A disease-associated Aifm1 variant induces severe myopathy in knockin mice.
A disease-associated Aifm1 variant induces severe myopathy in knockin mice.
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DOI：
10.1016/j.molmet.2018.05.002
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发表时间：
2018-07
影响因子：
8.1
通讯作者：
Bano D
中科院分区：
文献类型：
--
作者：
Wischhof L;Gioran A;Sonntag-Bensch D;Piazzesi A;Stork M;Nicotera P;Bano D
已在隐性X连锁线粒体疾病中发现AIFM1基因突变。这些致病AIFM1突变的功能和分子后果在体内研究得很少。在这里，我们提供了疾病相关的凋亡诱导因子(AIF)缺失的精氨酸201(啮齿动物中的R200)导致敲门小鼠病理的证据。在几个月内，突变的AIF蛋白的翻译后丢失导致严重的肌病，与较少数量的细胞色素c氧化酶阳性的肌肉纤维有关。在后来的阶段，Aifm1(R200 Del)敲击小鼠表现出周围神经病变，但它们不像年龄匹配的低形小丑(HQ)突变小鼠那样在小脑表现出神经变性过程。定量蛋白质组学和生化数据突出了线粒体疾病的常见分子特征，包括叶酸驱动的一碳代谢异常和持续的Akt/mTOR信号。我们的发现表明，由于致病的AIFM1突变，代谢缺陷和明显的组织特异性脆弱性，具有许多与患者相似的病理特征。Aifm1(R200 Del)突变导致敲门小鼠早发性肌病。Aifm1(R200 Del)敲击动物不会发生小脑变性。突变型AIF的表达改变了线粒体功能和Akt/mTOR活性。AIF缺乏导致叶酸驱动的一碳代谢异常。雷帕霉素治疗改善AIF缺陷小鼠的代谢功能障碍。
Mutations in the AIFM1 gene have been identified in recessive X-linked mitochondrial diseases. Functional and molecular consequences of these pathogenic AIFM1 mutations have been poorly studied in vivo. Here we provide evidence that the disease-associated apoptosis-inducing factor (AIF) deletion arginine 201 (R200 in rodents) causes pathology in knockin mice. Within a few months, posttranslational loss of the mutant AIF protein induces severe myopathy associated with a lower number of cytochrome c oxidase-positive muscle fibers. At a later stage, Aifm1 (R200 del) knockin mice manifest peripheral neuropathy, but they do not show neurodegenerative processes in the cerebellum, as observed in age-matched hypomorphic Harlequin (Hq) mutant mice. Quantitative proteomic and biochemical data highlight common molecular signatures of mitochondrial diseases, including aberrant folate-driven one-carbon metabolism and sustained Akt/mTOR signaling. Our findings indicate metabolic defects and distinct tissue-specific vulnerability due to a disease-causing AIFM1 mutation, with many pathological hallmarks that resemble those seen in patients. Aifm1 (R200 del) mutation causes early-onset myopathy in knockin mice. Aifm1 (R200 del) knockin animals do not develop cerebellar degeneration. Expression of mutant AIF alters mitochondrial function and Akt/mTOR activity. AIF deficiency induces aberrant folate-driven one-carbon metabolism. Rapamycin treatment improves metabolic dysfunction in AIF deficient mice.
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影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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