Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 27, 2024

Abstract Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, essential selective autophagic degradation mitochondria, also age. In our analysis mitophagy in multiple organs mito-QC reporter mouse, either increased or unchanged old versus young mice. Transcriptomic shows marked upregulation type I interferon response retina mice, which correlates levels cytosolic mtDNA activation cGAS/STING pathway. Crucially, these same alterations are replicated primary human fibroblasts from elderly donors. pharmacological induction urolithin A attenuates ameliorates deterioration neurological function. These findings point to as strategy decrease age-associated inflammation increase healthspan.

Язык: Английский

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International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis

Autophagy, Год журнала: 2024, Номер 20(6), С. 1213 - 1246

Опубликована: Март 6, 2024

Macroautophagy/autophagy is a complex degradation process with dual role in cell death that influenced by the types are involved and stressors they exposed to. Ferroptosis an iron-dependent oxidative form of characterized unrestricted lipid peroxidation context heterogeneous plastic mechanisms. Recent studies have shed light on involvement specific autophagy (e.g. ferritinophagy, lipophagy, clockophagy) initiating or executing ferroptotic through selective anti-injury proteins organelles. Conversely, other forms reticulophagy lysophagy) enhance cellular defense against damage. Dysregulated autophagy-dependent ferroptosis has implications for diverse range pathological conditions. This review aims to present updated definition ferroptosis, discuss influential substrates receptors, outline experimental methods, propose guidelines interpreting results.

Язык: Английский

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Molecular Mechanisms of Macroautophagy, Microautophagy, and Chaperone-Mediated Autophagy

Journal of Nippon Medical School, Год журнала: 2023, Номер 91(1), С. 2 - 9

Опубликована: Июнь 1, 2023

Autophagy is a self-digestive process that conserved in eukaryotic cells and responsible for maintaining cellular homeostasis through proteolysis. By this process, break down their own components lysosomes. can be classified into three categories: macroautophagy, microautophagy, chaperone-mediated autophagy (CMA). Macroautophagy involves membrane elongation microautophagy internalization, both pathways undergo selective or non-selective processes transport cytoplasmic lysosomes to degraded. CMA, however, incorporation of cytosolic materials without deformation. All categories have attracted much attention due involvement various biological phenomena relevance human diseases, such as neurodegenerative diseases cancer. Clarification the molecular mechanisms behind these key understanding recent studies made major progress regard, especially initiation macroautophagy substrate recognition CMA. Furthermore, it becoming evident are related each other despite implementation by different sets proteins completely dynamics. In review, CMA summarized.

Язык: Английский

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Atg8 family proteins, LIR/AIM motifs and other interaction modes

Autophagy Reports, Год журнала: 2023, Номер 2(1)

Опубликована: Март 19, 2023

The Atg8 family of ubiquitin-like proteins play pivotal roles in autophagy and other processes involving vesicle fusion transport where the lysosome/vacuole is end station. Nuclear are also emerging. Here, we review structural functional features their protein-protein interaction modes model organisms such as yeast, Arabidopsis, C. elegans Drosophila to humans. Although varying number homologs, from one yeast seven humans, more than ten some plants, there a strong evolutionary conservation modes. most prominent mode between LC3 interacting region (LIR), called motif (AIM), binding LIR docking site (LDS) homologs. There variants these motifs like "half-LIRs" helical LIRs. We discuss details how selectivity achieved well role multivalent LIR-LDS interactions selective autophagy. A known be regulated by phosphorylation. New methods predict have emerged that will aid discovery analyses. surfaces LDS becoming presently lack detailed information, N-terminal arm UIM-docking (UDS). More likely discovered future studies.

Язык: Английский

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The Role of ATG9 Vesicles in Autophagosome Biogenesis

Journal of Molecular Biology, Год журнала: 2024, Номер 436(15), С. 168489 - 168489

Опубликована: Фев. 10, 2024

Autophagy mediates the degradation and recycling of cellular material in lysosomal system. Dysfunctional autophagy is associated with a plethora diseases including uncontrolled infections, cancer neurodegeneration. In macroautophagy (hereafter autophagy) this encapsulated double membrane vesicles, autophagosomes, which form upon induction autophagy. The precursors to referred as phagophores, first appear small flattened cisternae, gradually enclose cargo they grow. assembly phagophores during initiation has been major subject investigation over past decades. A special focus ATG9, only conserved transmembrane protein among core machinery. majority ATG9 localizes Golgi-derived vesicles. Here we review recent advances breakthroughs regarding our understanding how vesicles it resides serve assemble machinery establish contact sites for autophagosome biogenesis. We also highlight open questions field that need be addressed years come.

Язык: Английский

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Autophagy in aging-related diseases and cancer: Principles, regulatory mechanisms and therapeutic potential

Ageing Research Reviews, Год журнала: 2024, Номер 100, С. 102428 - 102428

Опубликована: Июль 20, 2024

Язык: Английский

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Supramolecular Chiral Binding Affinity‐Achieved Efficient Synergistic Cancer Therapy

Advanced Science, Год журнала: 2024, Номер 11(16)

Опубликована: Фев. 21, 2024

Supramolecular chirality-mediated selective interaction among native assemblies is essential for precise disease diagnosis and treatment. Herein, to fully understand the supramolecular chiral binding affinity-achieved therapeutic efficiency, nanoparticles (WP5⊃D/L-Arg+DOX+ICG) with chirality transfer from arginine (D/L-Arg) water-soluble pillar[5]arene (WP5) are developed through non-covalent interactions, in which an anticancer drug (DOX, doxorubicin hydrochloride) a photothermal agent (ICG, indocyanine green) successfully loaded. Interestingly, WP5⊃D-Arg show 107 folds stronger capability toward phospholipid-composed liposomes compared WP5⊃L-Arg. The enantioselective further triggers chirality-specific accumulation cancer cells. As consequence, WP5⊃D-Arg+DOX+ICG exhibits extremely enhanced chemo-photothermal synergistic efficacy (tumor inhibition rate of 99.4%) than that WP5⊃L-Arg+DOX+ICG 56.4%) under same condition. This work reveals breakthrough can induce surprisingly large difference therapy, providing strong support significance bio-application.

Язык: Английский

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Enhancing antitumor efficacy of CLDN18.2-directed antibody-drug conjugates through autophagy inhibition in gastric cancer

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Сен. 3, 2024

Abstract Claudin18.2 (CLDN18.2) is overexpressed in cancers of the digestive system, rendering it an ideal drug target for antibody-drug conjugates (ADCs). Despite many CLDN18.2-directed ADCs undergoing clinical trials, inconclusive underlying mechanisms pose a hurdle to extending utility these agents. In our study, αCLDN18.2-MMAE, ADC composed anti-CLDN18.2 monoclonal antibody and tubulin inhibitor MMAE, induced dose-dependent apoptosis via cleavage caspase-9/PARP proteins CLDN18.2-positive gastric cancer cells. It was worth noting that autophagy remarkably activated during αCLDN18.2-MMAE treatment, which characterized by accumulation autophagosomes, conversion marker LC3 from its form I II, complete autophagic flux. Inhibiting LY294002 enhanced αCLDN18.2-MMAE-induced cytotoxicity caspase-mediated apoptosis, indicating cytoprotective role ADC-treated Combination with significantly potentiated vivo antitumoral efficacy αCLDN18.2-MMAE. Besides, Akt/mTOR pathway inactivation demonstrated be implicated initiation αCLDN18.2-MMAE-treated conclusion, study highlighted groundbreaking investigation into mechanism ADC, focusing on crucial autophagy, providing novel insight treat combination inhibitor.

Язык: Английский

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Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Апрель 22, 2024

Abstract Cancer-associated fibroblasts (CAFs), the main stromal component of tumor microenvironment (TME), play multifaceted roles in cancer progression through paracrine signaling, exosome transfer, and cell interactions. Attractively, recent evidence indicates that CAFs can modulate various forms regulated death (RCD) adjacent cells, thus involving proliferation, therapy resistance, immune exclusion. Here, we present a brief introduction to basic knowledge RCD, including apoptosis, autophagy, ferroptosis, pyroptosis. In addition, further summarize different types RCD tumors are mediated by CAFs, as well effects these modes on CAFs. This review will deepen our understanding interactions between might offer novel therapeutic avenues for future treatments.

Язык: Английский

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The Endo-Lysosomal Damage Response

Annual Review of Biochemistry, Год журнала: 2024, Номер 93(1), С. 367 - 387

Опубликована: Апрель 10, 2024

Lysosomes are the degradative endpoints of material delivered by endocytosis and autophagy therefore particularly prone to damage. Membrane permeabilization or full rupture lysosomal late endosomal compartments is highly deleterious because it threatens cellular homeostasis can elicit cell death inflammatory signaling. Cells have developed a complex response endo-lysosomal damage that largely consists three branches. Initially, number repair pathways activated restore integrity membrane. If fails if too extensive, lysosomes isolated degraded form selective termed lysophagy. Meanwhile, an mTORC1-governed signaling cascade drives biogenesis regeneration new components reestablish capacity cell. This vital counteract effects various conditions, including neurodegeneration infection, constitute critical vulnerability in cancer cells.

Язык: Английский

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