Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction
Abstract Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07457-6 |
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| author | Shih-Cheng Wu Yan-Jhen Chen Shih-Han Su Pai-Hsiang Fang Rei-Wen Liu Hui-Ying Tsai Yen-Jui Chang Hsing-Han Li Jian-Chiuan Li Chun-Hong Chen |
| author_facet | Shih-Cheng Wu Yan-Jhen Chen Shih-Han Su Pai-Hsiang Fang Rei-Wen Liu Hui-Ying Tsai Yen-Jui Chang Hsing-Han Li Jian-Chiuan Li Chun-Hong Chen |
| author_sort | Shih-Cheng Wu |
| collection | DOAJ |
| description | Abstract Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions. |
| format | Article |
| id | doaj-art-fb5586af25a94644b1320c471004db3c |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-fb5586af25a94644b1320c471004db3c2025-01-26T12:48:14ZengNature PortfolioCommunications Biology2399-36422025-01-018111710.1038/s42003-025-07457-6Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interactionShih-Cheng Wu0Yan-Jhen Chen1Shih-Han Su2Pai-Hsiang Fang3Rei-Wen Liu4Hui-Ying Tsai5Yen-Jui Chang6Hsing-Han Li7Jian-Chiuan Li8Chun-Hong Chen9Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan UniversityNational Institute of Infectious Diseases and Vaccinology, National Health Research InstitutesDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan UniversityNational Institute of Infectious Diseases and Vaccinology, National Health Research InstitutesNational Institute of Infectious Diseases and Vaccinology, National Health Research InstitutesNational Institute of Infectious Diseases and Vaccinology, National Health Research InstitutesDepartment of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan UniversityNational Institute of Infectious Diseases and Vaccinology, National Health Research InstitutesNational Institute of Infectious Diseases and Vaccinology, National Health Research InstitutesNational Institute of Infectious Diseases and Vaccinology, National Health Research InstitutesAbstract Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.https://doi.org/10.1038/s42003-025-07457-6 |
| spellingShingle | Shih-Cheng Wu Yan-Jhen Chen Shih-Han Su Pai-Hsiang Fang Rei-Wen Liu Hui-Ying Tsai Yen-Jui Chang Hsing-Han Li Jian-Chiuan Li Chun-Hong Chen Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction Communications Biology |
| title | Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction |
| title_full | Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction |
| title_fullStr | Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction |
| title_full_unstemmed | Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction |
| title_short | Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction |
| title_sort | dysfunctional bcaa degradation triggers neuronal damage through disrupted ampk mitochondrial axis due to enhanced pp2ac interaction |
| url | https://doi.org/10.1038/s42003-025-07457-6 |
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