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Lookup NU author(s): Dr Amy VincentORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2025 The AuthorsThe importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.
Author(s): Jackson CB, Marmyleva A, Monteuuis G, Awadhpersad R, Mito T, Zamboni N, Tatsuta T, Vincent AE, Wang L, Khan NA, Langer T, Carroll CJ, Suomalainen A
Publication type: Article
Publication status: Published
Journal: Cell Reports
Year: 2025
Volume: 44
Issue: 5
Online publication date: 27/05/2025
Acceptance date: 25/04/2025
Date deposited: 27/05/2025
ISSN (print): 2639-1856
ISSN (electronic): 2211-1247
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.celrep.2025.115710
DOI: 10.1016/j.celrep.2025.115710
Data Access Statement: All data are available upon reasonable request from the lead contact. Metabolomics data are provided as supplemental information. No original code has been generated for this study. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
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