Mitochondrial BCAA transporter in physiology and disease

项目总结 新出现的证据表明，棕色脂肪组织(BAT)在人体内起着重要的新陈代谢作用。 葡萄糖和脂肪酸，但也支链氨基酸(支链氨基酸；缬氨酸、亮氨酸和异亮氨酸)。我们最近 研究表明，蝙蝠体内冷激活的支链氨基酸分解代谢促进了小鼠全身支链氨基酸的清除。 这种代谢-吸收作用与其改善糖耐量和 胰岛素敏感性。 BAT是BCAA的代谢池的概念为流行病学观察提供了新的见解 循环中支链氨基酸水平的升高与胰岛素抵抗和2型糖尿病有关， 在这种情况下，蝙蝠的质量/活动减少。然而，这些机制仍然没有得到充分的了解，因为 线粒体支链氨基酸转运的守门人，即决定支链氨基酸的线粒体支链氨基酸转运体 线粒体和胞浆的命运，多年来都是未知的。 我们最近在哺乳动物中发现了第一个线粒体支链氨基酸转运蛋白SLC25A44。我们的初步数据 提示SLC25A44是线粒体支链氨基酸氧化、BAT产热和全身葡萄糖所必需的 动态平衡。因此，本提案旨在确定SLC25A44损失造成的机制 全身性糖耐量异常和胰岛素抵抗。首先，我们将确定主要是 通过鉴定新开发的BAT特异性SLC25A44来确定糖尿病的表型 有缺陷的小鼠。其次，我们将使用代谢组学和生化方法来确定分子 SLC25A44缺失改变线粒体功能和细胞内信号通路的机制。最后， 我们的目标是研究SLC25A44的表达和功能的调控机制。由以下原因产生的工作 这一应用将建立一个概念框架来理解细胞内支链氨基酸命运的调节， 还提供了一个新的路线图来逆转源于BCAA失调的疾病表型 分解代谢过程。

PROJECT SUMMARY Emerging evidence suggests that brown adipose tissue (BAT) functions as a significant metabolic-sink for glucose and fatty acids, but also branched-chain amino acids (BCAA; valine, leucine, and isoleucine). Our recent study shows that cold-activated BCAA catabolism in the BAT promotes systemic BCAA clearance in mice and humans, and that this metabolic-sink action is tightly coupled with its ability to improve glucose tolerance and insulin sensitivity. The notion of BAT being a metabolic-sink for BCAA provides new insights into the epidemiological observations that increased circulating BCAA levels are associated with insulin resistance and type 2 diabetes, conditions under which BAT mass/activity is reduced. However, the mechanisms remain insufficiently understood because the gatekeeper of mitochondrial BCAA transport, i.e., mitochondrial BCAA transporter that determines BCAA fate in the mitochondria vs. cytosol, was unknown for many years. We recently identified the first mitochondrial BCAA transporter, SLC25A44, in mammals. Our preliminary data suggest that SLC25A44 is required for mitochondria BCAA oxidation, BAT thermogenesis, and systemic glucose homeostasis. Accordingly, this proposal aims to determine the mechanisms by which SLC25A44 loss causes systemic glucose intolerance and insulin resistance. First, we will determine the metabolic organ that is primarily responsible for the diabetic phenotype through characterization of the newly developed BAT-specific SLC25A44 deficient mice. Second, we will employ metabolomics and biochemical approaches to determine the molecular mechanisms by which SLC25A44 loss alters mitochondrial function and intracellular signaling pathways. Lastly, we aim to examine the regulatory mechanisms of SLC25A44 expression and function. The work resulting from this application will establish a conceptual framework to understand the regulation of intracellular BCAA fate, and also provide a new roadmap to reverse disease phenotypes that stem from dysregulation in the BCAA catabolic processes.