Phospholipid metabolism and autophagy

There is a complex cross-regulatory relationship between phospholipid metabolism and autophagy, with numerous new findings emerging in related research in recent years, as detailed below:

PI3P phosphatase negatively regulates autophagosome formation: The research group led by Gong Qingqiu from the School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, found that the PI3P phosphatase MTM2 in Arabidopsis thaliana specifically negatively regulates autophagosome formation. MTM2 co-localizes with PI3KC3; overexpression of MTM2 blocks autophagic flux, leading to abnormal accumulation of core autophagy machinery proteins downstream of PI3P, while MTM2 knockout mutants exhibit higher autophagic levels. MTM2 is exclusively localized at the endoplasmic reticulum (ER) exit sites, specifically binds to the COPII component SEC23A, and inhibits COPII-mediated protein secretion. Additionally, salt stress induces MTM2 expression, enabling it to negatively regulate autophagosome formation, thereby resetting autophagic flux to baseline levels.

ATG-9 regulates lysosome repair through phospholipid flippase activity: The team led by Academician Zhang Hong from the Institute of Biophysics, Chinese Academy of Sciences, discovered that the key autophagy protein ATG-9 possesses pro-phospholipid flippase activity, which can regulate the asymmetric distribution of membrane lipids, affect membrane morphology and function, and thus promote the elongation of autophagic isolation membranes. In epg-5 mutant nematodes, ATG-9 vesicles selectively accumulate around mildly damaged lysosomes. When the pro-phospholipid flippase activity of ATG-9 is weakened, it significantly promotes the repair of mildly damaged lysosomes, enhances lysosomal activity, and rescues autophagy defects. Reducing phosphatidylethanolamine synthesis produces a similar phenotype, suggesting that ATG-9 may promote lysosome repair by altering the phospholipid distribution in the lysosomal membrane.

Phosphatidic acid (PA) competitively inhibits plant autophagy: A research group at Shanghai Jiao Tong University found that PA can inhibit plant autophagy. PA can bind to the glycolytic key proteins glyceraldehyde-3-phosphate dehydrogenases (GAPCs) or phosphoglycerate kinase 3 (PGK3), promoting the interactions of GAPCs-ATG3 or PGK3-ATG6. This further impairs the formation of key autophagic complexes (ATG3-ATG8e or ATG6-VPS34), thereby inhibiting autophagy. Under environmental stimuli and nutrient deficiency, autophagy is induced, while a large amount of PA is simultaneously produced to inhibit autophagy, forming a feedback regulatory loop to maintain autophagy at an appropriate level.

Fatty acids from phospholipid synthesis drive phagophore expansion: Researchers from the University of Cologne, Germany, found that local fatty acids produced during phospholipid synthesis can drive phagophore expansion in autophagy. The conserved acyl-CoA synthetase Faa1 accumulates on nucleated phagocytes, activates fatty acids required for phagophore elongation and autophagy, and promotes their entry into the phospholipid synthesis pathway for assembly into autophagic membranes. The first step of phospholipid synthesis in the ER—forming stable contacts with nascent phagophores—is critical for autophagy.