Targeted clearance of mitochondria by an autophagy-tethering compound (ATTEC) and its potential therapeutic effects DOI Creative Commons
Shuixia Tan, Da Wang, Yuhua Fu

et al.

Science Bulletin, Journal Year: 2023, Volume and Issue: 68(23), P. 3013 - 3026

Published: Oct. 27, 2023

Increased mitochondrial damage plays a critical role in many neurodegeneration-related diseases such as Parkinson's disease (PD) and Down syndrome (DS). Thus, enhancement of degradation by small molecule compounds may provide promising new strategies to tackle these diseases. Here, we explored the strategy induce clearance mitochondria targeting them autophagy machinery autophagy-tethering (ATTECs). We provided proof-of-concept evidence demonstrating that bifunctional compound (mT1) binding both outer membrane protein TSPO autophagosome LC3B simultaneously enhance engulfment damaged autophagosomes subsequent autophagic them. In addition, preliminary experiments suggest mT1 attenuated disease-relevant phenotypes PD cellular model DS organoid model. Taken together, demonstrate possibility degrading ATTECs, which confirms capability organelles ATTECs provides potential intervention mitochondria-related disorders.

Language: Английский

Lipid droplets and cellular lipid flux DOI

Alyssa J. Mathiowetz,

James A. Olzmann

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(3), P. 331 - 345

Published: March 1, 2024

Language: Английский

Citations

80
ATG9 vesicles comprise the seed membrane of mammalian autophagosomes DOI Creative Commons
Taryn J. Olivas, Yumei Wu, Shenliang Yu

et al.

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(7)

Published: April 28, 2023

As the autophagosome forms, its membrane surface area expands rapidly, while volume is kept low. Protein-mediated transfer of lipids from another organelle to likely drives this expansion, but as these are only introduced into cytoplasmic-facing leaflet organelle, full growth also requires lipid scramblase activity. ATG9 harbors activity and essential formation; however, whether integrated mammalian autophagosomes remains unclear. Here we show that in absence transport, vesicles already competent collect proteins found on mature autophagosomes, including LC3-II. Further, use styrene-maleic acid particles reveal nanoscale organization protein LC3-II membranes; each fully expanding autophagosomes. The ratios two at different stages maturation demonstrate not continuously integrated, rather present seed become diluted membrane.

Language: Английский

Citations

60
Recent advances in targeting autophagy in cancer DOI
Vaibhav Jain,

Mahendra Pal Singh,

Ravi K. Amaravadi

et al.

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(5), P. 290 - 302

Published: March 15, 2023

Language: Английский

Citations

57
RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions DOI Creative Commons
Michael G. Hanna, Andrés Guillén-Samander, Pietro De Camilli

et al.

Annual Review of Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 39(1), P. 409 - 434

Published: July 5, 2023

The life of eukaryotic cells requires the transport lipids between membranes, which are separated by aqueous environment cytosol. Vesicle-mediated traffic along secretory and endocytic pathways lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few at time thought mediate shuttle-like mechanisms. Over last years, new family has been discovered that is defined repeating β-groove (RBG) rod-like structure with hydrophobic channel running their entire length. This localization these membrane contact sites suggest bridge-like mechanism Mutations some result neurodegenerative developmental disorders. Here we review properties well-established putative physiological roles proteins, highlight many questions remain open about functions.

Language: Английский

Citations

53
The Role of ATG9 Vesicles in Autophagosome Biogenesis DOI Creative Commons
Elisabeth Holzer, Sascha Martens, Susanna Tulli

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(15), P. 168489 - 168489

Published: Feb. 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.

Language: Английский

Citations

24
ATG9A facilitates the closure of mammalian autophagosomes DOI
Ruheena Javed, Muriel Mari, Einar S Trosdal

et al.

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(2)

Published: Jan. 2, 2025

Canonical autophagy captures within specialized double-membrane organelles, termed autophagosomes, an array of cytoplasmic components destined for lysosomal degradation. An autophagosome is completed when the growing phagophore undergoes ESCRT-dependent membrane closure, a prerequisite its subsequent fusion with endolysosomal organelles and degradation sequestered cargo. ATG9A, key integral protein pathway, best known role in formation expansion phagophores. Here, we report hitherto unappreciated function mammalian ATG9A directing closure. partners IQGAP1 ESCRT-III component CHMP2A to facilitate this final stage formation. Thus, central hub governing all major aspects biogenesis, from unique ATG factor progressive functionalities affecting physiological outputs autophagy.

Language: Английский

Citations

2
Autophagosome Biogenesis DOI Creative Commons
Zhen Yan, Harald Stenmark

Cells, Journal Year: 2023, Volume and Issue: 12(4), P. 668 - 668

Published: Feb. 20, 2023

Autophagy–the lysosomal degradation of cytoplasm–plays a central role in cellular homeostasis and protects cells from potentially harmful agents that may accumulate the cytoplasm, including pathogens, protein aggregates, dysfunctional organelles. This process is initiated by formation phagophore membrane, which wraps around portion cytoplasm or cargo closes to form double-membrane autophagosome. Upon fusion autophagosome with lysosome, sequestered material degraded hydrolases resulting autolysosome. Several alternative membrane sources autophagosomes have been proposed, plasma endosomes, mitochondria, endoplasmic reticulum, lipid droplets, hybrid organelles, de novo synthesis. Here, we review recent progress our understanding how formed highlight proposed vesicles contain scramblase ATG9 as potential seeds for biogenesis. We also discuss sealed action endosomal sorting complex required transport (ESCRT) proteins.

Language: Английский

Citations

34
Parallel phospholipid transfer by Vps13 and Atg2 determines autophagosome biogenesis dynamics DOI Creative Commons
Rahel Dabrowski, Susanna Tulli, Martin Graef

et al.

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(7)

Published: April 28, 2023

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, tether Atg2 is only PLT protein known to drive phagophore expansion in vivo. Here, our quantitative live-cell imaging analysis reveals a poor correlation between duration and size forming autophagosomes number molecules at PERCS starving yeast cells. Strikingly, we find Atg2-mediated non-rate limiting for autophagosome biogenesis because Vps13 localizes rim promotes parallel with Atg2. In absence Vps13, determines an apparent vivo rate ∼200 per molecule second. We propose conserved proteins cooperate channeling organelle contact sites non-rate-limiting during biogenesis.

Language: Английский

Citations

30
In situ snapshots along a mammalian selective autophagy pathway DOI Creative Commons
Meijing Li,

Ishita Tripathi‐Giesgen,

Brenda A. Schulman

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(12)

Published: March 14, 2023

Selective macroautophagy (hereafter referred to as autophagy) describes a process in which cytosolic material is engulfed double membrane organelle called an autophagosome. Autophagosomes are carriers responsible for delivering their content lytic compartment destruction. The cargo can be of diverse origin, ranging from macromolecular complexes protein aggregates, organelles, and even invading pathogens. Each unique composition size, presenting different challenges autophagosome biogenesis. Among the largest cargoes targeted by autophagy machinery intracellular bacteria, can, case Salmonella, range 2 5 μm length 0.5 1.5 width. How phagophores form expand on such large remains mechanistically unclear. Here, we used HeLa cells infected with auxotrophic Salmonella study phagophore biogenesis using situ correlative cryo-ET. We show that host generate multiple at site damaged -containing vacuoles (SCVs). observed structures disk-shaped expanded cup-shaped phagophores, have thin intermembrane lumen dilating rim region SCV, outer , or existing templates. Phagophore rims establish forms contact endoplasmic reticulum (ER) via structurally distinct molecular entities formation expansion. Early omegasomes correlated marker Double-FYVE domain-Containing Protein 1 (DFCP1) close association ER without apparent continuity. Our provides insights into around one selective cargoes.

Language: Английский

Citations

27
Metamorphic proteins at the basis of human autophagy initiation and lipid transfer DOI Creative Commons
Anh Nguyen,

Francesca Lugarini,

Céline David

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(12), P. 2077 - 2090.e12

Published: May 19, 2023

Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly contact site between ER and nascent autophagosome. Here, we report in vitro reconstitution full-length seven-subunit human supercomplex built on core complex ATG13-101 ATG9. Assembly this rare ability ATG13 ATG101 switch distinct folds. The slow spontaneous metamorphic conversion rate limiting self-assembly supercomplex. interaction with ATG2-WIPI4 enhances tethering membrane vesicles accelerates lipid transfer ATG2 by both ATG9 ATG13-101. Our work uncovers molecular basis its mechanisms imposed metamorphosis regulate autophagosome biogenesis space time.

Language: Английский

Citations

27