| Autor: |
Jie Jiao, Ge Gao, Junge Zhu, Chaodong Wang, Lei Liu, Hui Yang |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Redox Biology, Vol 77, Iss , Pp 103399- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2213-2317 |
| DOI: |
10.1016/j.redox.2024.103399 |
| Popis: |
The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner—mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity in vitro and in vivo. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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