Mitochondrial replacement by genome transfer in human oocytes: Efficacy, concerns, and legality.
Mitochondrial replacement by genome transfer in human oocytes: Efficacy, concerns, and legality.
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DOI：
10.1002/rmb2.12356
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发表时间：
2021-01
影响因子：
3.4
通讯作者：
Tanaka M
中科院分区：
文献类型：
--
作者：
Yamada M;Sato S;Ooka R;Akashi K;Nakamura A;Miyado K;Akutsu H;Tanaka M
致病性线粒体（mt）DNA突变通常会导致危及生命的疾病，通过卵母细胞的细胞质进行母系遗传。线粒体替代疗法（MRT）有望防止mtDNA突变的第二代传播。然而，MRT可能会影响由核蛋白和线粒体蛋白组成的呼吸链复合物的功能。基于文献和当前的监管指南（特别是在日本），我们分析和回顾了MRT人体模型的最新进展。MRT不会影响植入前发育或干细胞分离。MRT后干细胞中的线粒体功能也正常。虽然mtDNA携带通常小于0.5%，但即使是低水平的异质性也会影响mtDNA基因型的稳定性，并且在干细胞系的子集中发生定向或随机mtDNA漂移（mtDNA遗传漂移）。MRT可以防止严重的遗传疾病遗传给后代。然而，应该注意的是，这种技术目前对用于植入的胚胎的使用构成了重大风险。母体基因组与不同的线粒体基因型基本上是相容的，并且正常的线粒体功能不需要垂直遗传。关于mtDNA遗传漂变的未解决的问题可以通过使用MRT的基础研究来解决。这篇综述讨论了目前的方法和合法性有关的线粒体替代，以防止遗传的线粒体疾病，如脑肌病，心肌病，听力损失，糖尿病和肾功能损害，所造成的致病性突变的线粒体DNA。虽然在预防突变mtDNA传播的治疗领域已经取得了相关进展，但仍然存在一些问题和挑战，例如mtDNA携带，mtDNA遗传漂变和供体-受体相容性。
Pathogenic mitochondrial (mt)DNA mutations, which often cause life‐threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second‐generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins. Based on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT. MRT does not compromise pre‐implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation. The maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT. This review discusses current approaches and legality regarding mitochondrial replacement for preventing the inheritance of mitochondrial diseases such as encephalomyopathy, cardiomyopathy, hearing loss, diabetes, and renal impairment, caused by pathogenic mutations in mtDNA. Although relevant advances have been achieved in the field of treatments for preventing mutant mtDNA transmission, some concerns and challenges remain such as mtDNA carryover, mtDNA genetic drift, and donor‐recipient compatibility.
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影响因子：
8.8
作者：
Lee HS;Ma H;Juanes RC;Tachibana M;Sparman M;Woodward J;Ramsey C;Xu J;Kang EJ;Amato P;Mair G;Steinborn R;Mitalipov S
通讯作者：
Mitalipov S
影响因子：
9.8
作者：
Elliott, Hannah R.;Samuels, David C.;Eden, James A.;Relton, Caroline L.;Chinnery, Patrick F.
通讯作者：
Chinnery, Patrick F.
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
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影响因子：
6.7
作者：
Fiorentino, Francesco;Biricik, Anil;Michel, Claude-Edouard
通讯作者：
Michel, Claude-Edouard