Autocatalytic Processing of m-AAA Protease Subunits in Mitochondria
Autocatalytic Processing of m-AAA Protease Subunits in Mitochondria
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DOI：
10.1091/mbc.e09-03-0218
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发表时间：
2009-10-01
影响因子：
3.3
通讯作者：
Langer, Thomas
中科院分区：
文献类型：
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作者：
Koppen, Mirko;Bonn, Florian;Langer, Thomas
m-AAA蛋白酶是线粒体内膜中的ATP依赖性蛋白水解机器，其对于维持线粒体活性至关重要。保守的核编码的亚基，称为paraplegin，Afg 3l 1，和Afg 3l 2，形成各种同工酶不同的亚基组成在哺乳动物线粒体。不同m-AAA蛋白酶亚基的突变与人类不同的神经元疾病相关。然而，m-AAA蛋白酶复合物或单个亚基的生物起源仅知之甚少。在这里，我们已经检查了加工的核编码的m-AAA蛋白酶亚基后，进口到线粒体和展示自催化加工的Afg 3L 1和Afg 3L 2。线粒体加工肽酶MPP产生自催化成熟的Afg 3l 2的中间形式。Afg 3l 1或Afg 3l 2也是新输入的paraplegin亚基在被MPP切割后成熟所必需的。我们的研究结果表明，哺乳动物的m-AAA蛋白酶可以作为加工酶在体内，并揭示重叠活动的Afg 3L 1和Afg 3L 2。这些发现可能与不同m-AAA蛋白酶亚基突变相关的神经退行性疾病的发病机制有关。
m-AAA proteases are ATP-dependent proteolytic machines in the inner membrane of mitochondria which are crucial for the maintenance of mitochondrial activities. Conserved nuclear-encoded subunits, termed paraplegin, Afg3l1, and Afg3l2, form various isoenzymes differing in their subunit composition in mammalian mitochondria. Mutations in different m-AAA protease subunits are associated with distinct neuronal disorders in human. However, the biogenesis of m-AAA protease complexes or of individual subunits is only poorly understood. Here, we have examined the processing of nuclear-encoded m-AAA protease subunits upon import into mitochondria and demonstrate autocatalytic processing of Afg3l1 and Afg3l2. The mitochondrial processing peptidase MPP generates an intermediate form of Afg3l2 that is matured autocatalytically. Afg3l1 or Afg3l2 are also required for maturation of newly imported paraplegin subunits after their cleavage by MPP. Our results establish that mammalian m-AAA proteases can act as processing enzymes in vivo and reveal overlapping activities of Afg3l1 and Afg3l2. These findings might be of relevance for the pathogenesis of neurodegenerative disorders associated with mutations in different m-AAA protease subunits.