SHIH CHENG WUChen, Yan-JhenYan-JhenChenSu, Shih-HanShih-HanSuFang, Pai-HsiangPai-HsiangFangLiu, Rei-WenRei-WenLiuTsai, Hui-YingHui-YingTsaiChang, Yen-JuiYen-JuiChangLi, Hsing-HanHsing-HanLiLi, Jian-ChiuanJian-ChiuanLiChen, Chun-HongChun-HongChen2025-02-182025-02-182025-01-21https://scholars.lib.ntu.edu.tw/handle/123456789/725303Article Number : 105Metabolic 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.entrue[SDGs]SDG2[SDGs]SDG3journal article10.1038/s42003-025-07457-6398380822-s2.0-85216563748