Dysfunctional BCAA degradation triggers neuronal damage through disrupted AMPK-mitochondrial axis due to enhanced PP2Ac interaction.
Journal
Communications biology
Journal Volume
8
Journal Issue
1
ISSN
2399-3642
Date Issued
2025-01-21
Author(s)
Chen, Yan-Jhen
Su, Shih-Han
Fang, Pai-Hsiang
Liu, Rei-Wen
Tsai, Hui-Ying
Chang, Yen-Jui
Li, Hsing-Han
Li, Jian-Chiuan
Chen, Chun-Hong
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.
Description
Article Number : 105
Type
journal article