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PNAS:新研究构建出同时携带父母双方线粒体的胚胎

来源:生物谷 2016-09-08 12:21


(红色代表精子线粒体,蓝色代表父母来源DNA,绿色代表泛素蛋白)

2016年9月8日讯 /生物谷BIOON/ --最近来自美国密苏里大学的研究人员在国际学术期刊PNAS上发表了一项新研究,在该研究中他们成功构建出存在线粒体DNA异质性(heteroplasmy)的胚胎,胚胎细胞中既有母系来源的线粒体DNA也有父系来源的线粒体DNA。这将帮助科学家们开发治疗人类线粒体疾病的新方法,同时研究线粒体遗传的重要性。

在基因的遗传过程中,子代获得的绝大多数基因都会非常平均地来自父亲和母亲,只有线粒体DNA只来自母亲,进入受精卵的父系来源的线粒体会被自然清除。在这项研究中研究人员在猪的胚胎中发现了一条阻止父系来源的线粒体DNA被移除的新途径,因此构建出存在线粒体DNA异质性的胚胎。

在这项研究中,研究人员发现两个泛素结合蛋白,分别叫做SQSTM1和VCP,他们认为在胚胎内这两个分子负责移除父亲精子来源的线粒体及其中的线粒体DNA。

研究人员通过分别抑制SQSTM1和VCP进行了实验研究,结果发现当一个蛋白被抑制,另外一个蛋白仍然能够执行功能将受精卵中父系来源的线粒体清除。但是当研究人员同时抑制两个蛋白,父系来源的线粒体没有被清除,保存在胚胎中。

“这项研究非常重要,我们现在非常确定地知道哪些过程会导致父系来源的线粒体从胚胎中清除。了解这些信息将帮助我们进一步探索一些儿童如何发展为严重的线粒体疾病。借助该项研究我们可以开发出新的治疗方法,或可帮助预防或减少线粒体DNA异质性和其他线粒体紊乱造成的影响。”研究人员这样说道。(生物谷Bioon.com)

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 doi: 10.1073/pnas.1605844113

Autophagy and ubiquitin–proteasome system contribute to sperm mitophagy after mammalian fertilization

Maternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochondria after fertilization. However, it is not clear how the 26S proteasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mammalian sperm mitophagy. We found that the SQSTM1, but not GABARAP or LC3, associated with sperm mitochondria after fertilization in pig and rhesus monkey zygotes. Three sperm mitochondrial proteins copurified with the recombinant, ubiquitin-associated domain of SQSTM1. The accumulation of GABARAP-containing protein aggregates was observed in the vicinity of sperm mitochondrial sheaths in the zygotes and increased in the embryos treated with proteasomal inhibitor MG132, in which intact sperm mitochondrial sheaths were observed. Pharmacological inhibition of VCP significantly delayed the process of sperm mitophagy and completely prevented it when combined with microinjection of autophagy-targeting antibodies specific to SQSTM1 and/or GABARAP. Sperm mitophagy in higher mammals thus relies on a combined action of SQSTM1-dependent autophagy and VCP-mediated dislocation and presentation of ubiquitinated sperm mitochondrial proteins to the 26S proteasome, explaining how the whole sperm mitochondria are degraded inside the fertilized mammalian oocytes by a protein recycling system involved in degradation of single protein molecules.

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