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多组学分析揭示了苯丙氨酸通过 LKB1/AMPK 的激活来增强线粒体功能和耐缺氧能力。

Multi-omics analysis reveals phenylalanine enhance mitochondrial function and hypoxic endurance via LKB1/AMPK activation.

机构信息

Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.

Department of Pharmacy, Peking University Third Hospital, Beijing, 100191, China.

出版信息

J Transl Med. 2024 Oct 10;22(1):920. doi: 10.1186/s12967-024-05696-5.

DOI:10.1186/s12967-024-05696-5
PMID:39390477
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11465566/
Abstract

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.

摘要

许多研究都集中在小分子（如氨基酸）对缺氧条件下代谢的影响。最近的研究结果表明，苯丙氨酸水平在适应慢性缺氧时明显升高。这就提出了一种可能性，即苯丙氨酸治疗可能显著提高缺氧耐力。然而，缺氧调节苯丙氨酸的重要性仍不清楚。本研究利用缺氧斑马鱼模型和多组学分析研究了苯丙氨酸在缺氧适应中的作用。我们发现，苯丙氨酸相关代谢途径在缺氧下显著上调，有助于增强缺氧耐力。苯丙氨酸处理可降低缺氧细胞中的 ROS 水平，提高线粒体耗氧率（OCR）和细胞外酸化率（ECAR）。Western blot 显示，通过 L 型氨基酸转运体（LAT1）增加苯丙氨酸摄取，激活 LKB1/AMPK 信号通路。这种激活上调过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）和 Bcl-2/Bax 比值，同时下调解偶联蛋白 2（UCP2），从而改善缺氧下的线粒体功能。这是首次进行全面的多组学分析，证明了苯丙氨酸在缺氧适应中的关键作用，为开发抗缺氧药物提供了新的思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/ce80927aaa44/12967_2024_5696_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/c56587c73158/12967_2024_5696_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/8969a5836143/12967_2024_5696_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/6c9726929270/12967_2024_5696_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/b42803611d44/12967_2024_5696_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/ce80927aaa44/12967_2024_5696_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/c56587c73158/12967_2024_5696_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/365930f3d9cd/12967_2024_5696_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/b8db570c1474/12967_2024_5696_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/6fdc9ca890b8/12967_2024_5696_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/8969a5836143/12967_2024_5696_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/6c9726929270/12967_2024_5696_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/b42803611d44/12967_2024_5696_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01f5/11465566/ce80927aaa44/12967_2024_5696_Fig8_HTML.jpg

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