Cenini Giovanna, Rüb Cornelia, Bruderek Michael, Voos Wolfgang
Institut für Biochemie und Molekularbiologie, Universität Bonn, 53115 Bonn, Germany.
Institut für Biochemie und Molekularbiologie, Universität Bonn, 53115 Bonn, Germany
Mol Biol Cell. 2016 Nov 1;27(21):3257-3272. doi: 10.1091/mbc.E16-05-0313. Epub 2016 Sep 14.
Aβ peptides play a central role in the etiology of Alzheimer disease (AD) by exerting cellular toxicity correlated with aggregate formation. Experimental evidence has shown intraneuronal accumulation of Aβ peptides and interference with mitochondrial functions. Nevertheless, the relevance of intracellular Aβ peptides in the pathophysiology of AD is controversial. Here we found that the two major species of Aβ peptides, in particular Aβ42, exhibited a strong inhibitory effect on the preprotein import reactions essential for mitochondrial biogenesis. However, Aβ peptides interacted only weakly with mitochondria and did not affect the inner membrane potential or the structure of the preprotein translocase complexes. Aβ peptides significantly decreased the import competence of mitochondrial precursor proteins via an extramitochondrial coaggregation mechanism. Coaggregation and import inhibition were significantly stronger for the longer peptide Aβ42, correlating with its importance in AD pathology. Our results demonstrate that direct interference of aggregation-prone Aβ peptides with mitochondrial protein biogenesis represents a crucial aspect of the pathobiochemical mechanisms contributing to cellular damage in AD.
淀粉样β肽（Aβ肽）通过产生与聚集体形成相关的细胞毒性，在阿尔茨海默病（AD）的病因学中发挥核心作用。实验证据表明，Aβ肽在神经元内积累并干扰线粒体功能。然而，细胞内Aβ肽在AD病理生理学中的相关性仍存在争议。在此，我们发现两种主要的Aβ肽，特别是Aβ42，对线粒体生物发生所必需的前体蛋白导入反应表现出强烈的抑制作用。然而，Aβ肽与线粒体的相互作用较弱，不影响内膜电位或前体蛋白转位酶复合物的结构。Aβ肽通过线粒体外共聚集机制显著降低线粒体前体蛋白的导入能力。较长的肽Aβ42的共聚集和导入抑制作用明显更强，这与其在AD病理学中的重要性相关。我们的结果表明，易于聚集的Aβ肽对线粒体蛋白生物合成的直接干扰是导致AD细胞损伤的病理生化机制的一个关键方面。
