Leyfer Dmitriy, Fetterman Jessica L
Translational Sciences Department, Mitobridge, division of Astellas, Cambridge, MA 02138, USA.
Bioinformatics Program, Boston University, Boston, MA 02215, USA.
NAR Genom Bioinform. 2023 Dec 19;5(4):lqad107. doi: 10.1093/nargab/lqad107. eCollection 2023 Dec.
Mitochondrial diseases are the result of pathogenic variants in genes involved in the diverse functions of the mitochondrion. A comprehensive list of mitochondrial genes is needed to improve gene prioritization in the diagnosis of mitochondrial diseases and development of therapeutics that modulate mitochondrial function. MitoCarta is an experimentally derived catalog of proteins localized to mitochondria. We sought to expand this list of mitochondrial proteins to identify proteins that may not be localized to the mitochondria yet perform important mitochondrial functions. We used a computational approach to assign statistical significance to the overlap between STRING database gene network neighborhoods and MitoCarta proteins. Using a data-driven stringent significance threshold, 2059 proteins that were not located in MitoCarta were identified, which we termed mitochondrial proximal (MitoProximal) proteins. We identified all of the oxidative phosphorylation complex subunits and 90% of 149 genes that contain confirmed oxidative phosphorylation disease causal variants, lending validation to our methodology. Among the MitoProximal proteins, 134 are annotated to be localized to mitochondria but are not in the MitoCarta 3.0 database. We extend MitoCarta nearly 3-fold, generating a more comprehensive list of mitochondrial genes, a resource to facilitate the identification of pathogenic variants in mitochondrial and metabolic diseases.
线粒体疾病是由参与线粒体多种功能的基因中的致病变异引起的。需要一份全面的线粒体基因列表，以在诊断线粒体疾病和开发调节线粒体功能的治疗方法时更好地进行基因优先级排序。MitoCarta是一份通过实验得出的定位于线粒体的蛋白质目录。我们试图扩展这份线粒体蛋白质列表，以识别那些可能未定位于线粒体但执行重要线粒体功能的蛋白质。我们使用一种计算方法来确定STRING数据库基因网络邻域与MitoCarta蛋白质之间重叠的统计显著性。使用数据驱动的严格显著性阈值，我们鉴定出2059种不在MitoCarta中的蛋白质，我们将其称为线粒体近端（MitoProximal）蛋白质。我们鉴定出了所有氧化磷酸化复合体亚基以及149个含有已确认的氧化磷酸化疾病致病变体基因中的90%，这为我们的方法提供了验证。在MitoProximal蛋白质中，有134种被注释为定位于线粒体，但不在MitoCarta 3.0数据库中。我们将近似地将MitoCarta扩展了3倍，生成了一份更全面的线粒体基因列表，这是一种有助于识别线粒体和代谢疾病中致病变异的资源。
