Metabolic Profiling of OXPHOS Dysfunction

描述（由申请人提供）：氧化磷酸化（OXPHOS）是细胞产生ATP的核心生化途径。在过去的20年里，越来越明显的是，无论是先天的代谢错误，还是常见的退行性疾病，都源于OXPHOS功能障碍。单一途径中的缺陷如何传递到其他生化途径，从而导致如此多不同的综合征和疾病，目前尚不清楚。此外，诊断线粒体代谢的先天缺陷极具挑战性。我们假设多种生化途径在响应OXPHOS功能障碍时被有条件地激活，以允许细胞适应疾病状态。利用新兴的“代谢组学”技术，我们建议系统地识别这些耦合的生化途径。我们将利用培养细胞以及已知OXPHOS遗传疾病的人类，并分析细胞和血浆代谢物，以确定细胞代谢如何适应OXPHOS缺陷。我们发现的生化网络可能揭示疾病的发病机制，可能是治疗的目标，并可能立即提供OXPHOS疾病的生物标志物。目前的研究应该为更好地理解OXPHOS在许多常见人类疾病中的作用奠定基础。公共卫生相关性：我们最近发现了代谢紊乱（如糖尿病）中发生改变的关键细胞通路。使用新的测量技术，我们希望更好地了解这些途径的改变如何在细胞和人类中引起疾病。如果成功，我们的研究将有助于代谢性疾病的诊断，也有助于激发新疗法的设计。

DESCRIPTIONS (provided by applicant): Oxidative phosphorylation (OXPHOS) refers to the cell's core biochemical pathway for generating ATP. During the past 20 years, it's become abundantly evident that both inborn errors of metabolism as well as common, degenerative diseases stem from OXPHOS dysfunction. How defects in a single pathway transmit to other biochemical pathways to give rise to so many different syndromes and diseases is not clear. Moreover, diagnosing the inborn errors of mitochondrial metabolism is incredibly challenging. We hypothesize that a variety of biochemical pathways are conditionally activated in response to OXPHOS dysfunction, to permit the cell to adapt to the disease state. Using emerging "metabolomics" technologies, we propose to systematically identify such coupled biochemical pathways. We will utilize cells in culture as well as humans with known OXPHOS genetic diseases and profile cellular and plasma metabolites to determine how cellular metabolism adapts to defects in OXPHOS. The biochemical networks we uncover may shed insights into disease pathogenesis, may be targeted for therapy, and may immediately provide a biomarker for OXPHOS disease. The current study should lay the foundation for better understanding the role of OXPHOS in a number of common human diseases. PUBLIC HEALTH RELEVANCE: We have recently discovered a key cellular pathway that is altered in metabolic disorders such as diabetes. Using novel measurement technologies, we hope to better understand how alterations in these pathways give rise to disease in cells as well as in humans. If successful, our research could assist in the diagnosis of metabolic diseases, and also help motivate the design of novel therapies.