Adaptive antioxidant methionine accumulation in respiratory chain complexes explains the use of a deviant genetic code in mitochondria
Adaptive antioxidant methionine accumulation in respiratory chain complexes explains the use of a deviant genetic code in mitochondria
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DOI：
10.1073/pnas.0802779105
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发表时间：
2008-10-28
影响因子：
11.1
通讯作者：
Moosmann, Bernd
中科院分区：
文献类型：
--
作者：
Bender, Aline;Hajieva, Parvana;Moosmann, Bernd
人类和大多数其他动物使用两种不同的遗传密码来翻译他们的遗传信息：核编码蛋白质的标准代码和线粒体中该代码的现代变体。尽管遗传密码在细胞生物学中起着关键作用，但自1979年首次描述线粒体密码以来，其功能意义一直是个谜。在这里，我们发现在大多数线粒体谱系中，编码蛋白水平上深刻的和功能上有益的改变是导致AUA密码子从异亮氨酸重分配到蛋氨酸的原因。我们证明，这种密码子重分配导致易氧化氨基酸蛋氨酸在高度氧化的线粒体内膜大量积累。如果考虑到蛋氨酸的抗氧化表面化学，这个看似矛盾的结果可以顺利解决，我们提出了直接的实验证据，表明蛋氨酸的膜内积累在活细胞中具有抗氧化和细胞保护特性。我们的研究结果揭示了蛋氨酸是一种进化选择的呼吸链复合物的抗氧化剂构建块。因此，集体蛋白质改变可以构成密码子重配背后的选择优势，从而验证了遗传密码进化的“模糊解码”假说。氧化应激影响了线粒体的遗传密码。
Humans and most other animals use 2 different genetic codes to translate their hereditary information: the standard code for nuclear-encoded proteins and a modern variant of this code in mitochondria. Despite the pivotal role of the genetic code for cell biology, the functional significance of the deviant mitochondrial code has remained enigmatic since its first description in 1979. Here, we show that profound and functionally beneficial alterations on the encoded protein level were causative for the AUA codon reassignment from isoleucine to methionine observed in most mitochondrial lineages. We demonstrate that this codon reassignment leads to a massive accumulation of the easily oxidized amino acid methionine in the highly oxidative inner mitochondrial membrane. This apparently paradoxical outcome can yet be smoothly settled if the antioxidant surface chemistry of methionine is taken into account, and we present direct experimental evidence that intramembrane accumulation of methionine exhibits antioxidant and cytoprotective properties in living cells. Our results unveil that methionine is an evolutionarily selected antioxidant building block of respiratory chain complexes. Collective protein alterations can thus constitute the selective advantage behind codon reassignments, which authenticates the "ambiguous decoding" hypothesis of genetic code evolution. Oxidative stress has shaped the mitochondrial genetic code.