秀丽线虫Y56A3A.22调控线粒体铁代谢和蛋白稳态的机制研究

铁作为一种必需微量元素，在氧气运输、电子传递、细胞代谢、基因表达等生命活动中发挥重要功能。在动物细胞中，线粒体是铁代谢的主要场所。绝大部分铁离子要在线粒体内被合成血红素和铁硫簇，而线粒体的氧化磷酸化、三羧酸循环等代谢过程又依赖铁。我们过去在红细胞上发现一个新的线粒体蛋白FAM210B，它参与调节线粒体铁代谢。目前，FAM210B及其蛋白家族的功能机制还不清楚。我们发现秀丽线虫有且仅有一个FAM210家族基因，Y56A3A.22，它为研究该家族的功能机制提供了一个理想模式体系。通过初步的基因敲入、基因敲除等实验，我们发现Y56A3A.22也定位于线粒体，并且它在线虫生殖、线粒体铁代谢和蛋白代谢中发挥重要功能。本项目将在前期工作基础上，深入研究Y56A3A.22及其同源蛋白调控线粒体代谢及功能的分子机制。研究结果有望阐明FAM210蛋白家族的功能机制，并拓展对线粒体铁吸收及蛋白稳态调控的认识。

Iron is an essential trace element with a crucial role in regulating numerous processes such as oxygen transport, electron transport, cellular metabolism, and gene expression. Mitochondrion is the central hub for cellular iron homeostasis. The vast majority of iron needs to be imported into the mitochondrion for the synthesis of heme and iron-sulfur clusters. On the other hand, key mitochondrial metabolic processes including the oxidative phosphorylation and tricarboxylic acid cycle rely on iron-containing prosthetic groups to transfer electrons or catalyze enzymatic reactions. We have previously identified a protein, FAM210B, that may play a role in regulating mitochondrial iron import and heme synthesis during vertebrate erythropoiesis. However, the molecular function of FAM210B as well as the FAM210 protein family remains elusive. Using reciprocal BLAST searches we identified Y56A3A.22, a previously uncharacterized protein, as the FAM210 family member in C. elegans. Unlike vertebrate species, C. elegans contains only one FAM210 gene in its genome, thus providing an ideal model for interrogating the molecular function of FAM210 family through genetic manipulations. Single-GFP knock-in studies revealed that Y56A3A.22 primarily localizes to mitochondria in C. elegans cells. Our preliminary functional studies suggest that Y56A3A.22 plays a critical role in regulating mitochondrial iron metabolism, mitochondrial protein homeostasis, and animal reproduction. The main objective of this proposal is to dissect the molecular role of C. elegans Y56A3A.22 and its mammalian homologs using a combination of genetic, proteomic, and biochemical approaches. Results from this proposal will provide novel insights into the molecular function of FAM210 family proteins and will broaden the basic understanding of mitochondrial iron metabolism and protein homeostasis.