The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
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DOI：
10.1073/pnas.0806192105
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发表时间：
2008-09-02
影响因子：
11.1
通讯作者：
Ankarcrona, Maria
中科院分区：
文献类型：
--
作者：
Petersen, Camilla A. Hansson;Alikhani, Nyosha;Ankarcrona, Maria
淀粉样蛋白β-肽（A β）已被建议发挥其毒性细胞内。线粒体功能可能受到A β的负面影响，并且已在线粒体中检测到A11的积累。由于A β不太可能在线粒体中局部产生，我们决定研究线粒体A β摄取的机制。我们从大鼠线粒体的结果表明，A β是通过转运酶的外膜（TOM）机器进入线粒体。进口是不敏感的缬氨霉素，表明它是独立的线粒体膜电位。进口实验后的亚分级研究显示A β与内膜部分的关联，进口后的免疫电镜显示A β定位于线粒体嵴。在正常压力脑积水患者的脑皮质活检中，免疫电镜显示线粒体中A β的分布模式相似。因此，我们提出了一个独特的进口机制，在线粒体中的A β，并证明在体外和体内，A β位于线粒体嵴。重要是，我们还表明细胞外应用的A β可以被人神经母细胞瘤细胞内化，并可以与线粒体标记物共定位。总之，这些结果提供了对A β的线粒体摄取的进一步了解，A β是一种被认为在阿尔茨海默病中具有重要意义的肽。
The amyloid beta-peptide (A beta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by A beta and accumulation of All has been detected in mitochondria. Because A beta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial A beta uptake. Our results from rat mitochondria show that A beta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed A beta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of A beta to mitochondrial cristae. A similar distribution pattern of A beta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for A beta in mitochondria and demonstrate both in vitro and in vivo that A beta is located to the mitochondrial cristae. importantly, we also show that extracellulary applied A beta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of A beta, a peptide considered to be of major significance in Alzheimer's disease.