Scientists uncover novel function of autophagy protein ATG-9 in regulating lysosome integrity

Lysosomes are membrane-bound organelles in cells that act as recycling centers—breaking down waste materials, damaged organelles, and unwanted molecules using powerful digestive enzymes. Lysosomes play a vital role in maintaining cellular health by clearing debris and supporting processes like autophagy. Lysosome impairment contributes to many diseases, including Alzheimer's, Parkinson's, and Huntington's disease. A better understanding of lysosomal function may lead to new therapeutic strategies for these and other lysosome-related diseases.

Now, in a new study published in Journal of Cell Biology on April 9, a research team led by Prof. ZHANG Hong from the Institute of Biophysics of the Chinese Academy of Sciences has uncovered the molecular mechanism by which the key autophagy protein ATG-9 promotes the repair of damaged lysosomes by regulating phospholipid scramblase activity.

ATG-9 functions at multiple stages in the formation of autophagosomes—bubble-like structures that capture and transport damaged organelles or other unwanted cellular components to the lysosomes for processing. It also functions as a phospholipid scramblase, regulating the asymmetric distribution of membrane lipids and influencing membrane morphology and function. In doing so, it supports expansion of the autophagic isolation membrane.

In this study, the researchers found that in epg-5 mutant C. elegans, ATG-9 vesicles selectively accumulate around mildly damaged lysosomes. Notably, reducing the phospholipid scramblase activity of ATG-9 significantly enhanced the repair of mildly damaged lysosomes and improved lysosomal function, thus rescuing autophagy defects.

Further investigation revealed that decreasing the synthesis of phosphatidylethanolamine (PE) mimicked the effects of impaired ATG-9 scramblase activity, suggesting that lipid composition and distribution are tightly linked to lysosomal membrane dynamics.

These findings suggest that reduced ATG-9 scramblase activity may facilitate lysosome biogenesis and repair by modulating the distribution of phospholipids between the inner and outer leaflets of the lysosomal membrane, thereby altering membrane curvature and stability.

Given the central role of lysosomes in cellular waste clearance and the established connection between lysosomal damage and conditions such as lysosomal storage disorders and neurodegenerative diseases, this study not only advances the fundamental understanding of autophagy, but also highlights ATG-9 as a promising target for therapeutic intervention.