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PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION

Unc-51 Like Autophagy Activating Kinase 1 (Ulk1) is responsible for initiating selective degradation of damaged/dysfunctional mitochondria (mitophagy) once phosphorylated at S555 in response to energetic stress. Mitophagy is integral for mitochondrial health and Ulk1 has been implicated to be import...

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Detalles Bibliográficos
Autores principales: Drake, Joshua, Nichenko, Anna, Wiloughby, Orion, Brisendine, Matt, Hays, Garrett, DiGirolamo, Grace, Weingrad, Zach, McMillan, Ryan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9766411/
http://dx.doi.org/10.1093/geroni/igac059.1668
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author Drake, Joshua
Nichenko, Anna
Wiloughby, Orion
Brisendine, Matt
Hays, Garrett
DiGirolamo, Grace
Weingrad, Zach
McMillan, Ryan
author_facet Drake, Joshua
Nichenko, Anna
Wiloughby, Orion
Brisendine, Matt
Hays, Garrett
DiGirolamo, Grace
Weingrad, Zach
McMillan, Ryan
author_sort Drake, Joshua
collection PubMed
description Unc-51 Like Autophagy Activating Kinase 1 (Ulk1) is responsible for initiating selective degradation of damaged/dysfunctional mitochondria (mitophagy) once phosphorylated at S555 in response to energetic stress. Mitophagy is integral for mitochondrial health and Ulk1 has been implicated to be important for metabolic adaptation to exercise. Caloric restriction (CR), which extends lifespan and healthspan, has profound metabolic benefits, including improved mitochondrial health. However, the contribution of Ulk1 in adaptation to CR is unknown. To decipher a functional role of Ulk1(S555) in adaptations to CR we used CRISPR-Cas9 generated, loss-of-function Ulk1(S555A) mice, in which Ulk1 cannot be phosphorylated at S555. 6-month-old, male and female homozygous Ulk1(S555A) mice and C57BL6/J (wild type, WT) mice were placed on a 40% CR diet for 8 weeks. Body mass in both male and female Ulk1(S555A) and WT mice was reduced with CR (p < 0.001), however female Ulk1(S555A) were heavier than their WT counterparts (p=0.02). Via nuclear magnetic resonance (NMR), male and female Ulk1(S555A) mice did not lose fat mass during CR. In addition, periovarian (female) and epididymal (male) fat mass was greater in Ulk1(S555A) compared to WT mice post-CR (p < 0.001). Furthermore, fasting blood glucose increased in male and female Ulk1(S555A) post-CR (p < 0.0001), suggesting altered substrate metabolism. In support of this notion, glucose oxidation in both quadriceps muscle and liver of male mice increased in WT following CR but not in Ulk1(S555A) mice (interaction effect p< 0.002). In sum, these data suggest that phosphorylation of Ulk1 at S555 is required for metabolic adaptations to CR.
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spelling pubmed-97664112022-12-20 PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION Drake, Joshua Nichenko, Anna Wiloughby, Orion Brisendine, Matt Hays, Garrett DiGirolamo, Grace Weingrad, Zach McMillan, Ryan Innov Aging Abstracts Unc-51 Like Autophagy Activating Kinase 1 (Ulk1) is responsible for initiating selective degradation of damaged/dysfunctional mitochondria (mitophagy) once phosphorylated at S555 in response to energetic stress. Mitophagy is integral for mitochondrial health and Ulk1 has been implicated to be important for metabolic adaptation to exercise. Caloric restriction (CR), which extends lifespan and healthspan, has profound metabolic benefits, including improved mitochondrial health. However, the contribution of Ulk1 in adaptation to CR is unknown. To decipher a functional role of Ulk1(S555) in adaptations to CR we used CRISPR-Cas9 generated, loss-of-function Ulk1(S555A) mice, in which Ulk1 cannot be phosphorylated at S555. 6-month-old, male and female homozygous Ulk1(S555A) mice and C57BL6/J (wild type, WT) mice were placed on a 40% CR diet for 8 weeks. Body mass in both male and female Ulk1(S555A) and WT mice was reduced with CR (p < 0.001), however female Ulk1(S555A) were heavier than their WT counterparts (p=0.02). Via nuclear magnetic resonance (NMR), male and female Ulk1(S555A) mice did not lose fat mass during CR. In addition, periovarian (female) and epididymal (male) fat mass was greater in Ulk1(S555A) compared to WT mice post-CR (p < 0.001). Furthermore, fasting blood glucose increased in male and female Ulk1(S555A) post-CR (p < 0.0001), suggesting altered substrate metabolism. In support of this notion, glucose oxidation in both quadriceps muscle and liver of male mice increased in WT following CR but not in Ulk1(S555A) mice (interaction effect p< 0.002). In sum, these data suggest that phosphorylation of Ulk1 at S555 is required for metabolic adaptations to CR. Oxford University Press 2022-12-20 /pmc/articles/PMC9766411/ http://dx.doi.org/10.1093/geroni/igac059.1668 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Abstracts
Drake, Joshua
Nichenko, Anna
Wiloughby, Orion
Brisendine, Matt
Hays, Garrett
DiGirolamo, Grace
Weingrad, Zach
McMillan, Ryan
PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION
title PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION
title_full PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION
title_fullStr PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION
title_full_unstemmed PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION
title_short PHOSPHORYLATION OF ULK1 AT S555 IS REQUIRED FOR METABOLIC ADAPTATIONS TO CALORIC RESTRICTION
title_sort phosphorylation of ulk1 at s555 is required for metabolic adaptations to caloric restriction
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9766411/
http://dx.doi.org/10.1093/geroni/igac059.1668
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