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Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice

机译：Omi线粒体蛋白酶活性的丧失导致mnd2突变小鼠的神经肌肉疾病

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The mouse mutant mnd2 (motor neuron degeneration 2) exhibits muscle wasting, neurodegeneration, involution of the spleen and thymus, and death by 40 days of age. Degeneration of striatal neurons, with astrogliosis and microglia activation, begins at around 3 weeks of age, and other neurons are affected at later stages. Here we have identified the mnd2 mutation as the missense mutation Ser276Cys in the protease domain of the nuclear-encoded mitochondrial serine protease Omi (alsoknown as HtrA2 or Prss25). Protease activity of Omi is greatly reduced in tissues of mnd2 mice but is restored in mice rescued by a bacterial artificial chromosome transgene containing the wild-type Omi gene. Deletion of the PDZ domain partially restores protease activity to the inactive recombinant Omi protein carrying the Ser276Cys mutation, suggesting that the mutation impairs substrate access or binding to the active site pocket. Loss of Omi protease activity increases the susceptibility of mitochondria to induction of the permeability transition, and increases the sensitivity of mouse embryonic fibroblasts to stress-induced cell death. The neurodegeneration and juvenile lethality in mnd2 mice result from this defect in mitochondrial Omi protease.
机译：小鼠突变体mnd2（运动神经元变性2）在40天龄时表现出肌肉萎缩，神经变性，脾脏和胸腺退化以及死亡。星形胶质细胞增多和小胶质细胞活化导致的纹状体神经元变性在3周龄左右开始，其他神经元则在后期受到影响。在这里，我们已将mnd2突变鉴定为核编码的线粒体丝氨酸蛋白酶Omi（也称为HtrA2或Prss25）的蛋白酶结构域中的错义突变Ser276Cys。在mnd2小鼠的组织中，Omi的蛋白酶活性大大降低，但在包含野生型Omi基因的细菌人工染色体转基因拯救的小鼠中，Omi的蛋白酶活性得以恢复。 PDZ结构域的删除部分恢复了蛋白酶活性，使其恢复为带有Ser276Cys突变的非活性重组Omi蛋白，表明该突变会损害底物接近或结合至活性位点口袋。 Omi蛋白酶活性的丧失增加了线粒体对通透性转变的诱导的敏感性，并增加了小鼠胚胎成纤维细胞对应激诱导的细胞死亡的敏感性。 mnd2小鼠的神经变性和幼年致死率是由线粒体Omi蛋白酶的这种缺陷引起的。

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