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Cell biology

ULK1 complex

DEULK1-Komplex

The ULK1 complex is a four-part kinase assembly. It includes ULK1 (Unc-51-like autophagy-activating kinase 1), the scaffold FIP200, and two regulatory subunits, ATG13 and ATG101. In mammals, it is the main trigger for building an autophagosome (the cell's recycling bag that clears the junk out of your cells). Once active, ULK1 tags ATG14, fires up the class III PI3-kinase complex, and starts the phagophore forming. Two master regulators feed it opposite nutrient signals. When nutrients are plentiful, mTORC1 tags ULK1 at Ser757, which breaks its link to AMPK and shuts autophagy down. When energy is low (high AMP/ATP), AMPK tags ULK1 at Ser317 and Ser777, which switches the complex on (Kim et al., 2011; Egan et al., 2011). With age, Ser555 tagging falls in human and mouse skeletal muscle. That tracks with poor mitophagy, a build-up of mitochondrial ROS, and weaker muscle. In cognitively healthy adults (COGNORM, n=75), blood ULK1 drops with age. In Alzheimer's patients (NorCog Cohort, n=316), lower ULK1 went with poor autophagic flux and tau pathology. Boosting ULK1 in Alzheimer's mouse models restored autophagy, lowered amyloid-beta and acetylated tau, and delayed cognitive decline (Pan et al., 2026). No ULK1 activator has entered clinical trials.

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Sources

  1. Kim J, Kundu M, Viollet B, Guan KL. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biologydoi:10.1038/ncb2152
  2. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ. (2011). Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy. Sciencedoi:10.1126/science.1196371
  3. Zachari M, Ganley IG. (2017). The mammalian ULK1 complex and autophagy initiation. Essays in Biochemistrydoi:10.1042/EBC20170021
  4. Pan JP, Wang PJ, Zhang J, Knapskog AB, Watne LO, Fang EF, Zetterberg H, Aarsland D, et al. (2026). Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology. Nature Agingdoi:10.1038/s43587-026-01108-z