The potential benefits of PGC-1α in treating Alzheimer's disease are dependent on the integrity of the LLKYL L3 motif: Effect of regulating mitochondrial axonal transportation.

Autor: Shi HZ; The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, PR China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China., Wang YJ; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China., Wang YX; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China., Xu LF; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China., Pan W; The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, PR China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China., Shi L; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China. Electronic address: 13815480698@163.com., Wang J; The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province 212001, PR China; Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China; Zhenjiang Jieshengrui Biotechnology Co., Ltd, Zhenjiang, Jiangsu 212013, PR China. Electronic address: wangjia@ujs.edu.cn.
Jazyk: angličtina
Zdroj: Experimental gerontology [Exp Gerontol] 2024 Sep; Vol. 194, pp. 112514. Date of Electronic Publication: 2024 Jul 05.
DOI: 10.1016/j.exger.2024.112514
Abstrakt: Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). The transcriptional coactivator PPARγ coactivator 1 (PGC-1a) has been identified as a key regulator of mitochondrial biogenesis and function. However, the precise structure/function relationship between PGC-1a and mitochondrial quality control remains incompletely understood. In this study, we investigated the impact of PGC-1a on AD pathology and its underlying mechanisms with a specific focus on mitochondrial axonal transport. Additionally, we generated two PGC-1α mutants by substituting leucine residues at positions 148 and 149 within the LKKLL motif or at positions 209 and 210 within the LLKYL motif with alanine. Subsequently, we examined the effects of these mutants on mutAPP-induced abnormalities in anterograde and retrograde axonal transport, disrupted mitochondrial distribution, and impaired mitophagy. Mutagenesis studies revealed that the LLKYL motif at amino acid position 209-210 within PGC-1α plays an essential role in its interaction with estrogen-related receptors (ERRα), which is necessary for restoring normal mitochondrial anterograde axonal transport, maintaining proper mitochondrial distribution, and ultimately preventing neuronal apoptosis. Furthermore, it was found that the Leu-rich motif at amino acids 209-210 within PGC-1α is crucial for rescuing mutAPP-induced impairment in mitophagy and loss of membrane potential by restoring normal mitochondrial retrograde axonal transport. Conversely, mutation of residues 148 and 149 in the LKKLL motif does not compromise the effectiveness of PGC-1α. These findings provide valuable insights into the molecular determinants governing specificity of action for PGC-1α involved in regulating mutAPP-induced deficits in mitochondrial axonal trafficking. Moreover, they suggest a potential therapeutic target for addressing Alzheimer's disease.
Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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