Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26999-x
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Funding
- NIH Office of Research Infrastructure Programs [P40OD010440]
- NICHD [ZIA HD001607]
- NIDDK
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ATG9A is a transmembrane protein involved in lipid mobilization, essential for autophagosome expansion, mitochondrial fatty acid import, and beta-oxidation. Depletion of ATG9A inhibits autophagy, increases lipid droplet size/number, and blocks transfer of fatty acids to mitochondria. ATG9A localizes to vesicular-tubular clusters associated with TMEM41B and plays a critical role in lipid mobilization from lipid droplets to autophagosomes and mitochondria.
ATG9A is transmembrane autophagic machinery protein that delivers phospholipids to expanding autophagosomes. Mailler et al. show that ATG9A is required to mobilize lipids from lipid droplets for autophagosome expansion as well as mitochondrial fatty acid import and beta-oxidation. The multispanning membrane protein ATG9A is a scramblase that flips phospholipids between the two membrane leaflets, thus contributing to the expansion of the phagophore membrane in the early stages of autophagy. Herein, we show that depletion of ATG9A does not only inhibit autophagy but also increases the size and/or number of lipid droplets in human cell lines and C. elegans. Moreover, ATG9A depletion blocks transfer of fatty acids from lipid droplets to mitochondria and, consequently, utilization of fatty acids in mitochondrial respiration. ATG9A localizes to vesicular-tubular clusters (VTCs) that are tightly associated with an ER subdomain enriched in another multispanning membrane scramblase, TMEM41B, and also in close proximity to phagophores, lipid droplets and mitochondria. These findings indicate that ATG9A plays a critical role in lipid mobilization from lipid droplets to autophagosomes and mitochondria, highlighting the importance of ATG9A in both autophagic and non-autophagic processes.
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