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PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons

Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion ther...

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Autores principales: Li, Tao, Zhao, Lili, Li, Ye, Dang, Meijuan, Lu, Jialiang, Lu, Ziwei, Huang, Qiao, Yang, Yang, Feng, Yuxuan, Wang, Xiaoya, Jian, Yating, Wang, Heying, Guo, Yingying, Zhang, Lei, Jiang, Yu, Fan, Songhua, Wu, Shengxi, Fan, Hong, Kuang, Fang, Zhang, Guilian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522625/
https://www.ncbi.nlm.nih.gov/pubmed/37752100
http://dx.doi.org/10.1038/s41419-023-06135-x
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author Li, Tao
Zhao, Lili
Li, Ye
Dang, Meijuan
Lu, Jialiang
Lu, Ziwei
Huang, Qiao
Yang, Yang
Feng, Yuxuan
Wang, Xiaoya
Jian, Yating
Wang, Heying
Guo, Yingying
Zhang, Lei
Jiang, Yu
Fan, Songhua
Wu, Shengxi
Fan, Hong
Kuang, Fang
Zhang, Guilian
author_facet Li, Tao
Zhao, Lili
Li, Ye
Dang, Meijuan
Lu, Jialiang
Lu, Ziwei
Huang, Qiao
Yang, Yang
Feng, Yuxuan
Wang, Xiaoya
Jian, Yating
Wang, Heying
Guo, Yingying
Zhang, Lei
Jiang, Yu
Fan, Songhua
Wu, Shengxi
Fan, Hong
Kuang, Fang
Zhang, Guilian
author_sort Li, Tao
collection PubMed
description Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion therapy is the most effective treatment for ischemic stroke, it still has limited benefits for many patients, and ischemia-reperfusion (I/R) injury is a widely recognized cause of poor prognosis. Here, we aim to investigate the mechanism of protein phosphatase Mg(2+)/Mn(2+) dependent 1 K (PPM1K) mediates metabolic disorder of branched-chain amino acids (BCAA) by promoting fatty acid oxidation led to ferroptosis after cerebral I/R injury. We established the I/R model in mice and used BT2, a highly specific BCAA dehydrogenase (BCKD) kinase inhibitor to promote BCAA metabolism. It was further verified by lentivirus knocking down PPM1K in neurons. We found that BCAA levels were elevated after I/R injury due to dysfunctional oxidative degradation caused by phosphorylated BCKD E1α subunit (BCKDHA). Additionally, the level of phosphorylated BCKDHA was determined by decreased PPM1K in neurons. We next demonstrated that BCAA could induce oxidative stress, lipid peroxidation, and ferroptosis in primary cultured cortical neurons in vitro. Our results further showed that BT2 could reduce neuronal ferroptosis by enhancing BCAA oxidation through inhibition of BCKDHA phosphorylation. We further found that defective BCAA catabolism could induce neuronal ferroptosis by PPM1K knockdown. Furthermore, BT2 was found to alleviate neurological behavior disorders after I/R injury in mice, and the effect was similar to ferroptosis inhibitor ferrostatin-1. Our findings reveal a novel role of BCAA in neuronal ferroptosis after cerebral ischemia and provide a new potential target for the treatment of ischemic stroke.
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spelling pubmed-105226252023-09-28 PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons Li, Tao Zhao, Lili Li, Ye Dang, Meijuan Lu, Jialiang Lu, Ziwei Huang, Qiao Yang, Yang Feng, Yuxuan Wang, Xiaoya Jian, Yating Wang, Heying Guo, Yingying Zhang, Lei Jiang, Yu Fan, Songhua Wu, Shengxi Fan, Hong Kuang, Fang Zhang, Guilian Cell Death Dis Article Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion therapy is the most effective treatment for ischemic stroke, it still has limited benefits for many patients, and ischemia-reperfusion (I/R) injury is a widely recognized cause of poor prognosis. Here, we aim to investigate the mechanism of protein phosphatase Mg(2+)/Mn(2+) dependent 1 K (PPM1K) mediates metabolic disorder of branched-chain amino acids (BCAA) by promoting fatty acid oxidation led to ferroptosis after cerebral I/R injury. We established the I/R model in mice and used BT2, a highly specific BCAA dehydrogenase (BCKD) kinase inhibitor to promote BCAA metabolism. It was further verified by lentivirus knocking down PPM1K in neurons. We found that BCAA levels were elevated after I/R injury due to dysfunctional oxidative degradation caused by phosphorylated BCKD E1α subunit (BCKDHA). Additionally, the level of phosphorylated BCKDHA was determined by decreased PPM1K in neurons. We next demonstrated that BCAA could induce oxidative stress, lipid peroxidation, and ferroptosis in primary cultured cortical neurons in vitro. Our results further showed that BT2 could reduce neuronal ferroptosis by enhancing BCAA oxidation through inhibition of BCKDHA phosphorylation. We further found that defective BCAA catabolism could induce neuronal ferroptosis by PPM1K knockdown. Furthermore, BT2 was found to alleviate neurological behavior disorders after I/R injury in mice, and the effect was similar to ferroptosis inhibitor ferrostatin-1. Our findings reveal a novel role of BCAA in neuronal ferroptosis after cerebral ischemia and provide a new potential target for the treatment of ischemic stroke. Nature Publishing Group UK 2023-09-26 /pmc/articles/PMC10522625/ /pubmed/37752100 http://dx.doi.org/10.1038/s41419-023-06135-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Li, Tao
Zhao, Lili
Li, Ye
Dang, Meijuan
Lu, Jialiang
Lu, Ziwei
Huang, Qiao
Yang, Yang
Feng, Yuxuan
Wang, Xiaoya
Jian, Yating
Wang, Heying
Guo, Yingying
Zhang, Lei
Jiang, Yu
Fan, Songhua
Wu, Shengxi
Fan, Hong
Kuang, Fang
Zhang, Guilian
PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons
title PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons
title_full PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons
title_fullStr PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons
title_full_unstemmed PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons
title_short PPM1K mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons
title_sort ppm1k mediates metabolic disorder of branched-chain amino acid and regulates cerebral ischemia-reperfusion injury by activating ferroptosis in neurons
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522625/
https://www.ncbi.nlm.nih.gov/pubmed/37752100
http://dx.doi.org/10.1038/s41419-023-06135-x
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