Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism

Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.

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Publication Details

Journal
Molecular Metabolism
Published
2025-11-25
DOI
https://doi.org/10.1016/j.molmet.2025.102288
Primary Topic
Metabolism, Diabetes, and Cancer
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article
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article

Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism

Siobhan E. Craige, Timothy W. Rhoads, Spencer J. Tye, Joshua C. Drake et al.
Molecular Metabolism
Metabolism, Diabetes, and Cancer
article

Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism

Siobhan E. Craige, Timothy W. Rhoads, Spencer J. Tye, Joshua C. Drake, Matthew H. Brisendine, Niloufar Amiri, Charles P. Najt, Stephen D. Burrows, Kurt A. Jenkins, Kalyn S. Specht, Orion S Willoughby, Adele K. Addington, Ryan P. McMillan, Anna S. Nichenko, Haiyan Zhang, Alexey V. Zaitsev, Junco S. Warren, John Russell Brown, Sylvie Henry, Daniel S. Braxton
article en

Abstract

Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.

Molecular MetabolismVol. 103
University of Wisconsin–Madison (US), Biomedical Research Institute (US), Virginia Tech (US)
Openalex Percentile: Top 67%
Metabolism, Diabetes, and Cancer
DOIOpen Access PDFOpenAlex
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