotrophy with abnormally elongated mitochondria. In growing dendrites, AMPK is activated by neuronal activity and dynamically oscillates in synchrony with calcium spikes, and this AMPK oscillation is inhibited by CaMKK2 knockdown. AMPK activation leads to phosphorylation of MFF and ULK1, which initiate mitochondrial fission and mitophagy, respectively. Dendritic mitochondria in AMPK-depleted neurons exhibit impaired fission and mitophagy and display multiple signs of dysfunction. Genetic inhibition of fission leads to dendritic hypoplasia reminiscent of AMPK deficient neurons. Thus, AMPK activity is finely tuned by the calcium-CaMKK2 pathway and regulates mitochondrial homeostasis by facilitating removal of damaged components of mitochondria in growing neurons during normal brain development.
    Keywords:  AMPK; Dendritogenesis; Hippocampal neurons; Mitochondria; Neuronal activity
    DOI:  https://doi.org/10.1242/dev.201930
  30. Aging Cell. 2023 Oct 13. e14003
    Impaired mitophagosome-lysosome fusion mediates olanzapine-induced aging.
    Xi Chen, Zhizhen Wang, Peng Zheng, Anjila Dongol, Yuanyi Xie, Xing Ge, Mingxuan Zheng, Xuemei Dang, Zehra Boz Seyhan, Nathan Nagaratnam, Yinghua Yu, Xu-Feng Huang.
      The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome-lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome-lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.
    Keywords:  accelerated aging; antipsychotics; cognition; health span; lifespan; mitophagy; mitophagy inducer; olanzapine
    DOI:  https://doi.org/10.1111/acel.14003
  31. Galen Med J. 2023 ;12 e2903
    The Crosstalk Between Autophagy and MicroRNAs in Esophageal Carcinoma:.
    Neda Gorjizadeh, Sahar Poudineh, Behnaz Barghgir, Mohammadreza Eghbali, Alireza Sarlak, Maryam Poudineh.
      Esophageal cancer (EC) is considered one of the most prevalent and aggressive malignancies worldwide, with a variety of molecular alterations thought to contribute to its incidence, development, progression, and invasion. However, the exact underlying mechanism has not been elucidated. Autophagy is a highly conserved degradative and recycling process that can function with a dual role in either the progression or the treatment of EC. Since microRNAs (miRNAs) are described as upstream regulators capable of controlling both oncogenic pathways and autophagic flux, the present study has aimed to review the crosstalk between autophagy and miRNAs and the potential perspective of these mechanisms in EC prevention and treatment.
    Keywords:  Autophagy; Cancer; Esophageal Carcinoma; Squamous Cell Carcinoma; Therapy; microRNAs
    DOI:  https://doi.org/10.31661/gmj.v12i.2903
  32. Int J Mol Sci. 2023 Oct 06. pii: 14960. [Epub ahead of print]24(19):
    Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment.
    Shilpi Singh, Debashis Barik, Karl Lawrie, Iteeshree Mohapatra, Sujata Prasad, Afsar R Naqvi, Amar Singh, Gatikrushna Singh.
      The mTOR signaling pathway plays a pivotal and intricate role in the pathogenesis of glioblastoma, driving tumorigenesis and proliferation. Mutations or deletions in the PTEN gene constitutively activate the mTOR pathway by expressing growth factors EGF and PDGF, which activate their respective receptor pathways (e.g., EGFR and PDGFR). The convergence of signaling pathways, such as the PI3K-AKT pathway, intensifies the effect of mTOR activity. The inhibition of mTOR has the potential to disrupt diverse oncogenic processes and improve patient outcomes. However, the complexity of the mTOR signaling, off-target effects, cytotoxicity, suboptimal pharmacokinetics, and drug resistance of the mTOR inhibitors pose ongoing challenges in effectively targeting glioblastoma. Identifying innovative treatment strategies to address these challenges is vital for advancing the field of glioblastoma therapeutics. This review discusses the potential targets of mTOR signaling and the strategies of target-specific mTOR inhibitor development, optimized drug delivery system, and the implementation of personalized treatment approaches to mitigate the complications of mTOR inhibitors. The exploration of precise mTOR-targeted therapies ultimately offers elevated therapeutic outcomes and the development of more effective strategies to combat the deadliest form of adult brain cancer and transform the landscape of glioblastoma therapy.
    Keywords:  EGFR; PDGFR; PI3K-AKT signaling; PTEN; drug delivery; glioblastoma; mTOR inhibitor; mTOR pathway
    DOI:  https://doi.org/10.3390/ijms241914960
  33. Cells. 2023 Sep 24. pii: 2345. [Epub ahead of print]12(19):
    Stimulator of Interferon Genes (STING) Triggers Adipocyte Autophagy.
    Kornél Z Varga, Katalin Gyurina, Ádám Radványi, Tibor Pál, László Sasi-Szabó, Haidong Yu, Enikő Felszeghy, Tamás Szabó, Tamás Röszer.
      Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2'3'-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.
    Keywords:  STING; adipocyte; immunity; inflammation; interferons; mitochondria
    DOI:  https://doi.org/10.3390/cells12192345
  34. Nano Lett. 2023 Oct 12.
    Targeted Protein Degradation Mediated by Genetically Engineered Lysosome-Targeting Exosomes.
    Tao Wang, Liang Sun, Tianyu Ren, Min Hou, Ying Long, Jian-Hui Jiang, Jianjun He.
      Protein-degrading chimeras are superior drug modalities compared to traditional protein inhibitors because of their effective therapeutic performance. So far, various targeted protein degradation strategies, including proteolysis-targeting chimeras and lysosome-targeting chimeras, have emerged as essential technologies for tackling diseases caused by abnormal protein expression. Here, we report the development and application of lysosome-targeting exosomes (LYTEXs) for the selective degradation of membrane protein targets. LYTEXs are genetically engineered exosomes expressing multivalent single-chain fragment variables, simultaneously recognizing cell-surface lysosome-targeting and to-be-degraded protein. We show that by targeting the lysosome-directing asialoglycoprotein receptor, bispecific LYTEXs can induce lysosomal degradation of membrane-associated therapeutic targets. This strategy provides a generalizable, easy-to-prepare platform for modulating surface protein expression, with the advantage of therapeutic delivery.
    Keywords:  ASGPR; exosome; lysosomal degradation; targeted protein degradation
    DOI:  https://doi.org/10.1021/acs.nanolett.3c03148
  35. Int J Mol Sci. 2023 Sep 22. pii: 14421. [Epub ahead of print]24(19):
    Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.
    Hariprasath Ragupathy, Manasvi Vukku, Sandeep Kumar Barodia.
      Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.
    Keywords:  astrocytes; microglia; mitochondria; neurons; oligodendrocytes; oxidative stress
    DOI:  https://doi.org/10.3390/ijms241914421
  36. Cell Death Differ. 2023 Oct 12.
    Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids.
    Pengfei Yang, Jin Li, Tianyi Zhang, Yanxian Ren, Qiuning Zhang, Ruifeng Liu, Haining Li, Junrui Hua, Wen-An Wang, Jufang Wang, Heng Zhou.
      Ferroptosis is a type of cell death characterized by the accumulation of intracellular iron and an increase in hazardous lipid peroxides. Ferroptosis and autophagy are closely related. Ionizing radiation is a frequently used cancer therapy to kill malignancies. We found that ionizing radiation induces both ferroptosis and autophagy and that there is a form of mutualism between the two processes. Ionizing radiation also causes lipid droplets to form in proximity to damaged mitochondria, which, through the action of mitophagy, results in the degradation of the peridroplet mitochondria by lysosomes and the consequent release of free fatty acids and a significant increase in lipid peroxidation, thus promoting ferroptosis. Ionizing radiation has a stronger, fatal effect on cells with a high level of mitophagy, and this observation suggests a novel strategy for tumor treatment.
    DOI:  https://doi.org/10.1038/s41418-023-01230-0
  37. Ecotoxicol Environ Saf. 2023 Oct 10. pii: S0147-6513(23)01052-7. [Epub ahead of print]266 115548
    ZEA mediates autophagy through the ROS-AMPK-m-TOR pathway to enhance the susceptibility of mastitis induced by Staphylococcus aureus in mice.
    Yuhong He, Niri Su, Hengyi Yang, Wencheng Yang, Caijun Zhao, Yunhe Fu, Yubo Hu, Xiaoyu Hu.
      Mastitis is an inflammatory response of the mammary tissue caused by pathogenic bacterial infections, especially Staphylococcus aureus (S. aureus). Zearalenone (ZEA) is one of the common mycotoxins in moldy feed, which usually affects the cow's resistance to pathogenic microorganisms. However, it is not well understood whether ZEA affects the development of mastitis. Therefore, this study aimed to investigate the role of ZEA in the development of S. aureus-induced mastitis in mice. The results showed that administered daily by gavage for one week of ZEA (40 mg/kg) aggravated the severity of mastitis induced by S. aureus. Furthermore, we found that ZEA promotes the adhesion and invasion of S. aureus into mouse mammary epithelial cells (MMEC) by activating autophagy, and the activation of autophagy mediated by ROS-AMPK-m-TOR pathway. Taken together, the results showed that ZEA enhances S. aureus-induced mastitis susceptibility through activating autophagy mediated by ROS-AMPK-mTOR signaling pathway.
    Keywords:  AMPK-mTOR; Autophagy; ROS; S. aureus; Zearalenone
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.115548
  38. Front Endocrinol (Lausanne). 2023 ;14 1228045
    The role of autophagy in the treatment of type II diabetes and its complications: a review.
    Xuan Zhao, Lu-Yao Bie, Dao-Ran Pang, Xiao Li, Long-Fei Yang, Dan-Dan Chen, Yue-Rui Wang, Yan Gao.
      Type II diabetes mellitus (T2DM) is a chronic metabolic disease characterized by prolonged hyperglycemia and insulin resistance (IR). Its incidence is increasing annually, posing a significant threat to human life and health. Consequently, there is an urgent requirement to discover effective drugs and investigate the pathogenesis of T2DM. Autophagy plays a crucial role in maintaining normal islet structure. However, in a state of high glucose, autophagy is inhibited, resulting in impaired islet function, insulin resistance, and complications. Studies have shown that modulating autophagy through activation or inhibition can have a positive impact on the treatment of T2DM and its complications. However, it is important to note that the specific regulatory mechanisms vary depending on the target organ. This review explores the role of autophagy in the pathogenesis of T2DM, taking into account both genetic and external factors. It also provides a summary of reported chemical drugs and traditional Chinese medicine that target the autophagic pathway for the treatment of T2DM and its complications.
    Keywords:  Type II diabetes mellitus (T2DM); autophagy; complications; hypoglycemic agents; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fendo.2023.1228045
  39. Nat Commun. 2023 Oct 13. 14(1): 6431
    PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
    Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catherine E Balnis, Lianjie Wei, Andrew J Smith, Keri-Lyn Kozul, Merima Forny, Olivia M Connor, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Jonathan R Friedman, Julia K Pagan, Joshua J Coon, David J Pagliarini.
      PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
    DOI:  https://doi.org/10.1038/s41467-023-42069-w
  40. Eur J Pharmacol. 2023 Oct 05. pii: S0014-2999(23)00603-9. [Epub ahead of print]959 176091
    Scoparone induces autophagic cell death via the PAK1/AKT axis in colorectal cancer.
    Sha Huang, Luping Lin, Yifei Ma, Qing Zhu, Ningna Weng.
      Colorectal cancer (CRC) is one of most common malignancies worldwide, yet curative therapy remains a clinical challenge. Here, we demonstrate that scoparone (Scop), a traditional Chinese medicine monomer, inhibits the growth of CRC cells both in vitro and in vivo. Further studies found that Scop treatment induces complete autophagic flux in CRC cells, while inhibition of autophagy markedly represses the antiproliferative activities of Scop, suggesting an antitumour property of Scop-induced autophagy in CRC. Mechanistically, Scop induced autophagy initiation by reducing P21-activated kinase 1 (PAK1) expression and subsequently repressing the AKT/mTOR signaling pathway. Collectively, our study suggests that Scop is a potential anti-CRC therapeutic option and provides an underlying molecular mechanism for its antitumour effect in CRC.
    Keywords:  AKT; Autophagy; Colorectal cancer; PAK1; Scoparone
    DOI:  https://doi.org/10.1016/j.ejphar.2023.176091
  41. Toxicol In Vitro. 2023 Oct 11. pii: S0887-2333(23)00160-1. [Epub ahead of print] 105711
    PSAT1 promotes autophagy to resist insufficient autophagy caused by cigarette smoke extract in human airway epithelial cells.
    Lixing Wang, Furong Yan, Yongbin Shi, Yifei Liu, Xiaoshan Su, Yaping Zhang.
      The inhaling of cigarette smoke (CS) causes damage to airway epithelial cells, which is related to chronic obstructive pulmonary disease (COPD). It has been established that CS induces autophagy, but it is still unclear whether excessive or insufficient autophagy results in cell death. This study discovered that CS significantly elevates PSAT1 expression in bronchial epithelial cells. Further studies using autophagy inhibitor, RNA interference, RT-qPCR, western blot, and CCK-8 assay in 16-HBE cells have confirmed that autophagy is temporarily initiated by cigarette smoke extract, but insufficient autophagy leads to cell death. PSAT1 induced by CSE promotes autophagy and resists insufficient autophagy caused by CSE through Akt/mTOR pathway in human bronchial epithelial cells, playing a protective role.
    Keywords:  Airway epithelial cells; Autophagy; COPD; Cigarette smoke; PSAT1; mTOR
    DOI:  https://doi.org/10.1016/j.tiv.2023.105711
  42. Cells. 2023 Oct 05. pii: 2407. [Epub ahead of print]12(19):
    An Overview of the Role of Furin in Type 2 Diabetes.
    Sulaiman K Marafie, Fahd Al-Mulla.
      Post-translational modifications (PTMs) play important roles in regulating several human diseases, like cancer, neurodegenerative disorders, and metabolic disorders. Investigating PTMs' contribution to protein functions is critical for modern biology and medicine. Proprotein convertases (PCs) are irreversible post-translational modifiers that have been extensively studied and are considered as key targets for novel therapeutics. They cleave proteins at specific sites causing conformational changes affecting their functions. Furin is considered as a PC model in regulating growth factors and is involved in regulating many pro-proteins. The mammalian target of the rapamycin (mTOR) signaling pathway is another key player in regulating cellular processes and its dysregulation is linked to several diseases including type 2 diabetes (T2D). The role of furin in the context of diabetes has been rarely explored and is currently lacking. Moreover, furin variants have altered activity that could have implications on overall health. In this review, we aim to highlight the role of furin in T2D in relation to mTOR signaling. We will also address furin genetic variants and their potential effect on T2D and β-cell functions. Understanding the role of furin in prediabetes and dissecting it from other confounding factors like obesity is crucial for future therapeutic interventions in metabolic disorders.
    Keywords:  furin; furin variants; mTOR; metabolic disorders; prediabetes; proprotein convertase; therapeutic target; type 2 diabetes; β-cell
    DOI:  https://doi.org/10.3390/cells12192407
  43. Sci Rep. 2023 10 10. 13(1): 17137
    The autophagy protein Def8 is altered in Alzheimer's disease and Aβ42-expressing Drosophila brains.
    Sebastián Oyarce-Pezoa, Guilherme Gischkow Rucatti, Francisco Muñoz-Carvajal, Nicole Sanhueza, Wileidy Gomez, Sandra Espinoza, Mario Leiva, Nicolás García, Daniela P Ponce, Carol D SanMartín, Diego Rojas-Rivera, Natalia Salvadores, Maria I Behrens, Ute Woehlbier, Melissa Calegaro-Nassif, Mario Sanhueza.
      Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by protein accumulation in the brain as a main neuropathological hallmark. Among them, Aβ42 peptides tend to aggregate and create oligomers and plaques. Macroautophagy, a form of autophagy characterized by a double-membrane vesicle, plays a crucial role in maintaining neuronal homeostasis by degrading protein aggregates and dysfunctional organelles as a quality control process. Recently, DEF8, a relatively uncharacterized protein, has been proposed as a participant in vesicular traffic and autophagy pathways. We have reported increased DEF8 levels in lymphocytes from mild cognitive impairment (MCI) and early-stage AD patients and a neuronal profile in a murine transgenic AD model. Here, we analyzed DEF8 localization and levels in the postmortem frontal cortex of AD patients, finding increased levels compared to healthy controls. To evaluate the potential function of DEF8 in the nervous system, we performed an in silico assessment of its expression and network profiles, followed by an in vivo evaluation of a neuronal Def8 deficient model using a Drosophila melanogaster model of AD based on Aβ42 expression. Our findings show that DEF8 is an essential protein for maintaining cellular homeostasis in the nervous system, and it is upregulated under stress conditions generated by Aβ42 aggregation. This study suggests DEF8 as a novel actor in the physiopathology of AD, and its exploration may lead to new treatment avenues.
    DOI:  https://doi.org/10.1038/s41598-023-44203-6
  44. eNeuro. 2023 Oct;pii: ENEURO.0079-23.2023. [Epub ahead of print]10(10):
    Axonal Transport of Lysosomes Is Unaffected in Glucocerebrosidase-Inhibited iPSC-Derived Forebrain Neurons.
    A J Keefe, D R Gabrych, Y Zhu, D J Vocadlo, M A Silverman.
      Lysosomes are acidic organelles that traffic throughout neurons delivering catabolic enzymes to distal regions of the cell and maintaining degradative demands. Loss of function mutations in the gene GBA encoding the lysosomal enzyme glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher's disease (GD) and are the most common genetic risk factor for synucleinopathies like Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GCase degrades the membrane lipid glucosylceramide (GlcCer) and mutations in GBA, or inhibiting its activity, results in the accumulation of GlcCer and disturbs the composition of the lysosomal membrane. The lysosomal membrane serves as the platform to which intracellular trafficking complexes are recruited and activated. Here, we investigated whether lysosomal trafficking in axons was altered by inhibition of GCase with the pharmacological agent Conduritol B Epoxide (CBE). Using live cell imaging in human male induced pluripotent human stem cell (iPSC)-derived forebrain neurons, we demonstrated that lysosomal transport was similar in both control and CBE-treated neurons. Furthermore, we tested whether lysosomal rupture, a process implicated in various neurodegenerative disorders, was affected by inhibition of GCase. Using L-leucyl-L-leucine methyl ester (LLoME) to induce lysosomal membrane damage and immunocytochemical staining for markers of lysosomal rupture, we found no difference in susceptibility to rupture between control and CBE-treated neurons. These results suggest the loss of GCase activity does not contribute to neurodegenerative disease by disrupting either lysosomal transport or rupture.
    Keywords:  axonal transport; conduritol B epoxide; glucocerebrosidase; lysosomes
    DOI:  https://doi.org/10.1523/ENEURO.0079-23.2023
  45. Biochem Biophys Res Commun. 2023 Oct 10. pii: S0006-291X(23)01183-X. [Epub ahead of print]682 199-206
    Exosomes derived from cardiac fibroblasts with angiotensin II stimulation provoke hypertrophy and autophagy inhibition in cardiomyocytes.
    Si-Ting Xu, Yue-Xin Zhang, Si-Ling Liu, Fang Liu, Jian-Tao Ye.
      Although accumulating evidence has revealed that autophagy inhibition contributes to the development of pathological cardiac hypertrophy, the mechanisms leading to declined autophagy activity in the hypertrophic heart remain to be elucidated. Exosomes are known to be important mediators of intercellular communication, and the involvement of exosomes in cardiovascular abnormities has attracted increasing attentions. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. Here, we investigated the potential role of CFs-derived exosomes in regulating cardiomyocyte hypertrophy and autophagy. Exosomes from rat CFs treated with angiotensin II (Ang II-CFs-exosomes) were collected and characterized. Our experiments showed that these exosomes could induce hypertrophic responses and impair autophagy activity in primary neonatal rat cardiomyocytes (NRCMs). Ang II-CFs-exosomes blocked the autophagic flux of NRCMs via inhibiting the formation of autolysosomes. Moreover, the pro-hypertrophic effects and autophagy inhibition induced by Ang II-CFs-exosomes was validated in mice receiving injection of the exosomes. These findings highlight a novel role of Ang II-CFs-exosomes in suppressing cardiomyocyte autophagy, which may help to better understand the pathogenesis of cardiac hypertrophy.
    Keywords:  Autophagy; Cardiac fibroblasts; Cardiac hypertrophy; Exosomes
    DOI:  https://doi.org/10.1016/j.bbrc.2023.10.031
  46. Biochem Biophys Res Commun. 2023 Sep 29. pii: S0006-291X(23)01134-8. [Epub ahead of print]682 71-76
    PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models.
    Ji Eun Han, Kyong-Hwa Kang, Hyunjin Kim, Young Bin Hong, Byung-Ok Choi, Hyongjong Koh.
      Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones with the α-crystalline domain that is critical to their chaperone activity. Within the sHSP family, three (HSPB1, HSPB3, and HSPB8) proteins are linked with inherited peripheral neuropathies, including distal hereditary motor neuropathy (dHMN) and Charco-Marie-Tooth disease (CMT). In this study, we introduced the HSPB3 Y118H (HSPB3Y118H) mutant gene identified from the CMT2 family in Drosophila. With a missense mutation on its α-crystalline domain, this human HSPB3 mutant gene induced a loss of motor activity accompanied by reduced mitochondrial membrane potential in fly neuronal tissues. Moreover, mitophagy, a critical mechanism of mitochondrial quality control, is downregulated in fly motor neurons expressing HSPB3Y118H. Surprisingly, PINK1 and Parkin, the core regulators of mitophagy, successfully rescued these motor and mitochondrial abnormalities in HSPB3 mutant flies. Results from the first animal model of HSPB3 mutations suggest that mitochondrial dysfunction plays a critical role in HSPB3-associated human pathology.
    Keywords:  Charcot-Marie-Tooth disease; Distal hereditary motor neuropathies; Drosophila; HSPB3; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.bbrc.2023.09.092
  47. Int J Mol Sci. 2023 Oct 09. pii: 15016. [Epub ahead of print]24(19):
    Autophagy as a Target for Non-Immune Intrinsic Functions of Programmed Cell Death-Ligand 1 in Cancer.
    Blanca Estela García-Pérez, Christian Pérez-Torres, Shantal Lizbeth Baltierra-Uribe, Juan Castillo-Cruz, Nayeli Shantal Castrejón-Jiménez.
      Autophagy is a catabolic process that is essential to the maintenance of homeostasis through the cellular recycling of damaged organelles or misfolded proteins, which sustains energy balance. Additionally, autophagy plays a dual role in modulating the development and progression of cancer and inducing a survival strategy in tumoral cells. Programmed cell death-ligand 1 (PD-L1) modulates the immune response and is responsible for maintaining self-tolerance. Because tumor cells exploit the PD-L1-PD-1 interaction to subvert the immune response, immunotherapy has been developed based on the use of PD-L1-blocking antibodies. Recent evidence has suggested a bidirectional regulation between autophagy and PD-L1 molecule expression in tumor cells. Moreover, the research into the intrinsic properties of PD-L1 has highlighted new functions that are advantageous to tumor cells. The relationship between autophagy and PD-L1 is complex and still not fully understood; its effects can be context-dependent and might differ between tumoral cells. This review refines our understanding of the non-immune intrinsic functions of PD-L1 and its potential influence on autophagy, how these could allow the survival of tumor cells, and what this means for the efficacy of anti-PD-L1 therapeutic strategies.
    Keywords:  PD-L1; autophagy; cancer; immunotherapy; mTOR
    DOI:  https://doi.org/10.3390/ijms241915016
  48. Small. 2023 Oct 11. e2306760
    Bioorthogonal Aptamer-ATTEC Conjugates for Degradation of Alpha-Synuclein via Autophagy-Lysosomal Pathway.
    Xiaofeng Liao, Geng Qin, Zhenqi Liu, Jinsong Ren, Xiaogang Qu.
      Autophagosome-tethering compound (ATTEC) technology has recently been emerging as a novel approach for degrading proteins of interest (POIs). However, it still faces great challenges in how to design target-specific ATTEC molecules. Aptamers are single-stranded DNA or RNA oligonucleotides that can recognize their target proteins with high specificity and affinity. Here, ATTEC is combined with aptamers for POIs degradation. As a proof of concept, pathological protein α-synuclein (α-syn) is chosen as the target and an efficient α-syn degrader is generated. Aptamer as a targeting warhead of α-syn is conjugated with LC3B-binding compound 5,7-dihydroxy-4-phenylcoumarin (DP) via bioorthogonal click reaction. It is demonstrated that the aptamer conjugated with DP is capable of clearing α-syn through LC3 and autophagic degradation. These results indicate that aptamer-based ATTECs are a versatile approach to degrade POIs by taking advantage of the well-defined different aptamers for targeting diverse proteins, which provides a new way for the design of ATTECs to degradation of targeted proteins.
    Keywords:  Parkinson's disease; autophagic degradation; autophagosome-tethering compounds; targeted protein degradation; α-synuclein
    DOI:  https://doi.org/10.1002/smll.202306760
  49. Microbiol Spectr. 2023 Oct 11. e0279123
    Autophagy facilitates intracellular survival of pathogenic rickettsiae in macrophages via evasion of autophagosomal maturation and reduction of microbicidal pro-inflammatory IL-1 cytokine responses.
    Oliver H Voss, Hodalis Gaytan, Saif Ullah, Mohammad Sadik, Imran Moin, M Sayeedur Rahman, Abdu F Azad.
      The genus Rickettsia is comprised of obligate intracellular bacterial parasites of a wide range of arthropod and vertebrate hosts. Some Rickettsia species (spp.) are responsible for serious human diseases globally. One interesting feature of these stealthy group of pathogens is their ability to exploit host cytosolic defense responses to their benefits. However, the precise mechanism by which pathogenic Rickettsia spp. elude host immune defense responses remains to be determined. Here, we observed that pathogenic Rickettsia typhi and Rickettsia rickettsii (Sheila Smith [SS]), but not non-pathogenic Rickettsia montanensis, become ubiquitinated and induce autophagy upon entry into bone marrow-derived macrophages. Moreover, unlike R. montanensis, both R. typhi and R. rickettsii (SS) colocalized with LC3B and not with Lamp2 upon host cell entry. Finally, we observed that both R. typhi and R. rickettsii, but not R. montanensis, reduce pro-inflammatory interleukin-1 (IL-1) cytokine responses, likely via an autophagy-mediated mechanism. In summary, we identified a previously unappreciated pathway by which both pathogenic R. typhi and R. rickettsii (SS), but not the non-pathogenic R. montanensis, become ubiquitinated, induce autophagy, avoid autolysosomal destruction, and reduce microbicidal IL-1 cytokine responses to establish an intracytosolic niche in macrophages. IMPORTANCE Rickettsia spp. are intracellular bacterial parasites of a wide range of arthropod and vertebrate hosts. Some rickettsiae are responsible for several severe human diseases globally. One interesting feature of these pathogens is their ability to exploit host cytosolic defense responses to their benefits. However, the precise mechanism by which pathogenic Rickettsia spp. elude host defense responses remains unclear. Here, we observed that pathogenic Rickettsia typhi and Rickettsia rickettsii (Sheila Smith [SS]), but not non-pathogenic Rickettsia montanensis, become ubiquitinated and induce autophagy upon entry into macrophages. Moreover, unlike R. montanensis, R. typhi and R. rickettsii (SS) colocalized with LC3B but not with Lamp2 upon host cell entry. Finally, we observed that both R. typhi and R. rickettsii (SS), but not R. montanensis, reduce pro-inflammatory interleukin-1 (IL-1) responses, likely via an autophagy-mediated mechanism. In summary, we identified a previously unappreciated pathway by which both pathogenic R. typhi and R. rickettsii (SS) become ubiquitinated, induce autophagy, avoid autolysosomal destruction, and reduce microbicidal IL-1 cytokine responses to establish an intracytosolic niche in macrophages.
    Keywords:  IL-1α; IL-1β; R. montanensis; R. rickettsii; R. typhi; autophagy; bacterial host dissemination; macrophages
    DOI:  https://doi.org/10.1128/spectrum.02791-23
  50. MedComm (2020). 2023 Oct;4(5): e398
    LILAR, a novel long noncoding RNA regulating autophagy in the liver tissues of endotoxemic mice through a competing endogenous RNA mechanism.
    Tian Tian, Shan Li, Haihua Luo, Yijing Li, Hanghang Chen, Ying Yang, Guangqin Chen, Bingyao Xie, Zhengzheng Yan, Zhenqi Wang, Lei Li, Yong Jiang.
      Sepsis is an often-deadly complication of infection that can lead to multiple organ failure. Previous studies have demonstrated that autophagy has a protective effect on liver injury in sepsis. Here, we report a novel long noncoding RNA (lncRNA), named lipopolysaccharide (LPS)-induced liver autophagy regulator (LILAR), which was highly induced in the liver tissues of endotoxemic mice. LILAR deficiency significantly increased the susceptibility of mice to LPS. In contrast, LILAR overexpression rescued the liver injury mediated by LILAR deficiency and increased the survival of LILAR knockout mice with endotoxemia. Autophagy-related protein 13 (Atg13) is a potential downstream target gene of LILAR. LILAR deficiency notably decreased Atg13 expression and suppressed autophagy in the livers of mice challenged with LPS. A reporter gene assay showed that LILAR competitively adsorbed miR-705 to increase the expression of Atg13 in cultured cells, indicating that LILAR participates in the regulation of the autophagy in the liver tissues of endotoxemic mice through a competitive endogenous RNA mechanism. In summary, we identified a novel lncRNA, LILAR, as a hepatic autophagy regulator, which not only promotes our understanding of liver pathophysiology but also provides a potential therapeutic target and/or diagnostic biomarker for liver injury in endotoxemia.
    Keywords:  autophagy; endotoxemia; liver injury; long noncoding RNA; microRNA
    DOI:  https://doi.org/10.1002/mco2.398
  51. J Virol. 2023 Oct 09. e0104523
    SERPINB1 promotes Senecavirus A replication by degrading IKBKE and regulating the IFN pathway via autophagy.
    Junfang Yan, Yanni Gao, Juan Bai, Jian Li, Minjing Li, Xing Liu, Ping Jiang.
      Innate immunity and autophagy play crucial roles in regulating Senecavirus A (SVA) replication. However, the reciprocal coordination between these systems during virus infection is not understood. Our results show that SERPINB1, a member of the SERPINB family, facilitates SVA replication. Mechanistically, ectopic expression of SERPINB1 increases the degradation of IκB kinase epsilon (IKBKE) through the ubiquitin-proteasome pathway. The removal of IKBKE antagonizes the IKBKE-mediated inhibition of proliferation that normally generates an interferon response via the AKT/mTOR/BECN1 axis. We conclude that SERPINB1 promotes SVA replication by eliciting autophagy-triggered innate inhibition, suggesting that SERPINB1 is a potential therapeutic target for the control of viral infection.IMPORTANCESenecavirus A (SVA) is an emerging picornavirus associated with vesicular disease, which wide spreads around the world. It has evolved multiple strategies to evade host immune surveillance. The mechanism and pathogenesis of the virus infection remain unclear. In this study, we show that SERPINB1, a member of the SERPINB family, promotes SVA replication, and regulates both innate immunity and the autophagy pathway. SERPINB1 catalyzes K48-linked polyubiquitination of IκB kinase epsilon (IKBKE) and degrades IKBKE through the proteasome pathway. Inhibition of IKBKE expression by SERPINB1 induces autophagy to decrease type I interferon signaling, and ultimately promotes SVA proliferation. These results provide importantly the theoretical basis of SVA replication and pathogenesis. SERPINB1 could be a potential therapeutic target for the control of viral infection.
    Keywords:  IKBKE; SERPINB1; Senecavirus A; autophagy; interferons
    DOI:  https://doi.org/10.1128/jvi.01045-23
  52. Int J Mol Sci. 2023 Sep 30. pii: 14767. [Epub ahead of print]24(19):
    Ethanolic Extract of Propolis Modulates Autophagy-Related microRNAs in Osteoarthritic Chondrocytes.
    Consuelo Arias, Luis A Salazar.
      Osteoarthritis is a multifactorial joint disease characterized by degeneration, and aging stands as a significant risk factor. Autophagy, a crucial cellular homeostasis mechanism, is influenced by aging and closely linked to cartilage health. This correlation between autophagy, cell death, and OA underscores its relevance in disease progression. MicroRNAs have emerged as autophagy regulators, with miRNA-based interventions showing promise in preclinical models. Remarkably, the ethanolic extract of propolis exhibits positive effects on autophagy-related proteins and healthy cartilage markers in an in vitro osteoarthritis model. The aim of this brief report was to evaluate through in silico analysis and postulate five microRNAs that could regulate autophagy proteins (AKT1, ATG5, and LC3) and assess whether the ethanolic extract of propolis could regulate the expression of these microRNAs. Among the examined miRNAs (miR-19a, miR-125b, miR-181a, miR-185, and miR-335), the ethanolic extract of propolis induced significant changes in four of them. Specifically, miR-125b responded to EEP by counteracting IL-1β-induced effects, while miR-181a, miR-185, and miR-335 exhibited distinct patterns of expression under EEP treatment. These findings unveil a potential link between miRNAs, EEP, and autophagy modulation in OA, offering promising therapeutic insights. Nevertheless, further validation and clinical translation are warranted to substantiate these promising observations.
    Keywords:  autophagy; miRNA; osteoarthritic; propolis
    DOI:  https://doi.org/10.3390/ijms241914767
  53. Curr Opin Cell Biol. 2023 Oct 11. pii: S0955-0674(23)00107-2. [Epub ahead of print]85 102258
    Protein condensates as flexible platforms for membrane traffic.
    Florian Wilfling, Marko Kaksonen, Jeanne Stachowiak.
      With an essential role in nearly every physiological process and disease state, trafficking vesicles are fundamental to cell biology. Canonical understanding of membrane traffic has been driven by key achievements in structural biology. Nonetheless, discoveries over the past few years progressively point to the critical role of intrinsically disordered domains and proteins, which lack a well-defined secondary structure. From the initiation of endocytosis and the sequestration of synaptic vesicles to the stabilization of endoplasmic reticulum exit sites and the extension of the autophagic cup, flexible protein condensates, rich in intrinsic disorder, are increasingly implicated. While important debates about the physical nature and mechanistic interpretation of these findings remain, the significance of transient, multivalent protein assemblies in membrane traffic is increasingly clear.
    Keywords:  Autophagy; Endocytosis; Membrane traffic; Synapse
    DOI:  https://doi.org/10.1016/j.ceb.2023.102258
  54. Eur Heart J. 2023 Oct 13. pii: ehad661. [Epub ahead of print]
    Actionable autophagy checkpoints in cardiovascular ageing.
    Mahmoud Abdellatif, Léa Montégut, Guido Kroemer.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehad661
  55. Biochim Biophys Acta Mol Cell Res. 2023 Oct 06. pii: S0167-4889(23)00177-5. [Epub ahead of print]1871(1): 119604
    Ambra1 in exosomes secreted by HK-2 cells damaged by supersaturated oxalate induce mitophagy and autophagy-ferroptosis in normal HK-2 cells to participate in the occurrence of kidney stones.
    Xiaozhe Su, Chao Song, Ziqi He, Qianlin Song, Lingchao Meng, Caitao Dong, Jiawei Zhou, Hu Ke, Yunhe Xiong, Junwei Liu, Wenbiao Liao, Sixing Yang.
      Injury to the renal tubular epithelium has emerged as a leading factor underlying the formation of kidney stones. Indeed, epithelial cell damage contributes to the adherence and aggregation of crystals, thereby accelerating the formation of renal stones. Meanwhile, exosomes play an instrumental role in cellular communication, including DNA, RNA, mRNA, etc. In this study, homogenous cells were treated with exosomes derived from damaged cells in an attempt to establish "positive feedback" of cell damage, and the desired results were achieved. To begin, a serum-free medium and supersaturated concentrations of oxalate were added to the HK-2 cell line, and then exosomes were isolated from the two groups for analysis and comparison, and the autophagy-related gene Ambra1 (autophagy and beclin-1 regulator 1) was detected. Subsequently, normal HK-2 cells were treated with exosomes, and the related indexes of autophagy, ferroptosis and mitophagy were determined. Thereafter, Ambra1 was knocked down in exosome-derived HK-2 cells, resulting in the down-regulation of Ambra1 expression in exosomes produced by HK-2 cells following oxalate intervention. Thereafter, the ability of exosomes to stimulate autophagy, mitophagy and ferroptosis was re-evaluated in HK-2 cells after Ambra1 knockdown. The results corroborated that exosomes secreted by oxalate-treated HK-2 can directly elevate autophagy, ferroptosis and mitophagy levels in normal cells, and this effect was significantly mitigated following Ambra1 knockdown within exosomes. Meanwhile, exosomes-induced autophagy and ferroptosis were alleviated after knockdown of beclin-1 in recipient HK-2 cells. These results further suggest that beclin-1 plays a critical role in the process of exosome-induced autophagy-ferroptosis.
    Keywords:  Ambra1; Autophagy; Exosome; Ferroptosis; Kidney stone; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119604
  56. Virol J. 2023 Oct 11. 20(1): 231
    DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK/ERK/mTOR signaling pathway to induce autophagy.
    Ning Wu, Jinzhong Ji, Xiaoqin Gou, Pan Hu, Yao Cheng, Yuhang Liu, Yuanying Wang, Qilong Zhang, Li Zuo.
      The global incidence of dengue fever has gradually increased in recent years, posing a serious threat to human health. In the absence of specific anti-dengue drugs, understanding the interaction of Dengue virus (DENV) with the host is essential for the development of effective therapeutic measures. Autophagy is often activated during DENV infection to promote viral replication, but the mechanism of how DENV's own proteins induce autophagy has not been clarified. In this study, we first preliminarily identified DENV-2 NS1 as the most likely viral protein for DENV-2-induced autophagy with the help of molecular docking techniques. Further experimental results confirmed that DENV-2 NS1 regulates DENV-2 infection of HUVEC-induced autophagy through the AMPK/ERK/mTOR signaling pathway. Mechanistically, DENV-2 NS1 mainly interacted with AMPK by means of its Wing structural domain, and NS1 bound to all three structural domains on the AMPKα subunit. Finally, the experimental results showed that DENV-2 NS1 promoted the interaction between LKB1 and AMPKα1 and thus activated AMPK by both increasing the expression of LKB1 and binding LKB1. In conclusion, the results of this study revealed that DENV-2 NS1 protein served as a platform for the interaction between AMPK and LKB1 after DENV-2 infection with HUVEC, and pulled AMPK and LKB1 together to form a complex. LKB1 to form a complex, promoting LKB1 action on the kinase structural domain of AMPKα1, which in turn promotes phosphorylation of the Thr172 site on the AMPK kinase structural domain and activates AMPK, thereby positively regulating the AMPK/ERK/mTOR signaling pathway and inducing autophagy. The present discovery improves our understanding of DENV-2-induced host autophagy and contributes to the development of anti-dengue drugs.
    Keywords:  AMPK; AMPK/ERK/mTOR signaling pathway; Autophagy; DENV-2; DENV-2 NS1; LKB1
    DOI:  https://doi.org/10.1186/s12985-023-02166-0
  57. Nat Cell Biol. 2023 Oct;25(10): 1405
    Lysosomal cystine controls ferroptosis in cancer.
    Zhe Wang.
      
    DOI:  https://doi.org/10.1038/s41556-023-01252-3
  58. Adv Drug Deliv Rev. 2023 Oct 10. pii: S0169-409X(23)00427-1. [Epub ahead of print] 115112
    Lysosomal Therapies and Drug Delivery Strategies: An Overview.
    Silvia Muro.
      
    Keywords:  Lysosomes; antibody conjugates; cyclodextrin conjugates; disease models; enzyme replacement therapy; exosomes; gene editing; liposomes; lysosomal disorders; lysosomal escape; lysosomal nanotoxicity; polymer nanomedicines
    DOI:  https://doi.org/10.1016/j.addr.2023.115112
  59. Cell Metab. 2023 Sep 29. pii: S1550-4131(23)00341-8. [Epub ahead of print]
    Metabolic support by macrophages sustains colonic epithelial homeostasis.
    Stephanie Deborah Fritsch, Nyamdelger Sukhbaatar, Karine Gonzales, Alishan Sahu, Loan Tran, Andrea Vogel, Mario Mazic, Jayne Louise Wilson, Stephan Forisch, Hannah Mayr, Raimund Oberle, Jakob Weiszmann, Martin Brenner, Roeland Vanhoutte, Melanie Hofmann, Sini Pirnes-Karhu, Christoph Magnes, Torben Kühnast, Wolfram Weckwerth, Christoph Bock, Kristaps Klavins, Markus Hengstschläger, Christine Moissl-Eichinger, Gernot Schabbauer, Gerda Egger, Eija Pirinen, Steven H L Verhelst, Thomas Weichhart.
      The intestinal epithelium has a high turnover rate and constantly renews itself through proliferation of intestinal crypt cells, which depends on insufficiently characterized signals from the microenvironment. Here, we showed that colonic macrophages were located directly adjacent to epithelial crypt cells in mice, where they metabolically supported epithelial cell proliferation in an mTORC1-dependent manner. Specifically, deletion of tuberous sclerosis complex 2 (Tsc2) in macrophages activated mTORC1 signaling that protected against colitis-induced intestinal damage and induced the synthesis of the polyamines spermidine and spermine. Epithelial cells ingested these polyamines and rewired their cellular metabolism to optimize proliferation and defense. Notably, spermine directly stimulated proliferation of colon epithelial cells and colon organoids. Genetic interference with polyamine production in macrophages altered global polyamine levels in the colon and modified epithelial cell proliferation. Our results suggest that macrophages act as "commensals" that provide metabolic support to promote efficient self-renewal of the colon epithelium.
    Keywords:  arginase-1; homeostasis; immunometabolism; intestine; mTOR; mTORC1; macrophages; polyamines; spermine
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.010
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