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Nature Reviews. Molecular Cell Biology Aug 2023Maintenance of protein homeostasis and organelle integrity and function is critical for cellular homeostasis and cell viability. Autophagy is the principal mechanism... (Review)
Review
Maintenance of protein homeostasis and organelle integrity and function is critical for cellular homeostasis and cell viability. Autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling. A myriad of studies demonstrate important protective roles for autophagy against disease. However, in cancer, seemingly opposing roles of autophagy are observed in the prevention of early tumour development versus the maintenance and metabolic adaptation of established and metastasizing tumours. Recent studies have addressed not only the tumour cell intrinsic functions of autophagy, but also the roles of autophagy in the tumour microenvironment and associated immune cells. In addition, various autophagy-related pathways have been described, which are distinct from classical autophagy, that utilize parts of the autophagic machinery and can potentially contribute to malignant disease. Growing evidence on how autophagy and related processes affect cancer development and progression has helped guide efforts to design anticancer treatments based on inhibition or promotion of autophagy. In this Review, we discuss and dissect these different functions of autophagy and autophagy-related processes during tumour development, maintenance and progression. We outline recent findings regarding the role of these processes in both the tumour cells and the tumour microenvironment and describe advances in therapy aimed at autophagy processes in cancer.
Topics: Humans; Neoplasms; Autophagy; Lysosomes; Tumor Microenvironment
PubMed: 36864290
DOI: 10.1038/s41580-023-00585-z -
Autophagy Oct 2023Neuroinflammation caused by microglial activation and consequent neurological impairment are prominent features of diabetes-associated cognitive impairment (DACI)....
Neuroinflammation caused by microglial activation and consequent neurological impairment are prominent features of diabetes-associated cognitive impairment (DACI). Microglial lipophagy, a significant fraction of autophagy contributing to lipid homeostasis and inflammation, had mostly been ignored in DACI. Microglial lipid droplets (LDs) accumulation is a characteristic of aging, however, little is known about the pathological role of microglial lipophagy and LDs in DACI. Therefore, we hypothesized that microglial lipophagy could be an Achilles's heel exploitable to develop effective strategies for DACI therapy. Here, starting with characterization of microglial accumulation of LDs in leptin receptor-deficient (db/db) mice and in high-fat diet and STZ (HFD/STZ) induced T2DM mice, as well as in high-glucose (HG)-treated mice BV2, human HMC3 and primary mice microglia, we revealed that HG-dampened lipophagy was responsible for LDs accumulation in microglia. Mechanistically, accumulated LDs colocalized with the microglial specific inflammatory amplifier TREM1 (triggering receptor expressed on myeloid cells 1), resulting in the buildup of microglial TREM1, which in turn aggravates HG-induced lipophagy damage and subsequently promoted HG-induced neuroinflammatory cascades via NLRP3 (NLR family pyrin domain containing 3) inflammasome. Moreover, pharmacological blockade of TREM1 with LP17 in db/db mice and HFD/STZ mice inhibited accumulation of LDs and TREM1, reduced hippocampal neuronal inflammatory damage, and consequently improved cognitive functions. Taken together, these findings uncover a previously unappreciated mechanism of impaired lipophagy-induced TREM1 accumulation in microglia and neuroinflammation in DACI, suggesting its translational potential as an attractive therapeutic target for delaying diabetes-associated cognitive decline. ACTB: beta actin; AIF1/IBA1: allograft inflammatory factor 1; ALB: albumin; ARG1: arginase 1; ATG3: autophagy related 3; Baf: bafilomycin A; BECN1: beclin 1, autophagy related; BW: body weight; CNS: central nervous system; Co-IP: co-immunoprecipitation; DACI: diabetes-associated cognitive impairment; DAPI: 4',6-diamidino-2-phenylindole; DGs: dentate gyrus; DLG4/PSD95: discs large MAGUK scaffold protein 4; DMEM: Dulbecco's modified Eagle's medium; DSST: digit symbol substitution test; EDTA: ethylenedinitrilotetraacetic acid; ELISA: enzyme linked immunosorbent assay; GFAP: glial fibrillary acidic protein; HFD: high-fat diet; HG: high glucose; IFNG/IFN-γ: interferon gamma; IL1B/IL-1β: interleukin 1 beta; IL4: interleukin 4; IL6: interleukin 6; IL10: interleukin 10; LDs: lipid droplets; LPS: lipopolysaccharide; MAP2: microtubule associated protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MWM: morris water maze; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3: NLR family pyrin domain containing 3; NOS2/iNOS: nitric oxide synthase 2, inducible; NOR: novel object recognition; OA: oleic acid; PA: palmitic acid; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PLIN2: perilipin 2; PLIN3: perilipin 3; PS: penicillin-streptomycin solution; RAPA: rapamycin; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RELA/p65: RELA proto-oncogene, NF-kB subunit; ROS: reactive oxygen species; RT: room temperature; RT-qPCR: Reverse transcription quantitative real-time polymerase chain reaction; STZ: streptozotocin; SQSTM1/p62: sequestosome 1; SYK: spleen asociated tyrosine kinase; SYP: synaptophysin; T2DM: type 2 diabetes mellitus; TNF/TNF-α: tumor necrosis factor; TREM1: triggering receptor expressed on myeloid cells 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling.
Topics: Animals; Humans; Mice; Autophagy; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Glucose; Lipid Droplets; Microglia; Neuroinflammatory Diseases; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Triggering Receptor Expressed on Myeloid Cells-1
PubMed: 37204119
DOI: 10.1080/15548627.2023.2213984 -
Cell Death & Disease Oct 2023Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role... (Review)
Review
Autophagy is the process by which cells degrade and recycle proteins and organelles to maintain intracellular homeostasis. Generally, autophagy plays a protective role in cells, but disruption of autophagy mechanisms or excessive autophagic flux usually leads to cell death. Despite recent progress in the study of the regulation and underlying molecular mechanisms of autophagy, numerous questions remain to be answered. How does autophagy regulate cell death? What are the fine-tuned regulatory mechanisms underlying autophagy-dependent cell death (ADCD) and autophagy-mediated cell death (AMCD)? In this article, we highlight the different roles of autophagy in cell death and discuss six of the main autophagy-related cell death modalities, with a focus on the metabolic changes caused by excessive endoplasmic reticulum-phagy (ER-phagy)-induced cell death and the role of mitophagy in autophagy-mediated ferroptosis. Finally, we discuss autophagy enhancement in the treatment of diseases and offer a new perspective based on the use of autophagy for different functional conversions (including the conversion of autophagy and that of different autophagy-mediated cell death modalities) for the clinical treatment of tumors.
Topics: Endoplasmic Reticulum Stress; Autophagy; Endoplasmic Reticulum; Mitophagy; Cell Death
PubMed: 37794028
DOI: 10.1038/s41419-023-06154-8 -
Nature Reviews. Genetics Jun 2023Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic... (Review)
Review
Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic membrane dynamics regulated by autophagy-related proteins and other molecules, some of which are shared between the two pathways. Over the past few years, the application of new technologies, such as cryo-electron microscopy, coevolution-based structural prediction and in vitro reconstitution, has revealed the functions of individual autophagy gene products, especially in autophagy induction, membrane reorganization and cargo recognition. Concomitantly, mutations in autophagy genes have been linked to human disorders, particularly neurodegenerative diseases, emphasizing the potential pathogenic implications of autophagy defects. Accumulating genome data have also illuminated the evolution of autophagy genes within eukaryotes as well as their transition from possible ancestral elements in prokaryotes.
Topics: Humans; Cryoelectron Microscopy; Autophagy; Lysosomes; Proteins; Eukaryota; Biology
PubMed: 36635405
DOI: 10.1038/s41576-022-00562-w -
Signal Transduction and Targeted Therapy Sep 2023The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve... (Review)
Review
The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.
Topics: Humans; Endoplasmic Reticulum Stress; Unfolded Protein Response; Color Vision Defects; Autophagy; Epigenomics
PubMed: 37709773
DOI: 10.1038/s41392-023-01570-w -
Basic Research in Cardiology Oct 2023Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and... (Review)
Review
Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.
Topics: Humans; Adult; Mitophagy; Autophagy; Mitochondria; Heart Diseases; Myocytes, Cardiac; Mitochondrial Dynamics
PubMed: 37798455
DOI: 10.1007/s00395-023-01009-x -
EMBO Reports Nov 2023Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age-related diseases. At the cellular level,... (Review)
Review
Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age-related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age-related diseases and potentially for aging itself.
Topics: Animals; Autophagy; Aging; Cellular Senescence; Lysosomes; Cell Death
PubMed: 37811693
DOI: 10.15252/embr.202357265 -
Autophagy Sep 2023The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions,...
The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material's properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future. Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related β-ECD: β-ecdysone BMSC: bone marrow mesenchymal stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha HSC: hematopoietic stem cell HSP: heat shock protein IGF1: insulin like growth factor 1 IL1B/IL-1β: interleukin 1 beta IVDD: intervertebral disc degradation LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase MSC: mesenchymal stem cell MTOR: mechanistic target of rapamycin kinase NP: nucleus pulposus NPWT: negative pressure wound therapy OA: osteoarthritis OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin 1 SIRT3: sirtuin 3 SQSTM1/p62: sequestosome 1 TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis factor receptor superfamily, member 11a TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11 TSC1: tuberous sclerosis complex 1 ULK1: unc-51 like autophagy activating kinase 1.
Topics: Humans; Autophagy; Signal Transduction; AMP-Activated Protein Kinases; Clinical Relevance; Osteoarthritis; TOR Serine-Threonine Kinases; Osteoporosis; Metabolic Diseases
PubMed: 36858962
DOI: 10.1080/15548627.2023.2186112 -
Nature Jun 2023The endoplasmic reticulum (ER) undergoes continuous remodelling via a selective autophagy pathway, known as ER-phagy. ER-phagy receptors have a central role in this...
The endoplasmic reticulum (ER) undergoes continuous remodelling via a selective autophagy pathway, known as ER-phagy. ER-phagy receptors have a central role in this process, but the regulatory mechanism remains largely unknown. Here we report that ubiquitination of the ER-phagy receptor FAM134B within its reticulon homology domain (RHD) promotes receptor clustering and binding to lipidated LC3B, thereby stimulating ER-phagy. Molecular dynamics (MD) simulations showed how ubiquitination perturbs the RHD structure in model bilayers and enhances membrane curvature induction. Ubiquitin molecules on RHDs mediate interactions between neighbouring RHDs to form dense receptor clusters that facilitate the large-scale remodelling of lipid bilayers. Membrane remodelling was reconstituted in vitro with liposomes and ubiquitinated FAM134B. Using super-resolution microscopy, we discovered FAM134B nanoclusters and microclusters in cells. Quantitative image analysis revealed a ubiquitin-mediated increase in FAM134B oligomerization and cluster size. We found that the E3 ligase AMFR, within multimeric ER-phagy receptor clusters, catalyses FAM134B ubiquitination and regulates the dynamic flux of ER-phagy. Our results show that ubiquitination enhances RHD functions via receptor clustering, facilitates ER-phagy and controls ER remodelling in response to cellular demands.
Topics: Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Intracellular Signaling Peptides and Proteins; Ubiquitination; Ubiquitins; Microtubule-Associated Proteins; Receptors, Autocrine Motility Factor
PubMed: 37225996
DOI: 10.1038/s41586-023-06089-2 -
Autophagy Dec 2023Lactate is a glycolysis product that is produced from pyruvate by LDH (lactate dehydrogenase) and plays an important role in physiological and pathological processes....
Lactate is a glycolysis product that is produced from pyruvate by LDH (lactate dehydrogenase) and plays an important role in physiological and pathological processes. However, whether lactate regulates autophagy is still unknown. We recently reported that LDHA is phosphorylated at serine 196 by ULK1 (unc-51 like kinase 1) under nutrient-deprivation conditions, promoting lactate production. Then, lactate mediates PIK3C3/VPS34 lactylation at lysine 356 and lysine 781 via acyltransferase KAT5/TIP60. PIK3C3/VPS34 lactylation enhances the association of PIK3C3/VPS34 with BECN1 (beclin 1, autophagy related), ATG14 and UVRAG, increases PIK3C3/VPS34 lipid kinase activity, promotes macroautophagy/autophagy and facilitates the endolysosomal degradation pathway. PIK3C3/VPS34 hyperlactylation induces autophagy and plays an essential role in skeletal muscle homeostasis and cancer progression. Overall, this study describes an autophagy regulation mechanism and the integration of two highly conserved life processes: glycolysis and autophagy.
Topics: Autophagy; Autophagy-Related Proteins; Lactic Acid; Lysine; Beclin-1; Class III Phosphatidylinositol 3-Kinases; Glycolysis
PubMed: 37565742
DOI: 10.1080/15548627.2023.2246356