线粒体功能障碍是帕金森病(PD)病理的一个中心方面,然而,潜在的机制还没有完全理解。这项研究调查了α-突触核蛋白(α-Syn)病理与线粒体外膜40(TOM40)转位酶丢失之间的联系,揭示其对神经元线粒体功能障碍的影响。我们发现,TOM40蛋白耗竭发生在关岛帕金森病痴呆(关岛PD)患者的大脑和培养的表达α-Syn蛋白病的神经元,特别是,TOM40mRNA水平没有相应变化。表达α-Syn突变体的培养神经元,有或没有线粒体靶向信号(MTS)强调了α-Syn线粒体定位在诱导TOM40降解中的作用。帕金森病相关病因,如6-羟基多巴胺或ROS/金属离子胁迫,促进α-Syn寡聚化,SNCA基因三重复会加剧PD患者来源细胞的TOM40耗竭。尽管α-Syn与线粒体外膜中的TOM40和TOM20相互作用,降解对TOM40具有选择性,TOM40通过泛素-蛋白酶体系统(UPS)途径发生。我们使用海马技术进行综合分析,线粒体DNA测序,和损害评估,证明突变型α-Syn诱导的TOM40丢失导致线粒体功能障碍,以降低的膜电位为特征,mtDNA损伤的积累,缺失/插入突变,和改变耗氧率。值得注意的是,使用ADP-核糖基化抑制剂异位补充TOM40或减少α-Syn的病理形式可改善这些线粒体缺陷,建议潜在的治疗途径。总之,我们的发现为α-Syn积累如何导致TOM40降解和线粒体功能障碍提供了关键的机制见解,为有针对性的干预措施提供见解,以减轻PD中的线粒体缺陷。
Mitochondrial dysfunction is a central aspect of Parkinson\'s disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (
TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that
TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in
TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscore the role of α-Syn\'s mitochondrial localization in inducing TOM40 degradation. Parkinson\'s Disease related etiological factors, such as 6-hydroxy dopamine or ROS/metal ions stress, which promote α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both
TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for
TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.