Abstract

Reductions in the activities of mitochondrial electron transport chain (ETC) enzymes have been implicated in the pathogenesis of numerous chronic neurodegenerative disorders. Maintenance of the mitochondrial membrane potential (Δψ_m) is a primary function of these enzyme complexes, and is essential for ATP production and neuronal survival. We examined the effects of inhibition of mitochondrial ETC complexes I, II/III, III and IV activities by titrations of respective inhibitors on Δψ_m in synaptosomal mitochondria. Small perturbations in the activity of complex I, brought about by low concentrations of rotenone (1–50 nM), caused depolarisation of Δψ_m. Small decreases in complex I activity caused an immediate and partial Δψ_m depolarisation, whereas inhibition of complex II/III activity by more than 70% with antimycin A was required to affect Δψ_m. A similarly high threshold of inhibition was found when complex III was inhibited with myxothiazol, and inhibition of complex IV by more than 90% with KCN was required. The plasma membrane potential (Δψ_p) had a complex I inhibition threshold of 40% whereas complex III and IV had to be inhibited by more than 90% before changes in Δψ_p were registered. These data indicate that in synaptosomes, both Δψ_m and Δψ_p are more susceptible to reductions in complex I activity than reductions in the other ETC complexes. These findings may be of relevance to the mechanism of neuronal cell death in Parkinson’s disease in particular, where such reductions in complex I activity are present.

中文翻译：

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复合体 I 控制神经末梢的线粒体和质膜电位

摘要

线粒体电子传递链 (ETC) 酶活性的降低与许多慢性神经退行性疾病的发病机制有关。维持线粒体膜电位 (Δ ψ _m ) 是这些酶复合物的主要功能，对 ATP 产生和神经元存活至关重要。我们通过滴定各个抑制剂对突触体线粒体中的Δ ψ _m来检查对线粒体 ETC 复合物 I、II/III、III 和 IV 活性的抑制作用。由低浓度鱼藤酮 (1-50 nM) 引起的复合物 I 活性的小扰动导致 Δ ψ _m去极化。复合物 I 活性的小幅下降导致立即和部分 Δψ _m去极化，而需要用抗霉素 A 抑制复合物 II/III 活性 70% 以上才能影响 Δ ψ _m。当用粘噻唑抑制复合物 III 时发现了类似的高抑制阈值，需要用 KCN 抑制复合物 IV 90% 以上。质膜电位 (Δ ψ _p ) 的复合物 I 抑制阈值为 40%，而复合物 III 和 IV 必须被抑制 90% 以上才能记录 Δ ψ _{p 的}变化。这些数据表明，在突触体中，Δ ψ _m和 Δ ψ _p与其他 ETC 复合物的减少相比，更容易受到复合物 I 活性减少的影响。这些发现可能与帕金森病中神经元细胞死亡的机制有关，特别是在复合物 I 活性降低的情况下。