The autophagy protein ATG9A enables lipid mobilization from lipid droplets

Elodie Mailler, Carlos M. Guardia, Xiaofei Bai, Michal Jarnik, Chad D. Williamson, Yan Li, Nunziata Maio, Andy Golden and Juan S. Bonifacino ()
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Elodie Mailler: Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Carlos M. Guardia: Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Xiaofei Bai: Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Michal Jarnik: Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Chad D. Williamson: Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Yan Li: Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Nunziata Maio: Metals Biology and Molecular Medicine Group, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Andy Golden: Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Juan S. Bonifacino: Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26999-x

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