Mitochondrial Parts, Pathways, and Pathogenesis

线粒体部分、途径和发病机制 摘要 线粒体是真核生物的核心古老的细胞器。这些细胞器的缺陷导致 一系列人类疾病，从罕见的先天性代谢缺陷到常见的年龄- 相关的退行性疾病。我们实验室的长期目标是实现一个系统- 这一细胞器，可以作为研究线粒体的基础， 健康和疾病。NIGMS为我们的实验室提供了基础资金， 使我们能够系统地定义线粒体的蛋白质部分， 他们进入功能途径，并确定蛋白质和途径，基础人类 疾病我们已经取得了巨大的进步，包括生产MitoCarta， 使用的线粒体蛋白部分目录。我们已经将许多以前未研究过的 蛋白质的生物途径和人类疾病。然而，蛋白质库存尚未 此外，它还包含数百种研究不足的蛋白质， 健康或疾病的生物过程。在未来5年，我们的目标是利用新兴的 蛋白质组学、贝叶斯统计、CRISPR和高分辨率代谢组学技术， 人类遗传学揭示了线粒体蛋白质组暗角的功能，同时也 开创了可以推广到细胞内其他途径的新方法。

Mitochondrial Parts, Pathways, and Pathogenesis ABSTRACT Mitochondria are ancient organelles central to eukaryotic life. Defects in these organelles underlie a spectrum of human diseases, ranging from rare inborn errors of metabolism to common age- associated degenerative diseases. The long-term goal of our laboratory is to achieve a systems- level understanding of this organelle that can serve as a foundation for studying mitochondria in health and in disease. NIGMS has provided the foundational funding for our laboratory which has enabled our ongoing efforts to systematically define the mitochondria's protein parts, organize them into functional pathways, and identify the proteins and pathways that underlie human disease. We have made tremendous progress, including producing MitoCarta, the most widely used catalog of mitochondrial protein parts. We have linked dozens of previously unstudied proteins to biological pathways and human diseases. However the protein inventory is not yet comprehensive and moreover contains hundreds of poorly studied proteins unlinked to any biological process in health or disease. In the next 5 years we aim to leverage emerging technologies in proteomics, Bayesian statistics, CRISPR, and high-resolution metabolomics, and human genetics to unveil the function of the dark corners of the mitochondrial proteome, while also pioneering new methods that can be generalized to other pathways within the cell.