Bola3通过调控铁硫簇生成影响米色脂肪细胞特性维持的作用研究

米色脂肪细胞是白色脂肪细胞在特定刺激条件下的重编程细胞类型，以依赖线粒体的氧化磷酸化驱动产热，促进能量消耗。然而一旦外部刺激撤除，米色脂肪细胞拥有固有的能力重新获得白色脂肪细胞表型。尽管大量研究报道了多种促米色脂肪生成、分化的内在机制和外部因素，但米色脂肪维持的机理仍不清楚。铁硫簇是铁硫蛋白的重要功能辅助基团，参与电子传递、酶促反应及氧化还原等多种细胞过程，铁硫簇的生物学发生是否对米色脂肪特性维持起调控作用，目前未见报道。铁硫簇的组装是多种装配蛋白参与、有序进行的催化反应，Bola3是铁硫簇组装核心因子，我们前期工作发现Bola3通过调节线粒体稳态和脂解参与维持米色脂肪细胞产热功能，高表达Bola3抑制米色脂肪细胞在诱导液撤除后的产热基因表达下调。本项目将深入研究Bola3如何通过影响铁硫簇的生物发生和相关铁硫依赖性代谢酶的活性，促进自噬依赖的线粒体重塑，以此调控米色脂肪的白色化。

Beige adipocytes are the re-programmed type of white adipocytes, which are interspersed within white adipose tissue (WAT) under certain internal and external stimuli. They contain dense mitochondria and depend on mitochondrial oxidative phosphorylation to drive heat production and then promote energy metabolism. However, once the external stimuli are withdrawn, beige adipocytes have the inherent capacity to regain the white adipocyte phenotype. Although a large number of studies have confirmed that various internal and external factors promote beige fat development, the potential mechanisms of beige adipocytes maintenance remain unclear. Mitochondrial iron-sulfur (Fe-S) clusters are important cofactors for the maturation of Fe-S proteins, which are ubiquitously involved in a wide range of cellular processes, such as electron transfer, enzymatic catalysis and regulation. It is unknown whether the biological pathway of Fe-S cluster biogenesis plays an important role in maintaining the identity of the induced beige adipocytes. Mitochondria are the primary sites for the synthesis of Fe-S clusters and the maturation of Fe-S proteins, which are assisted by 17 proteins forming the Fe-S cluster assembly machinery. Mammalian BOLA3 belongs to a BolA-like family of proteins that is conserved from prokaryotes to eukaryotes. It is reported that BOLA3 is interacting with glutaredoxin 5, which along with several chaperones is involved in inserting [2Fe-2S] and [4Fe-4S] clusters into a subset of targeted proteins at the last step. Our previous work found that Bola3 regulated beige adipocyte thermogenesis by maintaining mitochondrial homeostasis and adrenergic signaling-stimulated lipolysis. We further found that Bola3 overexpression obviously inhibited the down-regulation of thermogenesis-related genes in cultured beige adipocytes after the withdrawl of the maintaining medium. Therefore, we will further study how Bola3-mediated pathway regulate the whitening process of beige adipocytes by affecting the biogenesis of Fe-S clusters and the activities of Fe-S-dependent metabolic enzymes, and subsequently promoting autophagy-dependent mitochondrial remodeling. Our study will further reveal the metabolic adaptation of beige adipocytes and may provide new strategies for treating obesity and its related metabolic disorders.