Delivery of bioactive molecules to mitochondria in vivo
Delivery of bioactive molecules to mitochondria in vivo
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DOI：
10.1073/pnas.0931245100
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发表时间：
2003-04-29
影响因子：
11.1
通讯作者：
Murphy, MP
中科院分区：
文献类型：
--
作者：
Smith, RAJ;Porteous, CM;Murphy, MP
线粒体功能障碍导致许多人类退行性疾病，但特定的治疗受到阻碍。在体内将生物活性分子递送到线粒体的困难。为了克服这个问题，我们开发了一种策略，通过连接到亲脂性三苯基膦阳离子通过烷基接头将生物活性分子靶向线粒体。这些分子迅速渗透脂质双层，并且由于大的线粒体膜电位（内部为负），在分离的线粒体内和培养细胞的线粒体内积累数百倍。为了确定这种策略是否可以导致开发的ESTA-特异性疗法，我们调查了简单的烷基三苯基鳞阳离子和ESTA-靶向的抗氧化剂，包括一个三苯基鳞阳离子耦合到辅酶Q或维生素E衍生物的小鼠的管理和组织分布。这些化合物的显著剂量可以安全地长期喂养小鼠，在心脏，大脑，肝脏和肌肉中达到稳态分布。因此，可以口服给予靶向生物活性分子，导致它们在受线粒体功能障碍影响最大的那些组织中以潜在的治疗浓度积累。这一发现为在人类退行性疾病的小鼠模型中测试Dopa特异性疗法开辟了道路。
Mitochondrial dysfunction contributes to many human degenerative diseases but specific treatments are hampered by the. difficulty of delivering bioactive molecules to mitochondria in vivo. To overcome this problem we developed a strategy to target bioactive molecules to mitochondria by attachment to the lipophilic triphenylphosphonium cation through an alkyl linker. These molecules rapidly permeate lipid bilayers and, because of the large mitochondrial membrane potential (negative inside), accumulate several hundredfold inside isolated mitochondria and within mitochondria in cultured cells. To determine whether this strategy could lead to the development of mitochondria-specific therapies, we investigated the administration and tissue distribution in mice of simple alkyltriphenylphosphonium cations and of mitochondria-targeted antioxidants comprising a triphenylphosphonium cation coupled to a coenzyme Q or vitamin E derivative. Significant doses of these compounds could be fed safely to mice over long periods, coming to steady-state distributions within the heart, brain, liver, and muscle. Therefore, mitochondria-targeted bioactive molecules can be administered orally, leading to their accumulation at potentially therapeutic concentrations in those tissues most affected by mitochondrial dysfunction. This finding opens the way to the testing of mitochondria-specific therapies in mouse models of human degenerative diseases.