Autophagy Mechanisms in Cellular Health and Disease

Autophagy is a conserved cellular degradation pathway that recycles cytoplasmic components to maintain homeostasis and respond to stress. It involves the formation of double-membrane vesicles called autophagosomes that engulf damaged organelles, protein aggregates and pathogens, delivering them to lysosomes for degradation. This process is tightly regulated by signalling networks, notably the mTORC1 and AMPK pathways, which sense nutrient availability and energy status. Selective forms of autophagy, including mitophagy and ER-phagy, ensure the removal of specific organelles, preserving their functional integrity and preventing the accumulation of toxic by-products. Dysregulation of autophagy is implicated in a wide range of diseases, including neurodegeneration, cancer, cardiovascular disorders and infections. Therapeutic modulation of autophagy is an emerging strategy for precision medicine, offering potential benefits in protein-aggregation disorders, metabolic syndromes and immune regulation.

Research from Nature Portfolio

Recent studies have elucidated how ubiquitination regulates selective ER-phagy to remodel endoplasmic reticulum (ER) membranes in response to cellular demands. Ubiquitination of an ER-phagy receptor within its reticulon homology domain promotes receptor clustering and enhances binding to lipidated LC3, driving membrane curvature and the sequestration of ER fragments. Molecular dynamics simulations and in vitro reconstitution have demonstrated how ubiquitin-mediated receptor oligomerisation induces large-scale lipid bilayer remodelling. Super-resolution imaging has revealed dynamic nanoclusters of the receptor, whose assembly is controlled by a specific E3 ligase. This work advances our understanding of how post-translational modification fine-tunes autophagy receptor function and adapts organellar quality control to shifting physiological conditions.

Autophagy Mechanisms in Cellular Health and Disease publication trend

The graph below shows the total number of articles in autophagy mechanisms in cellular health and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Autophagy: A conserved cellular process that degrades and recycles cytoplasmic content via lysosomal pathways.

Autophagosome: A double-membrane vesicle that sequesters cellular material for delivery to the lysosome.

Mitophagy: Selective autophagic degradation of mitochondria to maintain organellar quality and bioenergetics.

ER-phagy: Selective turnover of endoplasmic reticulum fragments via specialised autophagy receptors.

Ubiquitination: Attachment of ubiquitin proteins to substrates, directing them for recognition by autophagic or proteasomal systems.

Lysosome: A membrane-bound organelle containing hydrolases that digest autophagic cargo.

mTORC1: A nutrient-sensitive kinase complex that suppresses autophagy under conditions of nutrient abundance.

References

1. Ubiquitination regulates ER-phagy and remodelling of endoplasmic reticulum. Nature (2023).
2. Molecular mechanisms and physiological functions of mitophagy. The EMBO Journal (2021).
3. Nutrient-regulated control of lysosome function by signaling lipid conversion. Cell (2023).
4. Autophagy in major human diseases. The EMBO Journal (2021).