Bauer M F, Neupert W
Institut fur Klinische Chemie, Molekulare Diagnostik und Mitochondriale Genetik am Akad. Lehrkrankenhaus München-Schwabing, Germany.
J Inherit Metab Dis. 2001 Apr;24(2):166-80. doi: 10.1023/a:1010314900814.
The vast majority of mitochondrial proteins are encoded as precursors by the nuclear genome. A major aspect of mitochondrial biogenesis is therefore the transfer of nuclear-encoded, cytosplasmically synthesized precursor proteins across and into the mitochondrial membranes. During the past years the use of simple model organisms such as the yeasts S. cerevisiae and N. crassa has helped considerably to identify and unravel the structure and function of a substantial number of components involved in targeting of nuclear-encoded preproteins to mitochondria. Several pathways and a number of components were characterized that are involved in guiding mitochondrial preproteins to their specific sites of function. In particular, import of nuclear-encoded precursor proteins into and across the mitochondrial inner membrane is mediated by two distinct translocases, the TIM23 complex and the TIM22 complex. Both TIM complexes cooperate with the general preprotein translocase of the outer membrane, TOM complex. The TIM complexes differ in the their substrate specificity. While the TIM23 complex mediates import of preproteins with a positively charged matrix targeting signal, the TIM22 complex facilitates the insertion of a class of hydrophobic proteins with internal targeting signals into the inner membrane. Most recently the rapid progress of research has allowed elucidation of a new mitochondrial disease on the molecular level. This rare X-linked progressive neurodegenerative disorder, named Mohr-Tranebjaerg (MT syndrome), is caused by mutations in the DDP1 gene and includes sensorineural deafness, blindness, mental retardation and a complex movement disorder. The analysis of the novel pathomechanism is based on the homology of the affected DDP1 protein to a family of conserved yeast components acting along the TIM22 pathway. This contribution briefly summarizes the current knowledge of the pathways of protein import and proposes a mechanism to explain how defective import leads to neurodegeneration.
绝大多数线粒体蛋白由核基因组编码为前体。因此，线粒体生物发生的一个主要方面是将核编码、在细胞质中合成的前体蛋白转运穿过线粒体膜并进入线粒体膜。在过去几年中，使用简单的模式生物，如酿酒酵母和粗糙脉孢菌，极大地帮助识别和阐明了大量参与将核编码前体蛋白靶向线粒体的组分的结构和功能。已鉴定出几种途径和许多参与将线粒体前体蛋白引导至其特定功能位点的组分。特别是，核编码前体蛋白进入线粒体内膜并穿过线粒体内膜是由两种不同的转位酶介导的，即TIM23复合物和TIM22复合物。这两种TIM复合物都与外膜的一般前体蛋白转位酶TOM复合物协同作用。TIM复合物在底物特异性方面有所不同。虽然TIM23复合物介导带有带正电荷的基质靶向信号的前体蛋白的导入，但TIM22复合物促进一类带有内部靶向信号的疏水蛋白插入内膜。最近，研究的快速进展使得在分子水平上阐明了一种新的线粒体疾病。这种罕见的X连锁进行性神经退行性疾病，名为莫尔-特拉内布尔耶格（MT综合征），由DDP1基因突变引起，包括感音神经性耳聋、失明、智力迟钝和复杂的运动障碍。对这种新发病机制的分析基于受影响的DDP1蛋白与沿TIM22途径起作用的一组保守酵母组分的同源性。本文简要总结了目前关于蛋白质导入途径的知识，并提出了一种机制来解释导入缺陷如何导致神经退行性变。
