bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2023–04–30
67 papers selected by
Viktor Korolchuk, Newcastle University
  1. Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration.
  2. Quantitative analysis of autophagy reveals the role of ATG9 and ATG2 in autophagosome formation.
  3. Autophagy and regulation of aquaporins in the kidneys.
  4. Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin.
  5. [Regulatory function and mechanism of autophagy on osteoclast].
  6. Identification of potential selective autophagy receptors from protein-content profiling of autophagosomes.
  7. Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer.
  8. Nuclear autophagy promotes longevity and germline immortality.
  9. FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels.
  10. Cellular proteins act as surfactants to control the interfacial behavior and function of biological condensates.
  11. Echovirus induces autophagy to promote viral replication via regulating mTOR/ULK1 signaling pathway.
  12. Nucleophagy delays aging and preserves germline immortality.
  13. From Diabetes to Diabetic Complications: Role of Autophagy.
  14. The role of crinophagy in quality control of the regulated secretory pathway.
  15. A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis.
  16. Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study.
  17. Autophagy Inhibition as a Potential Therapeutic Strategy for Breast Cancer with Mitochondrial Translation Defect Caused by CBFB-Deficiency.
  18. Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity.
  19. Gut Microbiota in Autophagy Regulation: New Therapeutic Perspective in Neurodegeneration.
  20. Autosis as a selective type of cell death.
  21. Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC.
  22. Mitophagy as a mitochondrial quality control mechanism in myocardial ischemic stress: from bench to bedside.
  23. Bile Acids Alter the Autophagy and Mitogenesis in Skeletal Muscle Cells.
  24. Placental Remote Control of Fetal Metabolism: Trophoblast mTOR Signaling Regulates Liver IGFBP-1 Phosphorylation and IGF-1 Bioavailability.
  25. Metabolically fitter with fibronectin.
  26. The Role of Mitochondrial Dysfunction in Alzheimer's: Molecular Defects and Mitophagy-Enhancing Approaches.
  27. Autophagy of the ER requires actin assembly driven by the interaction of ER with endocytic pits.
  28. A myeloid leukemia factor homolog is involved in tolerance to stresses and stress-induced protein metabolism in Giardia lamblia.
  29. Not4-dependent targeting of MMF1 mRNA to mitochondria limits its expression via ribosome pausing, Egd1 ubiquitination, Caf130, no-go-decay and autophagy.
  30. Intervertebral disc cell fate during aging and degeneration: apoptosis, senescence, and autophagy.
  31. Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.
  32. Astrovirus replication is dependent on induction of double membrane vesicles through a PI3K-dependent, LC3-independent pathway.
  33. New insights into autophagy in inflammatory subtypes of asthma.
  34. FURIN suppresses the progression of atherosclerosis by promoting macrophage autophagy.
  35. Caveolin-1 depletion attenuates hepatic fibrosis via promoting SQSTM1-mediated PFKL degradation in HSCs.
  36. Multi-locus deletion mutation induced by silver nanoparticles: Role of lysosomal-autophagy dysfunction.
  37. Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics.
  38. The establishment of mitotic errors-driven senescence depends on autophagy.
  39. Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy.
  40. Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics.
  41. Actin cytoskeletal reorganization is involved in hyperosmotic stress-induced autophagy in tubular epithelial cells.
  42. Structures of Vac8-containing protein complexes reveal the underlying mechanism by which Vac8 regulates multiple cellular processes.
  43. Research Progress on Autophagy Regulation by Active Ingredients of Traditional Chinese Medicine in the Treatment of Acute Lung Injury.
  44. MicroRNAs as the critical regulators of autophagy-mediated cisplatin response in tumor cells.
  45. The "Self-eating" of cancer-associated fibroblast: A potential target for cancer.
  46. Advances in Drug Discovery Targeting Lysosomal Membrane Proteins.
  47. Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways.
  48. Regulation of self-renewal in ovarian cancer stem cells by fructose via chaperone-mediated autophagy.
  49. Thyroid hormone upregulates LAMP2 expression and lysosome activity.
  50. Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells.
  51. Destabilizing heterochromatin by APOE mediates senescence.
  52. MicroRNAs in Age-Related Proteostasis and Stress Responses.
  53. Suppression of intestinal dysfunction in a Drosophila model of Parkinson's disease is neuroprotective.
  54. Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2.
  55. Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.
  56. LAMP3 induces lysosome-dependent cell death by impairing autophagic caspase-8 degradation in Sjögren's salivary glands.
  57. Michael J Clague: mitophagy, pexophagy, & metabolism.
  58. Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy.
  59. Acinetobacter baumannii outer membrane protein A induces autophagy in bone marrow-derived dendritic cells involving the PI3K/mTOR pathway.
  60. Research Progress on the Effect of Autophagy and Exosomes on Liver Fibrosis.
  61. Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells.
  62. Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle.
  63. Enhanced brain mitophagy slows systemic aging.
  64. Pleiotropic effects of mitochondria in aging.
  65. Mechanisms of spermidine-induced autophagy and geroprotection.
  66. BMAL1 involved in autophagy and injury of thoracic aortic endothelial cells of rats induced by intermittent heat stress through the AMPK/mTOR/ULK1 pathway.
  67. Metformin Collaborates with PINK1/Mfn2 Overexpression to Prevent Cardiac Injury by Improving Mitochondrial Function.
  1. Neuron. 2023 Apr 18. pii: S0896-6273(23)00268-4. [Epub ahead of print]
    Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration.
    Beatrice Paola Festa, Farah H Siddiqi, Maria Jimenez-Sanchez, Hyeran Won, Matea Rob, Alvin Djajadikerta, Eleanna Stamatakou, David C Rubinsztein.
      In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy, a degradative pathway critical for the removal of toxic, aggregate-prone proteins accumulating in neurodegenerative diseases. We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington's disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models.
    Keywords:  CCL5; CCR5; Huntington's disease; Tau; autophagy; dementia; mTORC1; maraviroc; microglia; neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuron.2023.04.006
  2. J Cell Biol. 2023 Jul 03. pii: e202210078. [Epub ahead of print]222(7):
    Quantitative analysis of autophagy reveals the role of ATG9 and ATG2 in autophagosome formation.
    David G Broadbent, Carlo Barnaba, Gloria I Perez, Jens C Schmidt.
      Autophagy is a catabolic pathway required for the recycling of cytoplasmic materials. To define the mechanisms underlying autophagy it is critical to quantitatively characterize the dynamic behavior of autophagy factors in living cells. Using a panel of cell lines expressing HaloTagged autophagy factors from their endogenous loci, we analyzed the abundance, single-molecule dynamics, and autophagosome association kinetics of autophagy proteins involved in autophagosome biogenesis. We demonstrate that autophagosome formation is inefficient and ATG2-mediated tethering to donor membranes is a key commitment step in autophagosome formation. Furthermore, our observations support the model that phagophores are initiated by the accumulation of autophagy factors on mobile ATG9 vesicles, and that the ULK1 complex and PI3-kinase form a positive feedback loop required for autophagosome formation. Finally, we demonstrate that the duration of autophagosome biogenesis is ∼110 s. In total, our work provides quantitative insight into autophagosome biogenesis and establishes an experimental framework to analyze autophagy in human cells.
    DOI:  https://doi.org/10.1083/jcb.202210078
  3. Kidney Res Clin Pract. 2023 Apr 18.
    Autophagy and regulation of aquaporins in the kidneys.
    Xiangdong Guo, Yonglun Kong, Tae-Hwan Kwon, Chunling Li, Weidong Wang.
      Aquaporins (AQPs) are water channel proteins that facilitate the transport of water molecules across cell membranes. To date, seven AQPs have been found to be expressed in mammal kidneys. The cellular localization and regulation of the transport properties of AQPs in the kidney have been widely investigated. Autophagy is known as a highly conserved lysosomal pathway, which degrades cytoplasmic components. Through basal autophagy, kidney cells maintain their functions and structure. As a part of the adaptive responses of the kidney, autophagy may be altered in response to stress conditions. Recent studies revealed that autophagic degradation of AQP2 in the kidney collecting ducts leads to impaired urine concentration in animal models with polyuria. Therefore, the modulation of autophagy could be a therapeutic approach to treat water balance disorders. However, as autophagy is either protective or deleterious, it is crucial to establish an optimal condition and therapeutic window where autophagy induction or inhibition could yield beneficial effects. Further studies are needed to understand both the regulation of autophagy and the interaction between AQPs and autophagy in the kidneys in renal diseases, including nephrogenic diabetes insipidus.
    Keywords:  Aquaporins; Autophagy; Nephrogenic diabetes insipidus; Urine concentration
    DOI:  https://doi.org/10.23876/j.krcp.22.247
  4. Nat Aging. 2022 Dec;2(12): 1145-1158
    Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin.
    Jennifer C Regan, Yu-Xuan Lu, Enric Ureña, Ralf L Meilenbrock, James H Catterson, Disna Kißler, Jenny Fröhlich, Emilie Funk, Linda Partridge.
      Pharmacological attenuation of mTOR presents a promising route for delay of age-related disease. Here we show that treatment of Drosophila with the mTOR inhibitor rapamycin extends lifespan in females, but not in males. Female-specific, age-related gut pathology is markedly slowed by rapamycin treatment, mediated by increased autophagy. Treatment increases enterocyte autophagy in females, via the H3/H4 histone-Bchs axis, whereas males show high basal levels of enterocyte autophagy that are not increased by rapamycin feeding. Enterocyte sexual identity, determined by transformerFemale expression, dictates sexually dimorphic cell size, H3/H4-Bchs expression, basal rates of autophagy, fecundity, intestinal homeostasis and lifespan extension in response to rapamycin. Dimorphism in autophagy is conserved in mice, where intestine, brown adipose tissue and muscle exhibit sex differences in autophagy and response to rapamycin. This study highlights tissue sex as a determining factor in the regulation of metabolic processes by mTOR and the efficacy of mTOR-targeted, anti-aging drug treatments.
    DOI:  https://doi.org/10.1038/s43587-022-00308-7
  5. Zhongguo Gu Shang. 2023 Apr 25. 36(4): 357-63
    [Regulatory function and mechanism of autophagy on osteoclast].
    Jian-Sen Miao, Xiang-Yang Wang, Hai-Ming Jin.
      Osteoclast (OC) is multinucleated, bone-resorbing cells originated from monocyte/macrophage lineage of cells, excessive production and abnormal activation of which could lead to many bone metabolic diseases, such as osteoporosis, osteoarthritis, etc. Autophagy, as a highly conserved catabolic process in eukaryotic cells, which plays an important role in maintaining cell homeostasis, stress damage repair, proliferation and differentiation. Recent studies have found that autophagy was also involved in the regulation of osteoclast generation and bone resorption. On the one hand, autophagy could be induced and activated by various factors in osteocalsts, such as nutrient deficiency, hypoxia, receptor activator of nuclear factor(NF)-κB ligand(RANKL), inflammatory factors, wear particles, microgravity environment, etc, different inducible factors, such as RANKL, inflammatory factors, wear particles, could interact with each other and work together. On the other hand, activated autophagy is involved in regulating various stages of osteoclast differentiation and maturation, autophagy could promote proliferation of osteoclasts, inhibiting apoptosis, and promoting differentiation, migration and bone resorption of osteoclast. The classical autophagy signaling pathway mediated by mammalian target of rapamycin complex 1(mTORC1) is currently a focus of research, and it could be regulated by upstream signalings such as phosphatidylinositol 3 kinase(PI-3K)/protein kinase B (PKB), AMP-activated protein kinase(AMPK). However, the paper found that mTORC1-mediated autophagy may play a bidirectional role in regulating differentiation and function of osteoclasts, and its underlying mechanism needs to be further ciarified. Integrin αvβ3 and Rab protein families are important targets for autophagy to play a role in osteoclast migration and bone resorption, respectively. In view of important role of osteoclast in the occurrence of various bone diseases, it is of great significance to elucidate the role of autophagy on osteoclast and its mechanism for the treatment of various bone diseases. The autophagy pathway could be used as a new therapeutic target for the treatment of clinical bone diseases such as osteoporosis.
    Keywords:   Autophagy; Review literature; Osteoclasts
    DOI:  https://doi.org/10.12200/j.issn.1003-0034.2023.04.012
  6. J Cell Biochem. 2023 Apr 23.
    Identification of potential selective autophagy receptors from protein-content profiling of autophagosomes.
    Alberto Cristiani, Arghya Dutta, Sergio Alejandro Poveda-Cuevas, Andreas Kern, Ramachandra M Bhaskara.
      Selective autophagy receptors (SARs) are central to cellular homeostatic and organellar recycling pathways. Over the last two decades, more than 30 SARs have been discovered and validated using a variety of experimental approaches ranging from cell biology to biochemistry, including high-throughput imaging and screening methods. Yet, the extent of selective autophagy pathways operating under various cellular contexts, for example, under basal and starvation conditions, remains unresolved. Currently, our knowledge of all known SARs and their associated cargo components is fragmentary and limited by experimental data with varying degrees of resolution. Here, we use classical predictive and modeling approaches to integrate high-quality autophagosome content profiling data with disparate datasets. We identify a global set of potential SARs and their associated cargo components active under basal autophagy, starvation-induced, and proteasome-inhibition conditions. We provide a detailed account of cellular components, biochemical pathways, and molecular processes that are degraded via autophagy. Our analysis yields a catalog of new potential SARs that satisfy the characteristics of bonafide, well-characterized SARs. We categorize them by the subcellular compartments they emerge from and classify them based on their likely mode of action. Our structural modeling validates a large subset of predicted interactions with the human ATG8 family of proteins and shows characteristic, conserved LC3-interacting region (LIR)-LIR docking site (LDS) and ubiquitin-interacting motif (UIM)-UIM docking site (UDS) binding modes. Our analysis also revealed the most abundant cargo molecules targeted by these new SARs. Our findings expand the repertoire of SARs and provide unprecedented details into the global autophagic state of HeLa cells. Taken together, our findings provide motivation for the design of new experiments, testing the role of these novel factors in selective autophagy.
    Keywords:  autophagosomes; cell biology; computational biology; data analysis; molecular models; proteomics; receptors
    DOI:  https://doi.org/10.1002/jcb.30405
  7. Int J Mol Sci. 2023 Apr 15. pii: 7310. [Epub ahead of print]24(8):
    Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer.
    Yin-Xiao Du, Abdullah Al Mamun, Ai-Ping Lyu, Hong-Jie Zhang.
      Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.
    Keywords:  autophagy; autophagy inhibitors; colorectal cancer; lysosome; natural products
    DOI:  https://doi.org/10.3390/ijms24087310
  8. Nat Aging. 2023 Jan;3(1): 11-12
    Nuclear autophagy promotes longevity and germline immortality.
      
    DOI:  https://doi.org/10.1038/s43587-022-00336-3
  9. EMBO J. 2023 Apr 27. e112799
    FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels.
    Hannah Elcocks, Ailbhe J Brazel, Katy R McCarron, Manuel Kaulich, Koraljka Husnjak, Heather Mortiboys, Michael J Clague, Sylvie Urbé.
      Selective autophagy of mitochondria, mitophagy, is linked to mitochondrial quality control and as such is critical to a healthy organism. We have used a CRISPR/Cas9 approach to screen human E3 ubiquitin ligases for influence on mitophagy under both basal cell culture conditions and upon acute mitochondrial depolarization. We identify two cullin-RING ligase substrate receptors, VHL and FBXL4, as the most profound negative regulators of basal mitophagy. We show that these converge, albeit via different mechanisms, on control of the mitophagy adaptors BNIP3 and BNIP3L/NIX. FBXL4 restricts NIX and BNIP3 levels via direct interaction and protein destabilization, while VHL acts through suppression of HIF1α-mediated transcription of BNIP3 and NIX. Depletion of NIX but not BNIP3 is sufficient to restore mitophagy levels. Our study contributes to an understanding of the aetiology of early-onset mitochondrial encephalomyopathy that is supported by analysis of a disease-associated mutation. We further show that the compound MLN4924, which globally interferes with cullin-RING ligase activity, is a strong inducer of mitophagy, thus providing a research tool in this context and a candidate therapeutic agent for conditions linked to mitochondrial dysfunction.
    Keywords:  BNIP3; FBXL4; NIX; VHL; mitophagy
    DOI:  https://doi.org/10.15252/embj.2022112799
  10. Dev Cell. 2023 Apr 18. pii: S1534-5807(23)00157-0. [Epub ahead of print]
    Cellular proteins act as surfactants to control the interfacial behavior and function of biological condensates.
    Zheng Wang, Chun Yang, Dongshi Guan, Jiaqi Li, Hong Zhang.
      Interfacial tension governs the behaviors and physiological functions of multiple biological condensates during diverse biological processes. Little is known about whether there are cellular surfactant factors that regulate the interfacial tension and functions of biological condensates within physiological environments. TFEB, a master transcription factor that controls expression of autophagic-lysosomal genes, assembles into transcriptional condensates to control the autophagy-lysosome pathway (ALP). Here, we show that interfacial tension modulates the transcriptional activity of TFEB condensates. MLX, MYC, and IPMK act as synergistic surfactants to decrease the interfacial tension and consequent DNA affinity of TFEB condensates. The interfacial tension of TFEB condensates is quantitatively correlated to their DNA affinity and subsequent ALP activity. The interfacial tension and DNA affinity of condensates formed by TAZ-TEAD4 are also regulated by the synergistic surfactant proteins RUNX3 and HOXA4. Our results indicate that the interfacial tension and functions of biological condensates can be controlled by cellular surfactant proteins in human cells.
    Keywords:  IPMK; MLX; MYC; TFEB; autophagy; interfacial tension; lysosome; phase separation; surfactant
    DOI:  https://doi.org/10.1016/j.devcel.2023.04.004
  11. Front Immunol. 2023 ;14 1162208
    Echovirus induces autophagy to promote viral replication via regulating mTOR/ULK1 signaling pathway.
    Chunchen Wu, Luzhi Zeng, Wenfu Yi, Yuanjiu Miao, Yihan Liu, Qiming Wang, Shi Liu, Guoping Peng, Zhenhua Zheng, Jianbo Xia.
      Among enteroviruses, echovirus can cause severe illnesses in neonates or infants, with high morbidity and mortality. Autophagy, a central component of host defense mechanisms, can function against diverse infections. In the present study, we investigated the interplay between echovirus and autophagy. We demonstrated that echovirus infection increases LC3-II expression dose-dependently, accompanied by an increased intracellular LC3 puncta level. In addition, echovirus infection induces the formation of autophagosome. These results suggest that echovirus infection induces autophagy machinery. Furthermore, phosphorylated mTOR and ULK1 were both decreased upon echovirus infection. In contrast, both levels of the vacuolar protein sorting 34 (VPS34) and Beclin-1, the downstream molecules which play essential roles in promoting the formation of autophagic vesicles, increased upon virus infection. These results imply that the signaling pathways involved in autophagosome formation were activated by echovirus infection. Moreover, induction of autophagy promotes echovirus replication and viral protein VP1 expression, while inhibition of autophagy impairs VP1 expression. Our findings suggest that autophagy can be induced by echovirus infection via regulating mTOR/ULK1 signaling pathway and exhibits a proviral function, revealing the potential role of autophagy in echovirus infection.
    Keywords:  autophagy; echovirus; enterovirus; viral replication; virus-host interaction
    DOI:  https://doi.org/10.3389/fimmu.2023.1162208
  12. Nat Aging. 2023 Jan;3(1): 34-46
    Nucleophagy delays aging and preserves germline immortality.
    Margarita-Elena Papandreou, Georgios Konstantinidis, Nektarios Tavernarakis.
      Marked alterations in nuclear ultrastructure are a universal hallmark of aging, progeroid syndromes and other age-related pathologies. Here we show that autophagy of nuclear proteins is an important determinant of fertility and aging. Impairment of nucleophagy diminishes stress resistance, germline immortality and longevity. We found that the nematode Caenorhabditis elegans nuclear envelope anchor protein, nuclear anchorage protein 1 (ANC-1) and its mammalian ortholog nesprin-2 are cleared out by autophagy and restrict nucleolar size, a biomarker of aging. We further uncovered a germline immortality assurance mechanism, which involves nucleolar degradation at the most proximal oocyte by ANC-1 and key autophagic components. Perturbation of this clearance pathway causes tumor-like structures in C. elegans, and genetic ablation of nesprin-2 causes ovarian carcinomas in mice. Thus, autophagic recycling of nuclear components is a conserved soma longevity and germline immortality mechanism that promotes youthfulness and delays aging under conditions of stress.
    DOI:  https://doi.org/10.1038/s43587-022-00327-4
  13. Curr Med Sci. 2023 Apr 28.
    From Diabetes to Diabetic Complications: Role of Autophagy.
    Lin-Hua Wang, Yang-Yang Wang, Lian Liu, Quan Gong.
      Diabetes and its complications reduce quality of life and are life-limiting. At present, diabetes treatment consists of hypoglycemic agents to control blood glucose and the use of insulin-sensitizing drugs to overcome insulin resistance. In diabetes, autophagy is impaired and thus there is poor intracellular environment homeostasis. Pancreatic β-cells and insulin target tissues are protected by enhancing autophagy. Autophagy decreases β-cell apoptosis, promotes β-cell proliferation, and alleviates insulin resistance. Autophagy in diabetes is regulated by the mammalian target of rapamycin (mTOR)/adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway and others. Autophagy enhancers can likely be used as a treatment for diabetes and its complications. This review examines the evidence linking autophagy to diabetes.
    Keywords:  autophagy; diabetes; diabetic complications; mechanism
    DOI:  https://doi.org/10.1007/s11596-023-2727-4
  14. J Cell Sci. 2023 Apr 15. pii: jcs260741. [Epub ahead of print]136(8):
    The role of crinophagy in quality control of the regulated secretory pathway.
    Győző Szenci, Tamás Csizmadia, Gábor Juhász.
      In specialized secretory cells that produce and release biologically active substances in a regulated fashion, tight control of both the quantity and quality of secretory material is of paramount importance. During crinophagy, abnormal, excess or obsolete secretory granules directly fuse with lysosomes to yield crinosomes, in which the delivered secretory material is degraded. Crinophagy maintains the proper intracellular pool of secretory granules, and it is enhanced when secretory material accumulates because of compromised secretion. Recent studies highlight that it can even degrade newly formed, nascent secretory granules that shed from the trans-Golgi network. This implies that crinophagy provides a quality control checkpoint acting at the formation of secretory vesicles, and this degradation mechanism might survey secretory granules throughout their maturation. Of note, a plethora of human disorders is associated with defective lysosomal clearance of secretory material via crinophagy or similar pathways, including macro- or micro-autophagic degradation of secretory granules (referred to here as macro- and micro-secretophagy, respectively). In our Review, we summarize key recent advances in this field and discuss potential links with disease.
    Keywords:  Autophagy; Crinophagy; Secretion
    DOI:  https://doi.org/10.1242/jcs.260741
  15. Nat Aging. 2022 Aug;2(8): 726-741
    A distinct astrocyte subtype in the aging mouse brain characterized by impaired protein homeostasis.
    Eunbeol Lee, Yeon-Joo Jung, Yu Rim Park, Seongjoon Lim, Young-Jin Choi, Se Young Lee, Chan Hyuk Kim, Ji Young Mun, Won-Suk Chung.
      The aging brain exhibits a region-specific reduction in synapse number and plasticity. Although astrocytes play central roles in regulating synapses, it is unclear how changes in astrocytes contribute to age-dependent cognitive decline and vulnerability to neurodegenerative diseases. Here, we identified a unique astrocyte subtype that exhibits dysregulated autophagy and morphology in aging hippocampus. In these autophagy-dysregulated astrocytes (APDAs), autophagosomes abnormally accumulate in swollen processes, impairing protein trafficking and secretion. We found that reduced mammalian target of rapamycin (mTOR) and proteasome activities with lysosomal dysfunction generate APDAs in an age-dependent manner. Secretion of synaptogenic molecules and astrocytic synapse elimination were significantly impaired in APDAs, suggesting that APDAs have lost their ability to control synapse number and homeostasis. Indeed, excitatory synapses and dendritic spines associated with APDAs were significantly reduced. Finally, we found that mouse brains with Alzheimer's disease showed a significantly accelerated increase in APDAs, suggesting potential roles for APDAs in age- and Alzheimer's disease-related cognitive decline and synaptic pathology.
    DOI:  https://doi.org/10.1038/s43587-022-00257-1
  16. Int J Mol Sci. 2023 Apr 21. pii: 7671. [Epub ahead of print]24(8):
    Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study.
    Bence Hajdú, Luca Csabai, Margita Márton, Marianna Holczer, Tamás Korcsmáros, Orsolya Kapuy.
      One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillatory characteristic of the AMPK-mTOR-ULK1 regulatory triangle. Here, we introduce a systems biology analysis to explain in detail the dynamical features of the essential negative and double-negative feedback loops and also the periodic repeat of autophagy induction upon cellular stress. We propose an additional regulatory molecule in the autophagy control network that delays some of AMPK's effect on the system, making the model output more consistent with experimental results. Furthermore, a network analysis on AutophagyNet was carried out to identify which proteins could be the proposed regulatory components in the system. These regulatory proteins should satisfy the following rules: (1) they are induced by AMPK; (2) they promote ULK1; (3) they down-regulate mTOR upon cellular stress. We have found 16 such regulatory components that have been experimentally proven to satisfy at least two of the given rules. Identifying such critical regulators of autophagy induction could support anti-cancer- and ageing-related therapeutic efforts.
    Keywords:  autophagy; bistable switch; feedback loops; mathematical modelling; oscillation
    DOI:  https://doi.org/10.3390/ijms24087671
  17. Autophagy. 2023 Apr 28.
    Autophagy Inhibition as a Potential Therapeutic Strategy for Breast Cancer with Mitochondrial Translation Defect Caused by CBFB-Deficiency.
    Navdeep Malik, Hualong Yan, Young-Im Kim, Gamze Ayaz, Shasha Wang, Payel Mondal, Ji Luo, Jing Huang.
      Autophagy plays a crucial role in tumor initiation and progression. However, targeting autophagy in cancer has proven challenging due to genetic or epigenetic factors that may affect the efficacy of autophagy inhibition. Therefore, identifying biomarkers is crucial for selecting patients who are likely to benefit from this treatment modality. We show that dysregulation of mitochondrial translation caused by CBFB (core-binding factor subunit beta) deficiency can sensitize the tumors to autophagy inhibition. CBFB and its binding partner HNRNPK (heterogeneous nuclear ribonucleoprotein K) interact with mRNAs encoded by the mitochondrial genome (mt-mRNAs) and maintain their translation. Specifically, CBFB enhances the binding of TUFM (Tu translation elongation factor, mitochondrial), an elongation factor for mitochondrial translation, to mt-mRNAs. CBFB deficiency, which often occurs in estrogen receptor-positive breast tumors, results in elevated autophagy and mitophagy that promote cancer cell survival. Consequently, these cells are hypersensitive to autophagy inhibition, creating a targetable vulnerability. Studies using in vivo models have shown that inhibiting autophagy selectively eliminates breast tumor cells with mitochondrial translation defects resulting from CBFB deficiency. Our results suggest that autophagy inhibition may be an effective treatment option for breast tumors carrying CBFB alterations.
    Keywords:  Autophagy; CBFB; PIK3CA; autophagy in cancer; autophagy targeting; breast cancer; mitochondria; mitochondrial translation; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2208481
  18. Nat Aging. 2022 Sep;2(9): 796-808
    Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity.
    Wenming Huang, Chun Kew, Stephanie de Alcantara Fernandes, Anna Löhrke, Lynn Han, Constantinos Demetriades, Adam Antebi.
      Changes in splicing fidelity are associated with loss of homeostasis and aging, yet only a handful of splicing factors have been shown to be causally required to promote longevity, and the underlying mechanisms and downstream targets in these paradigms remain elusive. Surprisingly, we found a hypomorphic mutation within ribonucleoprotein RNP-6/poly(U)-binding factor 60 kDa (PUF60), a spliceosome component promoting weak 3'-splice site recognition, which causes aberrant splicing, elevates stress responses and enhances longevity in Caenorhabditis elegans. Through genetic suppressor screens, we identify a gain-of-function mutation within rbm-39, an RNP-6-interacting splicing factor, which increases nuclear speckle formation, alleviates splicing defects and curtails longevity caused by rnp-6 mutation. By leveraging the splicing changes induced by RNP-6/RBM-39 activities, we uncover intron retention in egl-8/phospholipase C β4 (PLCB4) as a key splicing target prolonging life. Genetic and biochemical evidence show that neuronal RNP-6/EGL-8 downregulates mammalian target of rapamycin complex 1 (mTORC1) signaling to control organismal lifespan. In mammalian cells, PUF60 downregulation also potently and specifically inhibits mTORC1 signaling. Altogether, our results reveal that splicing fidelity modulates lifespan through mTOR signaling.
    DOI:  https://doi.org/10.1038/s43587-022-00275-z
  19. Life (Basel). 2023 Apr 06. pii: 957. [Epub ahead of print]13(4):
    Gut Microbiota in Autophagy Regulation: New Therapeutic Perspective in Neurodegeneration.
    Sarmistha Mitra, Yeasmin Akter Munni, Raju Dash, Toma Sadhu, Largess Barua, Md Ariful Islam, Dipannita Chowdhury, Debpriya Bhattacharjee, Kishor Mazumder, Il Soo Moon.
      Gut microbiota and the brain are related via a complex bidirectional interconnective network. Thus, intestinal homeostasis is a crucial factor for the brain, as it can control the environment of the central nervous system and play a significant role in disease progression. The link between neuropsychological behavior or neurodegeneration and gut dysbiosis is well established, but many involved pathways remain unknown. Accumulating studies showed that metabolites derived from gut microbiota are involved in the autophagy activation of various organs, including the brain, one of the major pathways of the protein clearance system that is essential for protein aggregate clearance. On the other hand, some metabolites are evidenced to disrupt the autophagy process, which can be a modulator of neurodegeneration. However, the detailed mechanism of autophagy regulation by gut microbiota remains elusive, and little research only focused on that. Here we tried to evaluate the crosstalk between gut microbiota metabolites and impaired autophagy of the central nervous system in neurodegeneration and the key to future research regarding gut dysbiosis and compromised autophagy in neurodegenerative diseases.
    Keywords:  autophagy; brain injuries; gut microbiota; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/life13040957
  20. Front Cell Dev Biol. 2023 ;11 1164681
    Autosis as a selective type of cell death.
    Lingge Bai, Qiong Wu, Xinyue Zhang, Yuting Zhao.
      
    Keywords:  Beclin 1; Na+/K+-ATPase; Tat-BECN1 peptide; autophagic cell death; autophagy; autosis; cardiac glycosides
    DOI:  https://doi.org/10.3389/fcell.2023.1164681
  21. PLoS Genet. 2023 Apr 25. 19(4): e1010493
    Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC.
    Rajit Narayanan Cheramangalam, Tarana Anand, Priyanka Pandey, Deepa Balasubramanian, Reshmi Varghese, Neha Singhal, Sonal Nagarkar Jaiswal, Manish Jaiswal.
      Cells under mitochondrial stress often co-opt mechanisms to maintain energy homeostasis, mitochondrial quality control and cell survival. A mechanistic understanding of such responses is crucial for further insight into mitochondrial biology and diseases. Through an unbiased genetic screen in Drosophila, we identify that mutations in lrpprc2, a homolog of the human LRPPRC gene that is linked to the French-Canadian Leigh syndrome, result in PINK1-Park activation. While the PINK1-Park pathway is well known to induce mitophagy, we show that PINK1-Park regulates mitochondrial dynamics by inducing the degradation of the mitochondrial fusion protein Mitofusin/Marf in lrpprc2 mutants. In our genetic screen, we also discover that Bendless, a K63-linked E2 conjugase, is a regulator of Marf, as loss of bendless results in increased Marf levels. We show that Bendless is required for PINK1 stability, and subsequently for PINK1-Park mediated Marf degradation under physiological conditions, and in response to mitochondrial stress as seen in lrpprc2. Additionally, we show that loss of bendless in lrpprc2 mutant eyes results in photoreceptor degeneration, indicating a neuroprotective role for Bendless-PINK1-Park mediated Marf degradation. Based on our observations, we propose that certain forms of mitochondrial stress activate Bendless-PINK1-Park to limit mitochondrial fusion, which is a cell-protective response.
    DOI:  https://doi.org/10.1371/journal.pgen.1010493
  22. Cell Stress Chaperones. 2023 Apr 24.
    Mitophagy as a mitochondrial quality control mechanism in myocardial ischemic stress: from bench to bedside.
    Tong Fu, Yanchun Ma, Yan Li, Yingwei Wang, Qi Wang, Ying Tong.
      Myocardial ischemia reduces the supply of oxygen and nutrients to cardiomyocytes, leading to an energetic crisis or cell death. Mitochondrial dysfunction is a decisive contributor to the reception, transmission, and modification of cardiac ischemic signals. Cells with damaged mitochondria exhibit impaired mitochondrial metabolism and increased vulnerability to death stimuli due to disrupted mitochondrial respiration, reactive oxygen species overproduction, mitochondrial calcium overload, and mitochondrial genomic damage. Various intracellular and extracellular stress signaling pathways converge on mitochondria, so dysfunctional mitochondria tend to convert from energetic hubs to apoptotic centers. To interrupt the stress signal transduction resulting from lethal mitochondrial damage, cells can activate mitophagy (mitochondria-specific autophagy), which selectively eliminates dysfunctional mitochondria to preserve mitochondrial quality control. Different pharmacological and non-pharmacological strategies have been designed to augment the protective properties of mitophagy and have been validated in basic animal experiments and pre-clinical human trials. In this review, we describe the process of mitophagy in cardiomyocytes under ischemic stress, along with its regulatory mechanisms and downstream effects. Then, we discuss promising therapeutic approaches to preserve mitochondrial homeostasis and protect the myocardium against ischemic damage by inducing mitophagy.
    Keywords:  Bnip3; Fundc1; Mitochondria; Mitophagy; Myocardial ischemia; Parkin
    DOI:  https://doi.org/10.1007/s12192-023-01346-9
  23. Adv Exp Med Biol. 2023 ;1408 183-199
    Bile Acids Alter the Autophagy and Mitogenesis in Skeletal Muscle Cells.
    Franco Tacchi, Josué Orozco-Aguilar, Mayalen Valero-Breton, Claudio Cabello-Verrugio.
      Muscle atrophy decreases muscle mass with the subsequent loss of muscle function. Among the mechanisms that trigger sarcopenia is mitochondrial dysfunction. Mitochondria, whose primary function is to produce ATP, are dynamic organelles that present the process of formation (mitogenesis) and elimination (mitophagy). Failure of any of these processes contributes to mitochondrial malfunction. Mitogenesis is mainly controlled by Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), a transcriptional coactivator that regulates the expression of TFAM, which participates in mitogenesis. Mitophagy is a process of selective autophagy. Autophagy corresponds to a degradative pathway of protein complexes and organelles. Liver disease caused sarcopenia and increased bile acids in the blood. We demonstrated that the treatment with cholic (CA) or deoxycholic (DCA) bile acids generates mitochondrial dysfunction and loss of biomass. This work assessed whether CA and DCA alter autophagy and mitogenesis. For this, western blot evaluated the autophagy process by determining the protein levels of the LC3II/LC3I ratio. In addition, we assessed mitogenesis using a luciferase-coupled plasmid reporter for the PGC-1α promoter and the protein levels of TFAM by western blot. Our results indicate that treatment with CA or DCA induces autophagy, represented by an increase in the LC3II/LC3I ratio. In addition, a decreased autophagic flux was observed. On the other hand, when treated with CA or DCA, a decrease in the activity of the PGC-1α promoter was observed. However, the levels of TFAM increased in myotubes incubated with CA and DCA. Our results demonstrate that CA and DCA modulate autophagy ad mitogenesis in C2C12 myotubes.
    Keywords:  Autophagy; Bile acids; Mitochondrial biogenesis; Mitophagy; Sarcopenia
    DOI:  https://doi.org/10.1007/978-3-031-26163-3_10
  24. Int J Mol Sci. 2023 Apr 14. pii: 7273. [Epub ahead of print]24(8):
    Placental Remote Control of Fetal Metabolism: Trophoblast mTOR Signaling Regulates Liver IGFBP-1 Phosphorylation and IGF-1 Bioavailability.
    Fredrick J Rosario, Anand Chopra, Kyle Biggar, Theresa L Powell, Madhulika B Gupta, Thomas Jansson.
      The mechanisms mediating the restricted growth in intrauterine growth restriction (IUGR) remain to be fully established. Mechanistic target of rapamycin (mTOR) signaling functions as a placental nutrient sensor, indirectly influencing fetal growth by regulating placental function. Increased secretion and the phosphorylation of fetal liver IGFBP-1 are known to markedly decrease the bioavailability of IGF-1, a major fetal growth factor. We hypothesized that an inhibition of trophoblast mTOR increases liver IGFBP-1 secretion and phosphorylation. We collected conditioned media (CM) from cultured primary human trophoblast (PHT) cells with a silenced RAPTOR (specific inhibition of mTOR Complex 1), RICTOR (inhibition of mTOR Complex 2), or DEPTOR (activates both mTOR Complexes). Subsequently, HepG2 cells, a well-established model for human fetal hepatocytes, were cultured in CM from PHT cells, and IGFBP-1 secretion and phosphorylation were determined. CM from PHT cells with either mTORC1 or mTORC2 inhibition caused the marked hyperphosphorylation of IGFBP-1 in HepG2 cells as determined by 2D-immunoblotting while Parallel Reaction Monitoring-Mass Spectrometry (PRM-MS) identified increased dually phosphorylated Ser169 + Ser174. Furthermore, using the same samples, PRM-MS identified multiple CK2 peptides coimmunoprecipitated with IGFBP-1 and greater CK2 autophosphorylation, indicating the activation of CK2, a key enzyme mediating IGFBP-1 phosphorylation. Increased IGFBP-1 phosphorylation inhibited IGF-1 function, as determined by the reduced IGF-1R autophosphorylation. Conversely, CM from PHT cells with mTOR activation decreased IGFBP-1 phosphorylation. CM from non-trophoblast cells with mTORC1 or mTORC2 inhibition had no effect on HepG2 IGFBP-1 phosphorylation. Placental mTOR signaling may regulate fetal growth by the remote control of fetal liver IGFBP-1 phosphorylation.
    Keywords:  casein kinase CK2; fetal growth retardation; human; pregnancy
    DOI:  https://doi.org/10.3390/ijms24087273
  25. Sci Signal. 2023 04 25. 16(782): eadi3398
    Metabolically fitter with fibronectin.
    Wei Wong.
      Activation of hepatic autophagy by skeletal muscle-secreted fibronectin underlies the metabolic benefits of exercise.
    DOI:  https://doi.org/10.1126/scisignal.adi3398
  26. Life (Basel). 2023 Apr 08. pii: 970. [Epub ahead of print]13(4):
    The Role of Mitochondrial Dysfunction in Alzheimer's: Molecular Defects and Mitophagy-Enhancing Approaches.
    Reem M Farsi.
      Alzheimer's disease (AD), a progressive and chronic neurodegenerative syndrome, is categorized by cognitive and memory damage caused by the aggregations of abnormal proteins, specifically including Tau proteins and β-amyloid in brain tissue. Moreover, mitochondrial dysfunctions are the principal causes of AD, which is associated with mitophagy impairment. Investigations exploring pharmacological therapies alongside AD have explicitly concentrated on molecules accomplished in preventing/abolishing the gatherings of the abovementioned proteins and mitochondria damages. Mitophagy is the removal of dead mitochondria by the autophagy process. Damages in mitophagy, the manner of diversified mitochondrial degeneracy by autophagy resulting in an ongoing aggregation of malfunctioning mitochondria, were also suggested to support AD. Recently, plentiful reports have suggested a link between defective mitophagy and AD. This treaty highlights updated outlines of modern innovations and developments on mitophagy machinery dysfunctions in AD brains. Moreover, therapeutic and nanotherapeutic strategies targeting mitochondrial dysfunction are also presented in this review. Based on the significant role of diminished mitophagy in AD, we suggest that the application of different therapeutic approaches aimed at stimulating mitophagy in AD would be beneficial for targeting or reducing the mitochondrial dysfunction induced by AD.
    Keywords:  Alzheimer’s disease; mitochondrial dysfunction; mitophagy; therapeutic and nanotherapeutic approaches
    DOI:  https://doi.org/10.3390/life13040970
  27. Contact (Thousand Oaks). 2022 Jan-Dec;5:5
    Autophagy of the ER requires actin assembly driven by the interaction of ER with endocytic pits.
    Peter Novick, Dongmei Liu, Susan Ferro-Novick.
      Autophagy of the cortical ER in budding yeast was unexpectedly found to require End3, a component of the endocytic machinery that promotes the assembly of actin at endocytic pits on the plasma membrane. The cortical ER transiently interacts with invaginating endocytic pits through a linkage consisting of VAP proteins, oxysterol binding proteins and type I myosins. These proteins are required for actin assembly and for autophagy of the ER. Assembly of actin at these contact sites may direct the movement of ER away from the cortex towards sites of autophagosome assembly.
    Keywords:  VAP; actin assembly; autophagy; autophagy receptor; endocytosis; endoplasmic reticulum
    DOI:  https://doi.org/10.1177/25152564221093215
  28. Biol Direct. 2023 Apr 24. 18(1): 20
    A myeloid leukemia factor homolog is involved in tolerance to stresses and stress-induced protein metabolism in Giardia lamblia.
    Jui-Hsuan Wu, Jen-Chi Lee, Chun-Che Ho, Pei-Wei Chiu, Chin-Hung Sun.
       BACKGROUND: The eukaryotic membrane vesicles contain specific sets of proteins that determine vesicle function and shuttle with specific destination. Giardia lamblia contains unknown cytosolic vesicles that are related to the identification of a homolog of human myeloid leukemia factor (MLF) named MLF vesicles (MLFVs). Previous studies suggest that MLF also colocalized with two autophagy machineries, FYVE and ATG8-like protein, and that MLFVs are stress-induced compartments for substrates of the proteasome or autophagy in response to rapamycin, MG132, and chloroquine treatment. A mutant protein of cyclin-dependent kinase 2, CDK2m3, was used to understand whether the aberrant proteins are targeted to degradative compratments. Interestingly, MLF was upregulated by CDK2m3 and they both colocalized within the same vesicles. Autophagy is a self-digestion process that is activated to remove damaged proteins for preventing cell death in response to various stresses. Because of the absence of some autophagy machineries, the mechanism of autophagy is unclear in G. lamblia.
    RESULTS: In this study, we tested the six autophagosome and stress inducers in mammalian cells, including MG132, rapamycin, chloroquine, nocodazole, DTT, and G418, and found that their treatment increased reactive oxygen species production and vesicle number and level of MLF, FYVE, and ATG8-like protein in G. lamblia. Five stress inducers also increased the CDK2m3 protein levels and vesicles. Using stress inducers and knockdown system for MLF, we identified that stress induction of CDK2m3 was positively regulated by MLF. An autophagosome-reducing agent, 3-methyl adenine, can reduce MLF and CDK2m3 vesicles and proteins. In addition, knockdown of MLF with CRISPR/Cas9 system reduced cell survival upon treatment with stress inducers. Our newly developed complementation system for CRISPR/Cas9 indicated that complementation of MLF restored cell survival in response to stress inducers. Furthermore, human MLF2, like Giardia MLF, can increase cyst wall protein expression and cyst formation in G. lamblia, and it can colocalize with MLFVs and interact with MLF.
    CONCLUSIONS: Our results suggest that MLF family proteins are functionally conserved in evolution. Our results also suggest an important role of MLF in survival in stress conditions and that MLFVs share similar stress-induced characteristics with autophagy compartments.
    Keywords:  ATG8-like; CDK2 mutant; Cyst; DTT; Differentiation; FYVE; G418; Giardia; MLF; Nocodazole
    DOI:  https://doi.org/10.1186/s13062-023-00378-6
  29. Nucleic Acids Res. 2023 Apr 24. pii: gkad299. [Epub ahead of print]
    Not4-dependent targeting of MMF1 mRNA to mitochondria limits its expression via ribosome pausing, Egd1 ubiquitination, Caf130, no-go-decay and autophagy.
    Siyu Chen, George Allen, Olesya O Panasenko, Martine A Collart.
      The Ccr4-Not complex is a conserved multi protein complex with diverse roles in the mRNA life cycle. Recently we determined that the Not1 and Not4 subunits of Ccr4-Not inversely regulate mRNA solubility and thereby impact dynamics of co-translation events. One mRNA whose solubility is limited by Not4 is MMF1 encoding a mitochondrial matrix protein. In this work we uncover a mechanism that limits MMF1 overexpression and depends upon its co-translational targeting to the mitochondria. We have named this mechanism Mito-ENCay. This mechanism relies on Not4 promoting ribosome pausing during MMF1 translation, and hence the co-translational docking of the MMF1 mRNA to mitochondria via the mitochondrial targeting sequence of the Mmf1 nascent chain, the Egd1 chaperone, the Om14 mitochondrial outer membrane protein and the co-translational import machinery. Besides co-translational Mitochondrial targeting, Mito-ENCay depends upon Egd1 ubiquitination by Not4, the Caf130 subunit of the Ccr4-Not complex, the mitochondrial outer membrane protein Cis1, autophagy and no-go-decay.
    DOI:  https://doi.org/10.1093/nar/gkad299
  30. N Am Spine Soc J. 2023 Jun;14 100210
    Intervertebral disc cell fate during aging and degeneration: apoptosis, senescence, and autophagy.
    Takashi Yurube, Yoshiki Takeoka, Yutaro Kanda, Ryosuke Kuroda, Kenichiro Kakutani.
       Background: Degenerative disc disease, a major cause of low back pain and associated neurological symptoms, is a global health problem with the high morbidity, workforce loss, and socioeconomic burden. The present surgical strategy of disc resection and/or spinal fusion results in the functional loss of load, shock absorption, and movement; therefore, the development of new biological therapies is demanded. This achievement requires the understanding of intervertebral disc cell fate during aging and degeneration.
    Methods: Literature review was performed to clarify the current concepts and future perspectives of disc cell fate, focused on apoptosis, senescence, and autophagy.
    Results: The intervertebral disc has a complex structure with the nucleus pulposus (NP), annulus fibrosus (AF), and cartilage endplates. While the AF arises from the mesenchyme, the NP originates from the notochord. Human disc NP notochordal phenotype disappears in adolescence, accompanied with cell death induction and chondrocyte proliferation. Discs morphologically and biochemically degenerate from early childhood as well, thereby suggesting a possible involvement of cell fate including age-related phenotypic changes in the disease process. As the disc is the largest avascular organ in the body, nutrient deprivation is a suspected contributor to degeneration. During aging and degeneration, disc cells undergo senescence, irreversible growth arrest, producing proinflammatory cytokines and matrix-degradative enzymes. Excessive stress ultimately leads to programmed cell death including apoptosis, necroptosis, pyroptosis, and ferroptosis. Autophagy, the intracellular degradation and recycling system, plays a role in maintaining cell homeostasis. While the incidence of apoptosis and senescence increases with age and degeneration severity, autophagy can be activated earlier, in response to limited nutrition and inflammation, but impaired in aged, degenerated discs. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is a signal integrator to determine disc cell fate.
    Conclusions: Cell fate and microenvironmental regulation by modulating PI3K/Akt/mTOR signaling is a potential biological treatment for degenerative disc disease.
    Keywords:  Aging; Apoptosis; Autophagy; Degeneration; Intervertebral disc; Mammalian target of rapamycin (mTOR); Phenotype; Senescence; Spine
    DOI:  https://doi.org/10.1016/j.xnsj.2023.100210
  31. Acta Neuropathol. 2023 Apr 28.
    Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.
    Fabia Filipello, Shih-Feng You, Farzaneh S Mirfakhar, Sidhartha Mahali, Bryan Bollman, Mariana Acquarone, Olena Korvatska, Jacob A Marsh, Anirudh Sivaraman, Rita Martinez, Claudia Cantoni, Luca De Feo, Laura Ghezzi, Miguel A Minaya, Arun Renganathan, Anil G Cashikar, Jun-Ichi Satoh, Wandy Beatty, Abhirami K Iyer, Marina Cella, Wendy H Raskind, Laura Piccio, Celeste M Karch.
      TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
    Keywords:  Induced pluripotent stem cells; Lysosome; Microglia; Nasu-Hakola disease; TREM2; Transcriptomics
    DOI:  https://doi.org/10.1007/s00401-023-02568-y
  32. bioRxiv. 2023 Apr 12. pii: 2023.04.11.536492. [Epub ahead of print]
    Astrovirus replication is dependent on induction of double membrane vesicles through a PI3K-dependent, LC3-independent pathway.
    Theresa Bub, Virginia Hargest, Shaoyuan Tan, Maria Smith, Ana Vazquez-Pagan, Tim Flerlage, Pamela H Brigleb, Victoria Meliopoulos, Brett Lindenbach, Valerie Cortez, Jeremy Chase Crawford, Stacey Schultz-Cherry.
      Human astrovirus is a positive sense, single stranded RNA virus. Astrovirus infection causes gastrointestinal symptoms and can lead to encephalitis in immunocompromised patients. Positive strand RNA viruses typically utilize host intracellular membranes to form replication organelles, which are potential antiviral targets. Many of these replication organelles are double membrane vesicles (DMVs). Here we show that astrovirus infection leads to an increase in DMV formation, and this process is replication-dependent. Our data suggest that astrovirus infection induces rearrangement of endoplasmic reticulum fragments, which may become the origin for DMV formation. Transcriptional data suggested that formation of DMVs during astrovirus infection requires some early components of the autophagy machinery. Results indicate that the upstream class III phosphatidylinositol 3-kinase (PI3K) complex, but not LC3 conjugation machinery, is utilized in DMV formation. Inhibition of the PI3K complex leads to significant reduction in viral replication and release from cells. Elucidating the role of autophagy machinery in DMV formation during astrovirus infection reveals a potential target for therapeutic intervention for immunocompromised patients.
    Importance: These studies provide critical new evidence that astrovirus replication requires formation of double membrane vesicles, which utilize class III PI3K, but not LC3 conjugation autophagy machinery for biogenesis. These results are consistent with replication mechanisms for other positive sense RNA viruses. This suggests that targeting PI3K could be a promising therapeutic option for not only astrovirus, but other positive sense RNA virus infections.
    DOI:  https://doi.org/10.1101/2023.04.11.536492
  33. Front Immunol. 2023 ;14 1156086
    New insights into autophagy in inflammatory subtypes of asthma.
    Hongna Dong, Wei Yang, Wei Li, Simin Zhu, Ling Zhu, Peng Gao, Yuqiu Hao.
      Asthma is a heterogeneous airway disease characterized by airway inflammation and hyperresponsiveness. Autophagy is a self-degrading process that helps maintain cellular homeostasis. Dysregulation of autophagy is involved in the pathogenesis of many diseases. In the context of asthma, autophagy has been shown to be associated with inflammation, airway remodeling, and responsiveness to drug therapy. In-depth characterization of the role of autophagy in asthma can enhance the understanding of the pathogenesis, and provide a theoretical basis for the development of new biomarkers and targeted therapy for asthma. In this article, we focus on the relationship of autophagy and asthma, and discuss its implications for asthma pathogenesis and treatment.
    Keywords:  asthma; autophagy; biomarker; inflammation; therapeutic target
    DOI:  https://doi.org/10.3389/fimmu.2023.1156086
  34. FASEB J. 2023 May;37(5): e22933
    FURIN suppresses the progression of atherosclerosis by promoting macrophage autophagy.
    Hongping Chen, Lihui Zhang, Shaohua Mi, Hua Wang, Chunxiao Wang, Wenjuan Jia, Lei Gong, Haibin Dong, Bowen Xu, Yanyan Jing, Peipei Ge, Zhigang Pei, Lin Zhong, Jun Yang.
      FURIN, a member of the mammalian proprotein convertases (PCs) family, can promote the proteolytic maturation of proproteins. It has been shown that FURIN plays an important role in the progression of atherosclerosis (AS). Current evidence indicates that autophagy widely participates in atherogenesis. This study aimed to explore whether FURIN could affect atherogenesis via autophagy. The effect of FURIN on autophagy was studied using aortic tissues from aortic dissection patients who had BENTALL surgery, as well as macrophages and ApoE-/- mice. In atherosclerotic plaques of aortic tissues from patients, FURIN expression and autophagy were elevated. In macrophages, FURIN-shRNA and FURIN-overexpression lentivirus were used to intervene in FURIN expression. The results showed that FURIN overexpression accelerated LC3 formation in macrophages during the autophagosome formation phase. Furthermore, FURIN-induced autophagy resulted in lower lipid droplet concentrations in macrophages. The western blot revealed that FURIN regulated autophagy via the AMPK/mTOR/ULK1/PI3KIII signaling pathway. In vivo, FURIN overexpression resulted in increased macrophage LC3 formation in ApoE-/- mice atherosclerotic plaques, confirming that FURIN could inhibit the progression of AS by promoting macrophage autophagy. The present study demonstrated that FURIN suppressed the progression of AS by promoting macrophage autophagy via the AMPK/mTOR/ULK1/PI3KIII signaling pathway, which attenuated atherosclerotic lesion formation. Based on this data, current findings add to our understanding of the complexity of AS.
    Keywords:  FURIN; atherosclerosis; autophagy; macrophage
    DOI:  https://doi.org/10.1096/fj.202201762RR
  35. Free Radic Biol Med. 2023 Apr 26. pii: S0891-5849(23)00379-9. [Epub ahead of print]
    Caveolin-1 depletion attenuates hepatic fibrosis via promoting SQSTM1-mediated PFKL degradation in HSCs.
    Yan Zhang, Yijie Zhang, Tingting Chen, Ying Lin, Jiacheng Gong, Qihan Xu, Jun Wang, Jierui Li, Ying Meng, Yang Li, Xu Li.
      The key glycolytic enzyme phosphofructokinase (PFK) is responsible for maintaining glycolytic stability and an important energy source for activating hepatic stellate cells (HSCs). However, its regulation in activated HSCs remains unclear. Caveolin-1 (Cav1), a major constituent of caveolae, has emerged as a key target for triggering glycolysis. However, the relationship between Cav1 and glycolysis during HSC activation is not well established. In this study, Cav1 was upregulated in mouse and human fibrotic liver tissues. We concluded that HSC-specific Cav1 knockdown markedly alleviates liver injury and fibrosis. Mechanistically, Cav1 was elevated during primary mouse HSC activation, competing with SQSTM1 for the regulatory subunit of PFK liver type and inhibiting the SQSTM1-mediated autophagy-independent lysosomal degradation pathway to sustain HSC activation. We also identified the heptapeptide alamandine as a promising therapeutic agent that downregulates Cav1 protein levels via proteasomal degradation and may impair glycolysis. Our study provides evidence of the crucial role and mechanism of Cav1 in the glucose metabolic network in HSCs and highlights Cav1 as a critical therapeutic target for the treatment of liver fibrosis.
    Keywords:  Caveolin-1; HSC; Lysosomal pathway; PFKL
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.04.009
  36. Ecotoxicol Environ Saf. 2023 Apr 25. pii: S0147-6513(23)00451-7. [Epub ahead of print]257 114947
    Multi-locus deletion mutation induced by silver nanoparticles: Role of lysosomal-autophagy dysfunction.
    Bo Si, Xue Wang, Yun Liu, Juan Wang, Yemian Zhou, Yaguang Nie, An Xu.
      Due to the rapid production growth and a wide range of applications, safety concerns are being raised about the genotoxic properties of silver nanoparticles (AgNPs). In this research, we found AgNPs induced a size-dependent genotoxicity via lysosomal-autophagy dysfunction in human-hamster hybrid (AL) cells. Compared with 25 nm and 75 nm particles, 5 nm AgNPs could accentuate the genotoxic responses, including DNA double-strand breaks (DSBs) and multi-locus deletion mutation, which could be significantly enhanced by autophagy inhibitors 3-methyl adenine (3-MA), Bafilomycin A1 (BFA), and cathepsin inhibitors, respectively. The autophagy dysfunction was closely related to the accumulation of 5 nm AgNPs in the lysosomes and the interruption of lysosome-autophagosome fusion. With lysosomal protective agent 3-O-Methylsphingomyelin (3-O-M) and endocytosis inhibitor wortmannin, the reactivation of lysosomal function and the recovery of autophagy significantly attenuated AgNP-induced genotoxicity. Our data provide clear evidence to illustrate the role of subcellular targets in the genotoxicity of AgNPs in mammalian cells, which laid the basis for better understanding the health risk of AgNPs and their related products.
    Keywords:  Autophagy dysfunction; Genotoxicity; Lysosomal impairment; Multi-locus deletion mutation; Silver nanoparticles (AgNPs)
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.114947
  37. J Cell Biol. 2023 Jul 03. pii: e202211039. [Epub ahead of print]222(7):
    Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics.
    Rahel Dabrowski, Susanna Tulli, Martin Graef.
      During autophagy, rapid membrane assembly expands small phagophores into large double-membrane autophagosomes. Theoretical modeling predicts that the majority of autophagosomal phospholipids are derived from highly efficient non-vesicular phospholipid transfer (PLT) across phagophore-ER contacts (PERCS). Currently, the phagophore-ER tether Atg2 is the only PLT protein known to drive phagophore expansion in vivo. Here, our quantitative live-cell imaging analysis reveals a poor correlation between the duration and size of forming autophagosomes and the number of Atg2 molecules at PERCS of starving yeast cells. Strikingly, we find that Atg2-mediated PLT is non-rate limiting for autophagosome biogenesis because membrane tether and the PLT protein Vps13 localizes to the rim and promotes the expansion of phagophores in parallel with Atg2. In the absence of Vps13, the number of Atg2 molecules at PERCS determines the duration and size of forming autophagosomes with an apparent in vivo transfer rate of ∼200 phospholipids per Atg2 molecule and second. We propose that conserved PLT proteins cooperate in channeling phospholipids across organelle contact sites for non-rate-limiting membrane assembly during autophagosome biogenesis.
    DOI:  https://doi.org/10.1083/jcb.202211039
  38. Redox Biol. 2023 Apr 17. pii: S2213-2317(23)00102-7. [Epub ahead of print]62 102701
    The establishment of mitotic errors-driven senescence depends on autophagy.
    Andreas Goutas, Zozo Outskouni, Ioanna Papathanasiou, Aphrodite Georgakopoulou, Georgios E Karpetas, Efstathios S Gonos, Varvara Trachana.
      We and others have reported that senescence onset is accompanied by genomic instability that is evident by several defects, such as aneuploidy or erroneous mitosis features. Here, we report that these defects also appear in young cells upon oxidative insult. We provide evidence that these errors could be the consequence of oxidative stress (OS)- either exogenous or senescence-associated - overriding the spindle assembly checkpoint (SAC). Young cells treated with Η2Ο2 as well as older cells fail to maintain mitotic arrest in the presence of spindle poisons and a significant higher percentage of them have supernumerary centrosomes and centrosome related anomalous characteristics. We also report that aging is escorted by expression modifications of SAC components, and especially of Bub1b/BubR1. Bub1b/BubR1 has been previously reported to decrease naturally upon aging. Here, we show that there is an initial increase in Bub1b/BubR1 levels, feasibly as part of the cells' response against OS-driven genomic instability, that is followed by its autophagy dependent degradation. This provides an explanation that was missing regarding the molecular entity responsible for the downregulation of Bub1b/BubR1 upon aging, especially since it is well established, by us and others, that the proteasome function decays as cells age. These results, not only serve the previously reported notion of a shift from proteasome to autophagy-dependent degradation upon aging, but also provide a mechanistic insight for mitotic errors-driven senescence. We believe that our conclusions deepen our understanding regarding the homeostatic function of autophagy that serves the establishment of senescence as a barrier against cellular transformation.
    Keywords:  Autophagy; Bub1b/BubR1; Oxidative stress; Senescence; Spindle assembly checkpoint
    DOI:  https://doi.org/10.1016/j.redox.2023.102701
  39. Nat Aging. 2023 Feb;3(2): 213-228
    Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy.
    Carine Moigneu, Soumia Abdellaoui, Mariana Ramos-Brossier, Bianca Pfaffenseller, Bianca Wollenhaupt-Aguiar, Taiane de Azevedo Cardoso, Aurélie Chiche, Nicolas Kuperwasser, Ricardo Azevedo da Silva, Fernanda Pedrotti Moreira, Han Li, Franck Oury, Flávio Kapczinski, Pierre-Marie Lledo, Lida Katsimpardi.
      Cognitive decline and mood disorders increase in frequency with age. Many efforts are focused on the identification of molecules and pathways to treat these conditions. Here, we demonstrate that systemic administration of growth differentiation factor 11 (GDF11) in aged mice improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. Mechanistically, GDF11 acts directly on hippocampal neurons to enhance neuronal activity via stimulation of autophagy. Transcriptomic and biochemical analyses of these neurons reveal that GDF11 reduces the activity of mammalian target of rapamycin (mTOR), a master regulator of autophagy. Using a murine model of corticosterone-induced depression-like phenotype, we also show that GDF11 attenuates the depressive-like behavior of young mice. Analysis of sera from young adults with major depressive disorder (MDD) reveals reduced GDF11 levels. These findings identify mechanistic pathways related to GDF11 action in the brain and uncover an unknown role for GDF11 as an antidepressant candidate and biomarker.
    DOI:  https://doi.org/10.1038/s43587-022-00352-3
  40. Int J Mol Sci. 2023 Apr 17. pii: 7405. [Epub ahead of print]24(8):
    Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics.
    Rodrigo Paulino, Clévio Nóbrega.
      Machado-Joseph disease (MJD) or spinocerebellar ataxia 3 (SCA3) is a rare, inherited, monogenic, neurodegenerative disease, and the most common SCA worldwide. MJD/SCA3 causative mutation is an abnormal expansion of the triplet CAG at exon 10 within the ATXN3 gene. The gene encodes for ataxin-3, which is a deubiquitinating protein that is also involved in transcriptional regulation. In normal conditions, the ataxin-3 protein polyglutamine stretch has between 13 and 49 glutamines. However, in MJD/SCA3 patients, the size of the stretch increases from 55 to 87, contributing to abnormal protein conformation, insolubility, and aggregation. The formation of aggregates, which is a hallmark of MJD/SCA3, compromises different cell pathways, leading to an impairment of cell clearance mechanisms, such as autophagy. MJD/SCA3 patients display several signals and symptoms in which the most prominent is ataxia. Neuropathologically, the regions most affected are the cerebellum and the pons. Currently, there are no disease-modifying therapies, and patients rely only on supportive and symptomatic treatments. Due to these facts, there is a huge research effort to develop therapeutic strategies for this incurable disease. This review aims to bring together current state-of-the-art strategies regarding the autophagy pathway in MJD/SCA3, focusing on evidence for its impairment in the disease context and, importantly, its targeting for the development of pharmacological and gene-based therapies.
    Keywords:  Machado–Joseph disease; ataxin-3; autophagy; neurodegeneration; spinocerebellar ataxia type 3
    DOI:  https://doi.org/10.3390/ijms24087405
  41. Biochem Biophys Res Commun. 2023 Apr 21. pii: S0006-291X(23)00487-4. [Epub ahead of print]663 1-7
    Actin cytoskeletal reorganization is involved in hyperosmotic stress-induced autophagy in tubular epithelial cells.
    Takashi Miyano, Atsushi Suzuki, Naoya Sakamoto.
      Tubular epithelial cells are routinely exposed to severe changes in osmolarity. Although the autophagic activity of cells is an indispensable process to maintain cellular homeostasis and respond to stressors, the effect of hyperosmotic stress on autophagic activity in tubular epithelial cells remains unknown. The aim of this study was to determine the effect of hyperosmotic stress on autophagy in rat kidney tubular epithelial cells focusing on the role of actin and microtubule cytoskeletons. Normal rat kidney (NRK)-52E cells exposed to mannitol-induced hyperosmotic stress. As a result, NRK-52E cells showed elevated protein levels of the autophagosome marker LC3-II, indicating enhancement of the autophagic flux. Hyperosmotic stress also transiently decreased cell volume and caused the reorganization of actin and microtubule cytoskeletal structures in NRK-52E cells. The inhibition of the actin cytoskeleton reorganization by cytochalasin D impaired the increase in the levels of LC3-II; however, disassembly of the microtubules following treatment with nocodazole did not affect the increase. These results indicate that hyperosmotic stress can induce autophagy mediated by the reorganization of the actin cytoskeleton in tubular epithelial cells.
    Keywords:  Actin cytoskeleton; Autophagy; Hyperosmotic stress; Microtubule; Tubular epithelial cell
    DOI:  https://doi.org/10.1016/j.bbrc.2023.04.070
  42. Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2211501120
    Structures of Vac8-containing protein complexes reveal the underlying mechanism by which Vac8 regulates multiple cellular processes.
    Hyejin Kim, Jihyeon Park, Hyunwoo Kim, Naho Ko, Jumi Park, Eunhong Jang, So Young Yoon, Joyce Anne R Diaz, Changwook Lee, Youngsoo Jun.
      Vac8, a yeast vacuolar protein with armadillo repeats, mediates various cellular processes by changing its binding partners; however, the mechanism by which Vac8 differentially regulates these processes remains poorly understood. Vac8 interacts with Nvj1 to form the nuclear-vacuole junction (NVJ) and with Atg13 to mediate cytoplasm-to-vacuole targeting (Cvt), a selective autophagy-like pathway that delivers cytoplasmic aminopeptidase I directly to the vacuole. In addition, Vac8 associates with Myo2, a yeast class V myosin, through its interaction with Vac17 for vacuolar inheritance from the mother cell to the emerging daughter cell during cell divisions. Here, we determined the X-ray crystal structure of the Vac8-Vac17 complex and found that its interaction interfaces are bipartite, unlike those of the Vac8-Nvj1 and Vac8-Atg13 complexes. When the key amino acids present in the interface between Vac8 and Vac17 were mutated, vacuole inheritance was severely impaired in vivo. Furthermore, binding of Vac17 to Vac8 prevented dimerization of Vac8, which is required for its interactions with Nvj1 and Atg13, by clamping the H1 helix to the ARM1 domain of Vac8 and thereby preventing exposure of the binding interface for Vac8 dimerization. Consistently, the binding affinity of Vac17-bound Vac8 for Nvj1 or Atg13 was markedly lower than that of free Vac8. Likewise, free Vac17 had no affinity for the Vac8-Nvj1 and Vac8-Atg13 complexes. These results provide insights into how vacuole inheritance and other Vac8-mediated processes, such as NVJ formation and Cvt, occur independently of one another.
    Keywords:  Saccharomyces cerevisiae; Vac17; Vac8; armadillo repeats; organelle inheritance
    DOI:  https://doi.org/10.1073/pnas.2211501120
  43. J Inflamm Res. 2023 ;16 1671-1691
    Research Progress on Autophagy Regulation by Active Ingredients of Traditional Chinese Medicine in the Treatment of Acute Lung Injury.
    Jin-Yan Dong, Hong-Lin Yin, Hao Hao, Yang Liu.
      Autophagy is a highly conserved process that maintains cell stability in eukaryotes, participates in the turnover of intracellular substances to maintain cell function, helps to resist pathogen invasion, and improves cell tolerance to environmental changes. Autophagy has been observed in many diseases, and the symptoms of these diseases are significantly improved by regulating autophagy. Autophagy is also involved in the development of lung diseases. Studies have shown that autophagy may play a beneficial or harmful role in acute lung injury (ALI), and ALI has been treated with traditional Chinese medicine designed to promote or inhibit autophagy. In this paper, the molecular mechanism and common pathways regulating autophagy and the relationship between autophagy and ALI are introduced, and the active ingredients of traditional Chinese medicine that improve ALI symptoms by regulating autophagy are summarized.
    Keywords:  apoptosis; autophagy; inflammation; oxidative stress
    DOI:  https://doi.org/10.2147/JIR.S398203
  44. Cancer Cell Int. 2023 Apr 25. 23(1): 80
    MicroRNAs as the critical regulators of autophagy-mediated cisplatin response in tumor cells.
    Faezeh Tolue Ghasaban, Amirhosein Maharati, Iman Akhlaghipour, Meysam Moghbeli.
      Chemotherapy is one of the most common therapeutic methods in advanced and metastatic tumors. Cisplatin (CDDP) is considered as one of the main first-line chemotherapy drugs in solid tumors. However, there is a high rate of CDDP resistance in cancer patients. Multi-drug resistance (MDR) as one of the main therapeutic challenges in cancer patients is associated with various cellular processes such as drug efflux, DNA repair, and autophagy. Autophagy is a cellular mechanism that protects the tumor cells toward the chemotherapeutic drugs. Therefore, autophagy regulatory factors can increase or decrease the chemotherapy response in tumor cells. MicroRNAs (miRNAs) have a pivotal role in regulation of autophagy in normal and tumor cells. Therefore, in the present review, we discussed the role of miRNAs in CDDP response through the regulation of autophagy. It has been reported that miRNAs mainly increased the CDDP sensitivity in tumor cells by inhibition of autophagy. PI3K/AKT signaling pathway and autophagy-related genes (ATGs) were the main targets of miRNAs in the regulation of autophagy-mediated CDDP response in tumor cells. This review can be an effective step to introduce the miRNAs as efficient therapeutic options to increase autophagy-mediated CDDP sensitivity in tumor cells.
    Keywords:  Autophagy; Cancer; Chemotherapy; Cisplatin; Drug resistance; microRNA
    DOI:  https://doi.org/10.1186/s12935-023-02925-7
  45. Biomed Pharmacother. 2023 Apr 24. pii: S0753-3322(23)00551-6. [Epub ahead of print]163 114762
    The "Self-eating" of cancer-associated fibroblast: A potential target for cancer.
    Yan Chen, Xiaozhen Zhang, Hanshen Yang, Tingbo Liang, Xueli Bai.
      Autophagy helps maintain energy homeostasis and protect cells from stress effects by selectively removing misfolded/polyubiquitylated proteins, lipids, and damaged mitochondria. Cancer-associated fibroblasts (CAFs) are cellular components of tumor microenvironment (TME). Autophagy in CAFs inhibits tumor development in the early stages; however, it has a tumor-promoting effect in advanced stages. In this review, we aimed to summarize the modulators responsible for the induction of autophagy in CAFs, such as hypoxia, nutrient deprivation, mitochondrial stress, and endoplasmic reticulum stress. In addition, we aimed to present autophagy-related signaling pathways in CAFs, and role of autophagy in CAF activation, tumor progression, tumor immune microenvironment. Autophagy in CAFs may be an emerging target for tumor therapy. In summary, autophagy in CAFs is regulated by a variety of modulators and can reshape tumor immune microenvironment, affecting tumor progression and treatment.
    Keywords:  Autophagy; Cancer; Cancer therapy; Cancer-associated fibroblast; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2023.114762
  46. Pharmaceuticals (Basel). 2023 Apr 17. pii: 601. [Epub ahead of print]16(4):
    Advances in Drug Discovery Targeting Lysosomal Membrane Proteins.
    Hongna Wang, Yidong Zhu, Huiyan Liu, Tianxiang Liang, Yongjie Wei.
      Lysosomes are essential organelles of eukaryotic cells and are responsible for various cellular functions, including endocytic degradation, extracellular secretion, and signal transduction. There are dozens of proteins localized to the lysosomal membrane that control the transport of ions and substances across the membrane and are integral to lysosomal function. Mutations or aberrant expression of these proteins trigger a variety of disorders, making them attractive targets for drug development for lysosomal disorder-related diseases. However, breakthroughs in R&D still await a deeper understanding of the underlying mechanisms and processes of how abnormalities in these membrane proteins induce related diseases. In this article, we summarize the current progress, challenges, and prospects for developing therapeutics targeting lysosomal membrane proteins for the treatment of lysosomal-associated diseases.
    Keywords:  disease; drug; lysosomal membrane protein; lysosome; target; therapy
    DOI:  https://doi.org/10.3390/ph16040601
  47. Cell Rep. 2023 Apr 24. pii: S2211-1247(23)00445-X. [Epub ahead of print]42(5): 112434
    Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways.
    Tatsuki Yasuda, Takaya Ishihara, Ayaka Ichimura, Naotada Ishihara.
      Skeletal muscle is highly developed after birth, consisting of glycolytic fast-twitch and oxidative slow-twitch fibers; however, the mechanisms of fiber-type-specific differentiation are poorly understood. Here, we found an unexpected role of mitochondrial fission in the differentiation of fast-twitch oxidative fibers. Depletion of the mitochondrial fission factor dynamin-related protein 1 (Drp1) in mouse skeletal muscle and cultured myotubes results in specific reduction of fast-twitch muscle fibers independent of respiratory function. Altered mitochondrial fission causes activation of the Akt/mammalian target of rapamycin (mTOR) pathway via mitochondrial accumulation of mTOR complex 2 (mTORC2), and rapamycin administration rescues the reduction of fast-twitch fibers in vivo and in vitro. Under Akt/mTOR activation, the mitochondria-related cytokine growth differentiation factor 15 is upregulated, which represses fast-twitch fiber differentiation. Our findings reveal a crucial role of mitochondrial dynamics in the activation of mTORC2 on mitochondria, resulting in the differentiation of muscle fibers.
    Keywords:  Akt; CP: Metabolism; Drp1; GDF-15; mTOR; mitochondria; mitochondrial dynamics; muscle atrophy; muscle differentiation
    DOI:  https://doi.org/10.1016/j.celrep.2023.112434
  48. Biochim Biophys Acta Mol Basis Dis. 2023 Apr 20. pii: S0925-4439(23)00089-3. [Epub ahead of print] 166723
    Regulation of self-renewal in ovarian cancer stem cells by fructose via chaperone-mediated autophagy.
    Eun Jung Sohn, Jae Ho Kim, Sec-Ok Oh, Jin-Young Kim.
      The chaperone-mediated autophagy (CMA) pathway is deregulated in different types of cancers; however, its role in cancer stem cells (CSCs) is unknown yet. Development of ovarian cancer, the most lethal gynecological type of cancer, involves the metastasis of CSCs to the abdominal cavity. This study aims to determine the role of CMA in ovarian CSCs. We found that the transcription factor EB (TFEB) and trehalose, a disaccharide that induces TFEB activation, enhance the expression of octamer-binding transcription factor 4 (OCT4) stem cell and lysosomal-associated membrane protein 2A (LAMP2A) CMA markers. However, trehalose did not increase the level of the LC3II macroautophagy marker in ovarian CSCs. In A2780 and SKOV3 ovarian CSCs, LAMP2A and heat shock protein 70 (HSC70) exhibited higher expression levels than in normal adherent cells. Our results showed that the silencing of the LAMP2A gene resulted in reduced sphere formation and enhanced GLUT5 expression in ovarian CSCs. Moreover, the treatment with fructose reduced sphere formation and enhanced the expression levels of LAMP2A, SOX2, and OCT4 in ovarian CSCs. The KEGG functional analysis revealed that differentially expressed genes were enriched in the ferroptosis pathway in A2780-spheroid (SP) cells after treatment with fructose. In A2780-SP and SKOV3-SP cells, the level of SLC7A11 decreased whereas FTH increased after treatment with fructose. Taken together, our results suggest that CMA is mediated in CSCs via fructose metabolism.
    Keywords:  Cancer stem cells; Chaperone-mediated autophagy; Fructose; LAMP2A; TFEB
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166723
  49. Biochem Biophys Res Commun. 2023 Apr 20. pii: S0006-291X(23)00476-X. [Epub ahead of print]662 66-75
    Thyroid hormone upregulates LAMP2 expression and lysosome activity.
    Yi-Hsin Tseng, Cheng-Chih Chang, Kwang-Huei Lin.
      Thyroid hormone (T3)-induced autophagy and its biological significance have been extensively investigated in recent years. However, limited studies to date have focused on the important role of lysosomes in autophagy. In this study, we explored the effects of T3 on lysosomal protein expression and trafficking in detail. Our findings showed that T3 activates rapid lysosomal turnover and expression of numerous lysosomal genes, including TFEB, LAMP2, ARSB, GBA, PSAP, ATP6V0B, ATP6V0D1, ATP6V1E1, CTSB, CTSH, CTSL, and CTSS, in a thyroid hormone receptor-dependent manner. In a murine model, LAMP2 protein was specifically induced in mice with hyperthyroidism. T3-promoted microtubule assembly was significantly disrupted by vinblastine, resulting in accumulation of the lipid droplet marker PLIN2. In the presence of the lysosomal autophagy inhibitors bafilomycin A1, chloroquine and ammonium chloride, we observed substantial accumulation of LAMP2 but not LAMP1 protein. T3 further enhanced the protein levels of ectopically expressed LAMP1 and LAMP2. Upon knockdown of LAMP2, cavities of lysosomes and lipid droplets accumulated in the presence of T3, although the changes in LAMP1 and PLIN2 expression were less pronounced. More specifically, the protective effect of T3 against ER stress-induced death was abolished by knockdown of LAMP2. Our collective results indicate that T3 not only promotes lysosomal gene expression but also LAMP protein stability and microtubule assembly, leading to enhancement of lysosomal activity in digesting any additional autophagosomal burden.
    Keywords:  ER stress; LAMP2; Lysosome; Thyroid hormone; Vesicle trafficking
    DOI:  https://doi.org/10.1016/j.bbrc.2023.04.061
  50. Int J Mol Sci. 2023 Apr 13. pii: 7178. [Epub ahead of print]24(8):
    Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells.
    Paul J Kamitsuka, Marwan M Ghanem, Rania Ziar, Sarah E McDonald, Morgan G Thomas, Gunnar F Kwakye.
      Exposure to heavy metals, including cadmium (Cd), can induce neurotoxicity and cell death. Cd is abundant in the environment and accumulates in the striatum, the primary brain region selectively affected by Huntington's disease (HD). We have previously reported that mutant huntingtin protein (mHTT) combined with chronic Cd exposure induces oxidative stress and promotes metal dyshomeostasis, resulting in cell death in a striatal cell model of HD. To understand the effect of acute Cd exposure on mitochondrial health and protein degradation pathways, we hypothesized that expression of mHTT coupled with acute Cd exposure would cooperatively alter mitochondrial bioenergetics and protein degradation mechanisms in striatal STHdh cells to reveal novel pathways that augment Cd cytotoxicity and HD pathogenicity. We report that mHTT cells are significantly more susceptible to acute Cd-induced cell death as early as 6 h after 40 µM CdCl2 exposure compared with wild-type (WT). Confocal microscopy, biochemical assays, and immunoblotting analysis revealed that mHTT and acute Cd exposure synergistically impair mitochondrial bioenergetics by reducing mitochondrial potential and cellular ATP levels and down-regulating the essential pro-fusion proteins MFN1 and MFN2. These pathogenic effects triggered cell death. Furthermore, Cd exposure increases the expression of autophagic markers, such as p62, LC3, and ATG5, and reduces the activity of the ubiquitin-proteasome system to promote neurodegeneration in HD striatal cells. Overall, these results reveal a novel mechanism to further establish Cd as a pathogenic neuromodulator in striatal HD cells via Cd-triggered neurotoxicity and cell death mediated by an impairment in mitochondrial bioenergetics and autophagy with subsequent alteration in protein degradation pathways.
    Keywords:  autophagy; bioenergetics; cadmium; huntington’s disease; mitochondrial dynamics; neurodegeneration; neurotoxicity; ubiquitin–proteasome system (UPS)
    DOI:  https://doi.org/10.3390/ijms24087178
  51. Nat Aging. 2022 Apr;2(4): 303-316
    Destabilizing heterochromatin by APOE mediates senescence.
    Hongkai Zhao, Qianzhao Ji, Zeming Wu, Si Wang, Jie Ren, Kaowen Yan, Zehua Wang, Jianli Hu, Qun Chu, Huifang Hu, Yusheng Cai, Qiaoran Wang, Daoyuan Huang, Zhejun Ji, Jingyi Li, Juan Carlos Izpisua Belmonte, Moshi Song, Weiqi Zhang, Jing Qu, Guang-Hui Liu.
      Apolipoprotein E (APOE) is a component of lipoprotein particles that function in the homeostasis of cholesterol and other lipids. Although APOE is genetically associated with human longevity and Alzheimer's disease, its mechanistic role in aging is largely unknown. Here, we used human genetic, stress-induced and physiological cellular aging models to explore APOE-driven processes in stem cell homeostasis and aging. We report that in aged human mesenchymal progenitor cells (MPCs), APOE accumulation is a driver for cellular senescence. By contrast, CRISPR-Cas9-mediated deletion of APOE endows human MPCs with resistance to cellular senescence. Mechanistically, we discovered that APOE functions as a destabilizer for heterochromatin. Specifically, increased APOE leads to the degradation of nuclear lamina proteins and a heterochromatin-associated protein KRAB-associated protein 1 via the autophagy-lysosomal pathway, thereby disrupting heterochromatin and causing senescence. Altogether, our findings uncover a role of APOE as an epigenetic mediator of senescence and provide potential targets to ameliorate aging-related diseases.
    DOI:  https://doi.org/10.1038/s43587-022-00186-z
  52. Noncoding RNA. 2023 Apr 13. pii: 26. [Epub ahead of print]9(2):
    MicroRNAs in Age-Related Proteostasis and Stress Responses.
    Latika Matai, Frank J Slack.
      Aging is associated with the accumulation of damaged and misfolded proteins through a decline in the protein homeostasis (proteostasis) machinery, leading to various age-associated protein misfolding diseases such as Huntington's or Parkinson's. The efficiency of cellular stress response pathways also weakens with age, further contributing to the failure to maintain proteostasis. MicroRNAs (miRNAs or miRs) are a class of small, non-coding RNAs (ncRNAs) that bind target messenger RNAs at their 3'UTR, resulting in the post-transcriptional repression of gene expression. From the discovery of aging roles for lin-4 in C. elegans, the role of numerous miRNAs in controlling the aging process has been uncovered in different organisms. Recent studies have also shown that miRNAs regulate different components of proteostasis machinery as well as cellular response pathways to proteotoxic stress, some of which are very important during aging or in age-related pathologies. Here, we present a review of these findings, highlighting the role of individual miRNAs in age-associated protein folding and degradation across different organisms. We also broadly summarize the relationships between miRNAs and organelle-specific stress response pathways during aging and in various age-associated diseases.
    Keywords:  HSPs; UPR; aging; autophagy; health-span; heat-shock; lifespan; longevity; miR; miRNA; proteostasis; stress response
    DOI:  https://doi.org/10.3390/ncrna9020026
  53. Nat Aging. 2022 Apr;2(4): 317-331
    Suppression of intestinal dysfunction in a Drosophila model of Parkinson's disease is neuroprotective.
    Giorgio Fedele, Samantha H Y Loh, Ivana Celardo, Nuno Santos Leal, Susann Lehmann, Ana C Costa, L Miguel Martins.
      The innate immune response mounts a defense against foreign invaders and declines with age. An inappropriate induction of this response can cause diseases. Previous studies showed that mitochondria can be repurposed to promote inflammatory signaling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1, a gene required for mitochondrial health, cause Parkinson's disease, and Drosophila melanogaster pink1 mutants accumulate damaged mitochondria. Here, we show that defective mitochondria in pink1 mutants activate Relish targets and demonstrate that inflammatory signaling causes age-dependent intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells, metabolic reprogramming and neurotoxicity. We found that Relish signaling is activated downstream of a pathway stimulated by cytosolic DNA. Suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and is neuroprotective. We thus conclude that gut-brain communication modulates neurotoxicity in a fly model of Parkinson's disease through a mechanism involving mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s43587-022-00194-z
  54. Front Pharmacol. 2023 ;14 1092943
    Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2.
    Shuang Zhao, Yili Sun, Xicheng Wu, Yongqiang Yang, Kerui Fan, Kai Hu, Yasha Qin, Kexin Li, Ling Lin, Kun Chen, Yuhua Ma, Min Zhu, Gang Liu, Li Zhang.
      Upregulation of pyruvate kinase M2 (PKM2) is critical for the orchestration of metabolism and inflammation in critical illness, while autophagic degradation is a recently revealed mechanism that counter-regulates PKM2. Accumulating evidence suggests that sirtuin 1 (SIRT1) function as a crucial regulator in autophagy. The present study investigated whether SIRT1 activator would downregulate PKM2 in lethal endotoxemia via promotion of its autophagic degradation. The results indicated that lethal dose of lipopolysaccharide (LPS) exposure decreased the level of SIRT1. Treatment with SRT2104, a SIRT1 activator, reversed LPS-induced downregulation of LC3B-II and upregulation of p62, which was associated with reduced level of PKM2. Activation of autophagy by rapamycin also resulted in reduction of PKM2. The decline of PKM2 in SRT2104-treated mice was accompanied with compromised inflammatory response, alleviated lung injury, suppressed elevation of blood urea nitrogen (BUN) and brain natriuretic peptide (BNP), and improved survival of the experimental animals. In addition, co-administration of 3-methyladenine, an autophagy inhibitor, or Bafilomycin A1, a lysosome inhibitor, abolished the suppressive effects of SRT2104 on PKM2 abundance, inflammatory response and multiple organ injury. Therefore, promotion of autophagic degradation of PKM2 might be a novel mechanism underlying the anti-inflammatory benefits of SIRT1 activator.
    Keywords:  autophagy; deacetylase; endotoxemia; pyruvate kinase M2; sirtuin 1
    DOI:  https://doi.org/10.3389/fphar.2023.1092943
  55. Adv Sci (Weinh). 2023 Apr 25. e2207257
    Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.
    Ting Jiang, Jiaojiao Zhu, Shilong Jiang, Zonglin Chen, Ping Xu, Rong Gong, Changxin Zhong, Yueying Cheng, Xinyuan Sun, Wenjun Yi, Jinming Yang, Wenhu Zhou, Yan Cheng.
      In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self-activatable siRNA/drug core-shell nanoparticle system, which effectively deliver both DDIT4-AS1 siRNA and paclitaxel to the tumor-bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient-derived organoids. These findings indicate that lncRNA DDIT4-AS1-mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4-AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC.
    Keywords:  TNBC; autophagy; chemotherapy; lncRNA DDIT4-AS1; nanoparticle
    DOI:  https://doi.org/10.1002/advs.202207257
  56. Arthritis Rheumatol. 2023 Apr 25.
    LAMP3 induces lysosome-dependent cell death by impairing autophagic caspase-8 degradation in Sjögren's salivary glands.
    Hiroyuki Nakamura, Tsutomu Tanaka, Changyu Zheng, Sandra A Afione, Blake M Warner, Masayuki Noguchi, Tatsuya Atsumi, John A Chiorini.
       OBJECTIVE: Lysosome-associated membrane protein 3 (LAMP3) overexpression is implicated in the development and progression of Sjögren's disease (SjD) by inducing lysosomal membrane permeabilization (LMP) and apoptotic cell death in salivary gland epithelium. The aim of this study is to clarify molecular details of LAMP3-induced lysosome-dependent cell death and to test lysosomal biogenesis as a therapeutic intervention.
    METHODS: Human labial minor salivary gland biopsies were immunofluorescently analyzed for LAMP3 expression levels and galectin-3 puncta formation, a marker of LMP. Expression level of caspase-8, an initiator of LMP, was determined by Western blotting in cell culture. Galectin-3 puncta formation and apoptosis were evaluated in cell culture and a mouse model treated with glucagon-like peptidase-1 receptor (GLP-1R) agonists, a known promoter of lysosomal biogenesis.
    RESULTS: Galectin-3 puncta formation was more frequent in SjD patients' salivary glands compared to control glands. The proportion of galectin-3 puncta-positive cells was positively correlated with LAMP3 expression levels in the glands. LAMP3 overexpression increased caspase-8 expression, and knockdown of caspase-8 decreased galectin-3 puncta formation and apoptosis in LAMP3-overexpressing cells. Inhibition of autophagy increased caspase-8 expression, while restoration of lysosomal function using GLP-1R agonists decreased caspase-8 expression, which reduced galectin-3 puncta formation and apoptosis in both LAMP3-overexpressing cells and mice.
    CONCLUSION: LAMP3 overexpression induced lysosomal dysfunction, resulting in lysosome-dependent cell death via impaired autophagic caspase-8 degradation, and restoring lysosomal function by GLP-1R agonists could prevent this. These findings suggested that LAMP3-induced lysosomal dysfunction is central to disease development and a target for therapeutic intervention in SjD. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/art.42540
  57. Life Sci Alliance. 2023 May;pii: e202302102. [Epub ahead of print]6(5):
    Michael J Clague: mitophagy, pexophagy, & metabolism.
    Michael J Clague.
      Michael J Clague is a Professor of Molecular and Cellular Physiology at The University of Liverpool, Institute of Systems, Molecular and Integrative Biology. We asked him about his recent paper published in Life Science Alliance (LSA) and his experience in science thus far.
    DOI:  https://doi.org/10.26508/lsa.202302102
  58. Nat Aging. 2022 Sep;2(9): 824-836
    Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy.
    Paula Juricic, Yu-Xuan Lu, Thomas Leech, Lisa F Drews, Jonathan Paulitz, Jiongming Lu, Tobias Nespital, Sina Azami, Jennifer C Regan, Emilie Funk, Jenny Fröhlich, Sebastian Grönke, Linda Partridge.
      The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side effects from continuous dosing. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice. In Drosophila, a brief, early rapamycin treatment of adults extended lifespan and attenuated age-related decline in the intestine to the same degree as lifelong dosing. Lasting memory of earlier treatment was mediated by elevated autophagy in intestinal enterocytes, accompanied by increased levels of intestinal LManV and lysozyme. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a 3-month, early treatment also induced a memory effect, with maintenance similar to chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn.
    DOI:  https://doi.org/10.1038/s43587-022-00278-w
  59. Immun Inflamm Dis. 2023 Apr;11(4): e830
    Acinetobacter baumannii outer membrane protein A induces autophagy in bone marrow-derived dendritic cells involving the PI3K/mTOR pathway.
    Hongyi Tan, Liyan Cao.
       BACKGROUND: Outer membrane protein A (OmpA) is the major virulence factor of Acinetobacter baumannii and plays a wide role in the pathogenesis and antimicrobial resistance of A. baumannii. Dendritic cells (DCs) are the most effective antigen-presenting cells and play a crucial role in regulating the immune response to multiple antigens and immune sentries. We aimed to study the role and molecular mechanisms of OmpA-induced mouse bone marrow-derived dendritic cells (BMDCs) autophagy in the immune response of A. baumannii.
    METHODS: First, purified A. baumannii OmpA was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. OmpA effect on BMDCs viability was evaluated by MTT assay. BMDCs were pretreated with autophagy inhibitor chloroquine or transfected with overexpression plasmids (oe-NC or oe-PI3K). Then BMDCs apoptosis, inflammatory cytokines, protein kinase B (PI3K)/mammalian target of rapamycin (mTOR) pathway, and autophagy-related factors levels were evaluated.
    RESULTS: SDS-PAGE and western blot verified the successful purification of OmpA. BMDCs viability repressed gradually with the increase of OmpA concentration. OmpA treatment of BMDCs led to apoptosis and inflammation in BMDCs. OmpA caused incomplete autophagy in BMDCs, and light chain 3 (LC3), Beclin1, P62, and LC3II/I levels were significantly elevated with the increase of the time and concentration of OmpA treatment. Chloroquine reversed OmpA effects on autophagy in BMDCs, that was, LC3, Beclin1, and LC3II/I levels were reduced, while P62 level was elevated. Furthermore, chloroquine reversed OmpA effects on apoptosis and inflammation in BMDCs. PI3K/mTOR pathway-related factor expression was affected by OmpA treatment of BMDCs. After overexpression of PI3K, these effects were reversed.
    CONCLUSIONS: A. baumannii OmpA induced autophagy in BMDCs involving the PI3K/mTOR pathway. Our study may provide a novel therapeutic target and theoretical basis for treating infections caused by A. baumannii.
    Keywords:  Acinetobacter baumannii; BMDCs; OmpA; PI3K/mTOR pathway; autophagy
    DOI:  https://doi.org/10.1002/iid3.830
  60. Curr Stem Cell Res Ther. 2023 Apr 27.
    Research Progress on the Effect of Autophagy and Exosomes on Liver Fibrosis.
    Yikuan Du, Silin Zhu, Haojie Zeng, Zhenjie Wang, Yixing Huang, Yuqi Zhou, Weichui Zhang, Jinfeng Zhu, Chun Yang.
      Chronic liver disease is a known risk factor for the development of liver cancer, and the development of microRNA (miRNA) liver therapies has been hampered by the difficulty of delivering miRNA to damaged tissues. In recent years, numerous studies have shown that hepatic stellate cell (HSC) autophagy and exosomes play an important role in maintaining liver homeostasis and ameliorating liver fibrosis. In addition, the interaction between HSC autophagy and exosomes also affects the progression of liver fibrosis. In this paper, we review the research progress of mesenchymal stem cell-derived exosomes (MSC-EVs) loaded with specific miRNA and autophagy, and their related signaling pathways in liver fibrosis, which will provide a more reliable basis for the use of MSC-EVs for therapeutic delivery of miRNAs targeting the chronic liver disease.
    Keywords:  Autophagy; Exosomes; Hepatic stellate cell; Liver fibrosis; MicroRNA; Signal pathway; Target of rapamycin
    DOI:  https://doi.org/10.2174/1574888X18666230427112930
  61. Nat Aging. 2021 Sep;1(9): 810-825
    Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells.
    Andromachi Pouikli, Swati Parekh, Monika Maleszewska, Chrysa Nikopoulou, Maarouf Baghdadi, Ignacio Tripodi, Kat Folz-Donahue, Yvonne Hinze, Andrea Mesaros, David Hoey, Patrick Giavalisco, Robin Dowell, Linda Partridge, Peter Tessarz.
      Aging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial-nuclear communication on stem cell aging. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). We demonstrate that aged cells showed enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC.
    DOI:  https://doi.org/10.1038/s43587-021-00105-8
  62. Life (Basel). 2023 Apr 13. pii: 1006. [Epub ahead of print]13(4):
    Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle.
    Yan Wang, Jialin Li, Ziyi Zhang, Runzi Wang, Hai Bo, Yong Zhang.
      The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.
    Keywords:  UPRmt; aging; endurance exercise; mitochondrial homeostasis; mitochondrial network; mitophagy; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.3390/life13041006
  63. Nat Aging. 2022 Jun;2(6): 463-464
    Enhanced brain mitophagy slows systemic aging.
    Sofie Lautrup, Evandro F Fang.
      
    DOI:  https://doi.org/10.1038/s43587-022-00226-8
  64. Nat Aging. 2022 Mar;2(3): 199-213
    Pleiotropic effects of mitochondria in aging.
    Tanes Lima, Terytty Yang Li, Adrienne Mottis, Johan Auwerx.
      Aging is typified by a progressive decline in mitochondrial activity and stress resilience. Here, we review how mitochondrial stress pathways have pleiotropic effects on cellular and systemic homeostasis, which can comprise protective or detrimental responses during aging. We describe recent evidence arguing that defects in these conserved adaptive pathways contribute to aging and age-related diseases. Signaling pathways regulating the mitochondrial unfolded protein response, mitochondrial membrane dynamics, and mitophagy are discussed, emphasizing how their failure contributes to heteroplasmy and de-regulation of key metabolites. Our current understanding of how these processes are controlled and interconnected explains how mitochondria can widely impact fundamental aspects of aging.
    DOI:  https://doi.org/10.1038/s43587-022-00191-2
  65. Nat Aging. 2022 Dec;2(12): 1112-1129
    Mechanisms of spermidine-induced autophagy and geroprotection.
    Sebastian J Hofer, Anna Katharina Simon, Martina Bergmann, Tobias Eisenberg, Guido Kroemer, Frank Madeo.
      Aging involves the systemic deterioration of all known cell types in most eukaryotes. Several recently discovered compounds that extend the healthspan and lifespan of model organisms decelerate pathways that govern the aging process. Among these geroprotectors, spermidine, a natural polyamine ubiquitously found in organisms from all kingdoms, prolongs the lifespan of fungi, nematodes, insects and rodents. In mice, it also postpones the manifestation of various age-associated disorders such as cardiovascular disease and neurodegeneration. The specific features of spermidine, including its presence in common food items, make it an interesting candidate for translational aging research. Here, we review novel insights into the geroprotective mode of action of spermidine at the molecular level, as we discuss strategies for elucidating its clinical potential.
    DOI:  https://doi.org/10.1038/s43587-022-00322-9
  66. Biochem Biophys Res Commun. 2023 Apr 14. pii: S0006-291X(23)00444-8. [Epub ahead of print]661 34-41
    BMAL1 involved in autophagy and injury of thoracic aortic endothelial cells of rats induced by intermittent heat stress through the AMPK/mTOR/ULK1 pathway.
    Chunli Yang, Ziwei Deng, Qihang Zeng, Xiaoyu Chang, Xiaomin Wu, Guanghua Li.
      Physiological activities of the body exhibit an obvious biological rhythm. At the core of the circadian rhythm, BMAL1 is the only clock gene whose deletion leads to abnormal physiological functions. However, whether intermittent heat stress influences cardiovascular function by altering the circadian rhythm of clock genes has not been reported. This study aimed to investigate whether intermittent heat stress induces autophagy and apoptosis, and the effects of BMAL1 on thoracic aortic autophagy and apoptosis. An intermittent heat stress model was established in vitro, and western blotting and immunofluorescence were used to detect the expression of autophagy, apoptosis, the AMPK/mTOR/ULK1 pathway, and BMAL1. After BMAL1 silencing, RT-qPCR was performed to detect the expression levels of autophagy and apoptosis-related genes. Our results suggest that heat stress induces autophagy and apoptosis in RTAECs. In addition, intermittent heat stress increased the phosphorylation of AMPK and ULK1, but reduced the phosphorylation of mTOR, AMPK inhibitor Compound C reversed the phosphorylation of AMPK, mTOR, and ULK1, and Beclin1 and LC3-II/LC3-I were downregulated. Furthermore, BMAL1 expression was elevated in vitro and shBMAL1 decreased autophagy and apoptosis. We revealed that intermittent heat stress induces autophagy and apoptosis, and that BMAL1 may be involved in the occurrence of autophagy and apoptosis.
    Keywords:  Apoptosis; Autophagy; BMAL1; Intermittent heat stress; RTAEC
    DOI:  https://doi.org/10.1016/j.bbrc.2023.04.035
  67. Biology (Basel). 2023 Apr 11. pii: 582. [Epub ahead of print]12(4):
    Metformin Collaborates with PINK1/Mfn2 Overexpression to Prevent Cardiac Injury by Improving Mitochondrial Function.
    Zhuang Ma, Zuheng Liu, Xudong Li, Hao Zhang, Dunzheng Han, Wenjun Xiong, Haobin Zhou, Xi Yang, Qingchun Zeng, Hao Ren, Dingli Xu.
      Both mitochondrial quality control and energy metabolism are critical in maintaining the physiological function of cardiomyocytes. When damaged mitochondria fail to be repaired, cardiomyocytes initiate a process referred to as mitophagy to clear defective mitochondria, and studies have shown that PTEN-induced putative kinase 1 (PINK1) plays an important role in this process. In addition, previous studies indicated that peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that promotes mitochondrial energy metabolism, and mitofusin 2 (Mfn2) promotes mitochondrial fusion, which is beneficial for cardiomyocytes. Thus, an integration strategy involving mitochondrial biogenesis and mitophagy might contribute to improved cardiomyocyte function. We studied the function of PINK1 in mitophagy in isoproterenol (Iso)-induced cardiomyocyte injury and transverse aortic constriction (TAC)-induced myocardial hypertrophy. Adenovirus vectors were used to induce PINK1/Mfn2 protein overexpression. Cardiomyocytes treated with isoproterenol (Iso) expressed high levels of PINK1 and low levels of Mfn2, and the changes were time dependent. PINK1 overexpression promoted mitophagy, attenuated the Iso-induced reduction in MMP, and reduced ROS production and the apoptotic rate. Cardiac-specific overexpression of PINK1 improved cardiac function, attenuated pressure overload-induced cardiac hypertrophy and fibrosis, and facilitated myocardial mitophagy in TAC mice. Moreover, metformin treatment and PINK1/Mfn2 overexpression reduced mitochondrial dysfunction by inhibiting ROS generation leading to an increase in both ATP production and mitochondrial membrane potential in Iso-induced cardiomyocyte injury. Our findings indicate that a combination strategy may help ameliorate myocardial injury by improving mitochondrial quality.
    Keywords:  Mfn2; PGC-1α; PINK1; isoprenaline; metformin; mitochondria
    DOI:  https://doi.org/10.3390/biology12040582
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