Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia
Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia
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DOI：
10.1128/mcb.01470-06
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发表时间：
2007-01-01
影响因子：
5.3
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
--
作者：
Koppen, Mirko;Metodiev, Metodi D.;Langer, Thomas
m-AAA蛋白酶是线粒体内膜上的一种atp依赖的蛋白水解复合物，它控制蛋白质质量并调节核糖体的组装，从而在线粒体内发挥重要的内务管理功能。在遗传性痉挛性截瘫（HSP）中，m-AAA蛋白酶亚基截瘫蛋白突变引起轴突变性，但这种意外组织特异性的基础尚不清楚。Paraplegin与同源Afg312亚基组装成异寡聚复合物，可以替代酵母m-AAA蛋白酶，具有功能保守性。在小鼠中表达的第三个平行序列Afg311的功能尚不清楚。在这里，我们分析了截瘫蛋白在m-AAA复合物中的组装，并在热休克蛋白成纤维细胞和热休克蛋白小鼠模型中监测截瘫蛋白缺乏的后果。我们的研究结果揭示了不同组织线粒体中m-AAA蛋白酶组装的变异性。可以形成具有截瘫蛋白的Afg311和Afg312的同质寡聚复合物和异质寡聚组合。酵母互补研究证明了这些组合的蛋白水解活性。HSP截瘫缺乏并不会导致脑线粒体中m-AAA蛋白酶活性的丧失。相反，同质寡聚Afg312复合物积累，这些复合物可以替代含有截瘫蛋白的m-AAA复合物的清洁功能。因此，我们提出，基质特异性改变的m-AAA蛋白酶的形成导致HSP的轴突变性。
The m-AAA protease, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, controls protein quality and regulates ribosome assembly, thus exerting essential housekeeping functions within mitochondria. Mutations in the m-AAA protease subunit paraplegin cause axonal degeneration in hereditary spastic paraplegia (HSP), but the basis for the unexpected tissue specificity is not understood. Paraplegin assembles with homologous Afg312 subunits into hetero-oligomeric complexes which can substitute for yeast m-AAA proteases, demonstrating functional conservation. The function of a third paralogue, Afg311 expressed in mouse, is unknown. Here, we analyze the assembly of paraplegin into m-AAA complexes and monitor consequences of paraplegin deficiency in HSP fibroblasts and in a mouse model for HSP. Our findings reveal variability in the assembly of m-AAA proteases in mitochondria in different tissues. Homo-oligomeric Afg311 and Afg312 complexes and hetero-oligomeric assemblies of both proteins with paraplegin can be formed. Yeast complementation studies demonstrate the proteolytic activity of these assemblies. Paraplegin deficiency in HSP does not result in the loss of m-AAA protease activity in brain mitochondria. Rather, homo-oligomeric Afg312 complexes accumulate, and these complexes can substitute for housekeeping functions of paraplegin-containing m-AAA complexes. We therefore propose that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in HSP.