Multi-omics analysis reveals phenylalanine enhance mitochondrial function and hypoxic endurance via LKB1/AMPK activation.
Animals
Mitochondria
/ metabolism
AMP-Activated Protein Kinases
/ metabolism
Phenylalanine
/ pharmacology
Zebrafish
Protein Serine-Threonine Kinases
/ metabolism
Hypoxia
/ metabolism
Signal Transduction
/ drug effects
Enzyme Activation
/ drug effects
Reactive Oxygen Species
/ metabolism
Humans
Genomics
AMP-Activated Protein Kinase Kinases
Adaptation, Physiological
/ drug effects
Oxygen Consumption
/ drug effects
Multiomics
AMPK
Hypoxia adaption
LAT1
LKB1
Mitochondrial function
Multi-omics
Phenylalanine
ROS
Zebrafish model
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
10 Oct 2024
10 Oct 2024
Historique:
received:
11
05
2024
accepted:
22
09
2024
medline:
11
10
2024
pubmed:
11
10
2024
entrez:
10
10
2024
Statut:
epublish
Résumé
Many studies have focused on the effects of small molecules, such as amino acids, on metabolism under hypoxia. Recent findings have indicated that phenylalanine levels were markedly elevated in adaptation to chronic hypoxia. This raises the possibility that phenylalanine treatment could markedly improve the hypoxic endurance. However, the importance of hypoxia-regulated phenylalanine is still unclear. This study investigates the role of phenylalanine in hypoxia adaptation using a hypoxic zebrafish model and multi-omics analysis. We found that phenylalanine-related metabolic pathways are significantly up-regulated under hypoxia, contributing to enhanced hypoxic endurance. Phenylalanine treatment reduced ROS levels, improved mitochondrial oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) in hypoxic cells. Western blotting revealed increased phenylalanine uptake via L-type amino transporters (LAT1), activating the LKB1/AMPK signaling pathway. This activation up-regulated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and the Bcl-2/Bax ratio, while down-regulating uncoupling protein 2 (UCP2), thereby improving mitochondrial function under hypoxia. This is the first comprehensive multi-omics analysis to demonstrate phenylalanine's crucial role in hypoxia adaptation, providing insights for the development of anti-hypoxic drugs.
Identifiants
pubmed: 39390477
doi: 10.1186/s12967-024-05696-5
pii: 10.1186/s12967-024-05696-5
doi:
Substances chimiques
AMP-Activated Protein Kinases
EC 2.7.11.31
Phenylalanine
47E5O17Y3R
Protein Serine-Threonine Kinases
EC 2.7.11.1
Reactive Oxygen Species
0
AMP-Activated Protein Kinase Kinases
EC 2.7.11.3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
920Subventions
Organisme : National Natural Science Foundation of China
ID : 81773803
Organisme : National Natural Science Foundation of China
ID : 82073925
Organisme : National Natural Science Foundation of China
ID : 81573683
Organisme : Key Technologies Research and Development Program of Anhui Province
ID : 2021YFE0202700
Informations de copyright
© 2024. The Author(s).
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