The Biology of Peroxiredoxin 6

项目摘要/摘要 过氧化还蛋白6(Prdx6)是一种表达谷胱甘肽过氧化物酶、磷脂酶A2的多功能酶 (PLA2)和溶血磷脂酰胆碱酰基转移酶(LPCAT)活性。Prdx6可以 减少磷脂过氧化氢，使磷脂脂肪酰基键水解和再酰化。Prdx6是， 因此，一种完全用于修复过氧化细胞膜的酶。Prdx6被牵连到 几种病理生理状态，包括急性肺损伤、炎症、癌变、各种 慢性中枢神经系统疾病、视网膜疾病、2型糖尿病、肌肉萎缩和男性不育， 但是关于这种独特的酶的生物学的基本问题仍然没有得到回答。我们的初步数据显示 提示Prdx6抑制铁下垂，铁下垂是一种铁依赖的调节性细胞死亡形式，由 磷脂过氧化氢的积累。新出现的证据表明铁性下垂与几个 退行性疾病、癌变、中风、创伤性脑损伤和缺血/再灌注损伤，其中 其他。因此，建立Prdx6调节铁性下垂的机制和生理相关性是 至关重要。我的实验室感兴趣的是研究谷胱甘肽过氧化物酶、PLA2和LPCAT活性的作用。 Prdx6对抑制胱氨酸摄取、缺氧/复氧引起的铁性下垂的调节作用 氧气中毒。我们将使用单点突变的小鼠和细胞，这些突变会使每一种活性失活 Prdx6，而不影响其他酶，以及最先进的分析工具来剖析这种酶的作用 关于铁性下垂的调节。在第二个项目中，我建议研究Prdx6在维持 线粒体功能。我们的初步数据显示，Prdx6缺陷改变了转录特征 线粒体新陈代谢，减少线粒体呼吸。我们将研究催化剂的作用 Prdx6对线粒体形态、动力学和功能影响的细胞外通量分析和 三维成像技术。这项提议的结果将有助于我们理解一个 细胞氧化还原平衡的关键介体。这些结果也将为未来提供必要的信息 预防和治疗与氧化还原失调相关疾病的翻译策略 动态平衡。

Project Summary/Abstract Peroxiredoxin 6 (Prdx6) is a multi-functional enzyme that expresses glutathione peroxidase, phospholipase A2 (PLA2), and lysophosphatidylcholine acyltransferase (LPCAT) activities in separate catalytic sites. Prdx6 can reduce phospholipid hydroperoxides and hydrolyze and re-acylate phospholipid fatty acyl bonds. Prdx6 is, therefore, a complete enzyme for the repair of peroxidized cell membranes. Prdx6 has been implicated in several pathophysiological conditions, including acute lung injury, inflammation, carcinogenesis, various chronic central nervous system diseases, retinal disease, type 2 diabetes, muscle atrophy, and male infertility, but basic questions about the biology of this unique enzyme remain unanswered. Our preliminary data strongly suggest that Prdx6 suppresses ferroptosis, an iron-dependent form of regulated cell death driven by the accumulation of phospholipid hydroperoxides. Emerging evidence implicates ferroptosis in several degenerative diseases, carcinogenesis, stroke, traumatic brain injury, and ischemia/reperfusion injury, among others. Hence, establishing the mechanisms and physiological relevance of ferroptosis regulation by Prdx6 is crucial. My lab is interested in studying the role of the glutathione peroxidase, PLA2, and LPCAT activities of Prdx6 on the regulation of ferroptosis induced by inhibition of cystine uptake, hypoxia/reoxygenation, and oxygen toxicity. We will use mice and cells with single point mutations that inactivate each of the activities of Prdx6 without affecting the others, along with state-of-the-art analytical tools to dissect the role of this enzyme on the regulation of ferroptosis. In a second project, I propose to study the role of Prdx6 in the maintenance of mitochondrial function. Our preliminary data show that Prdx6 deficiency alters transcriptional signatures of mitochondrial metabolism and reduces mitochondrial respiration. We will study the effects of the catalytic activities of Prdx6 on mitochondrial morphology, dynamics, and function using extracellular flux assays and three-dimensional imaging techniques. The results of this proposal will contribute to our understanding of one of the critical mediators of cellular redox balance. These results will also provide essential information for future translational strategies for the prevention and treatment of diseases associated with dysregulated redox homeostasis.