MODELS FOR NUCLEAR EXPRESSION OF MITOCHONDRIAL GENES

越来越多的患者被确定患有线粒体疾病。 这些疾病在临床症状、形态学和生化特征上表现出很大的多样性。 虽然mtDNA突变已在许多患者中发现，但目前还没有有效的治疗方法。一种具有克服mtDNA编码蛋白质突变的巨大潜力的方法是将受影响基因的野生型拷贝置于细胞核中，并将表达的蛋白质靶向于线粒体，以代替有缺陷的线粒体蛋白质发挥功能。人类线粒体DNA中编码的所有蛋白质都是疏水性的，位于线粒体内膜中，并具有多个跨膜区域。 有人提出，这些基因保留在mtDNA中的原因之一是它们编码的蛋白质疏水性太强，无法在细胞核中表达并转运到线粒体中。 绿藻Chlamyeliumreinhardtii和Polytomella spp. 有几个特定的呼吸链亚基基因编码在他们的核DNA，在人类中编码在线粒体DNA。 这些藻类将用于研究呼吸链亚基基因从线粒体DNA转移到细胞核。 线粒体DNA和几个核DNA编码的呼吸链复合物亚基的基因序列将被确定和分析。 这些多肽的结构特征的识别是重要的，它们的进口到线粒体中应适用于对人类疾病的基因疗法的发展所造成的突变mtDNA编码的多肽基因。

Increasing numbers of patients are being identified as suffering from mitochondrial diseases. Such diseases display great diversity in clinical symptoms and morphological and biochemical characteristics. Although mtDNA mutations have been identified in many patients, there are presently no effective treatments. One method which has great potential for overcoming mutations in mtDNA-encoded proteins is to place a wild-type copy of the affected gene in the nucleus, and target the expressed protein to the mitochondrion to function in place of the defective mitochondrial protein. All proteins encoded in human mtDNA are hydrophobic, are located in the mitochondrial inner membrane, and have multiple membrane-spanning regions. It has been proposed that one of the reasons that these genes have been retained in mtDNA is that the proteins they encode are too hydrophobic to be expressed in the nucleus and transported into mitochondria. The Chlorophytic algae Chlamydomonas reinhardtii and Polytomella spp. Have several specific respiratory chain subunit genes encoded in their nuclear DNA, that in humans are encoded in the mtDNA. These algae will be used to study the transfer of genes of the respiratory chain subunits from the mtDNA to the nucleus. The sequences of the mtDNA and of genes for several nuclear DNA-encoded respiratory chain complex subunits will be determined and analyzed. The identification of structural features of these polypeptides that are important for their import into mitochondria should be applicable towards the development of genetic therapies for human diseases resulting from mutations in mtDNA-encoded polypeptide genes.