Nolden Mark, Ehses Sarah, Koppen Mirko, Bernacchia Andrea, Rugarli Elena I, Langer Thomas
Institute for Genetics and Center for Molecular Medicine, University of Cologne, 50674 Cologne, Germany.
Cell. 2005 Oct 21;123(2):277-89. doi: 10.1016/j.cell.2005.08.003.
AAA proteases comprise a conserved family of membrane bound ATP-dependent proteases that ensures the quality control of mitochondrial inner-membrane proteins. Inactivation of AAA proteases causes pleiotropic phenotypes in various organisms, including respiratory deficiencies, mitochondrial morphology defects, and axonal degeneration in hereditary spastic paraplegia (HSP). The molecular basis of these defects, however, remained unclear. Here, we describe a regulatory role of an AAA protease for mitochondrial protein synthesis in yeast. The mitochondrial ribosomal protein MrpL32 is processed by the m-AAA protease, allowing its association with preassembled ribosomal particles and completion of ribosome assembly in close proximity to the inner membrane. Maturation of MrpL32 and mitochondrial protein synthesis are also impaired in a HSP mouse model lacking the m-AAA protease subunit paraplegin, demonstrating functional conservation. Our findings therefore rationalize mitochondrial defects associated with m-AAA protease mutants in yeast and shed new light on the mechanism of axonal degeneration in HSP.
AAA蛋白酶构成了一个保守的膜结合ATP依赖性蛋白酶家族，负责线粒体内膜蛋白的质量控制。AAA蛋白酶的失活在各种生物体中会导致多效性表型，包括呼吸缺陷、线粒体形态缺陷以及遗传性痉挛性截瘫（HSP）中的轴突变性。然而，这些缺陷的分子基础仍不清楚。在此，我们描述了一种AAA蛋白酶在酵母线粒体蛋白质合成中的调节作用。线粒体核糖体蛋白MrpL32由m-AAA蛋白酶加工处理，使其能够与预先组装好的核糖体颗粒结合，并在内膜附近完成核糖体组装。在缺乏m-AAA蛋白酶亚基截瘫蛋白的HSP小鼠模型中，MrpL32的成熟和线粒体蛋白质合成也受到损害，这证明了功能上的保守性。因此，我们的研究结果解释了酵母中与m-AAA蛋白酶突变体相关的线粒体缺陷，并为HSP中轴突变性的机制提供了新的线索。
