Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Korea
Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Korea
J Mol Endocrinol. 2018 Oct 1;61(3):R91-R105. doi: 10.1530/JME-18-0005.
Mitochondria perform essential roles as crucial organelles for cellular and systemic energy homeostasis, and as signaling hubs, which coordinate nuclear transcriptional responses to the intra- and extra-cellular environment. Complex human diseases, including diabetes, obesity, fatty liver disease and aging-related degenerative diseases are associated with alterations in mitochondrial oxidative phosphorylation (OxPhos) function. However, a recent series of studies in animal models have revealed that an integrated response to tolerable mitochondrial stress appears to render cells less susceptible to subsequent aging processes and metabolic stresses, which is a key feature of mitohormesis. The mitochondrial unfolded protein response (UPRmt) is a central part of the mitohormetic response and is a retrograde signaling pathway, which utilizes the mitochondria-to-nucleus communication network. Our understanding of the UPRmt has contributed to elucidating the role of mitochondria in metabolic adaptation and lifespan regulation. In this review, we discuss and integrate recent data from the literature on the present status of mitochondrial OxPhos function in the development of metabolic diseases, relying on evidence from human and other animal studies, which points to alterations in mitochondrial function as a key factor in the regulation of metabolic diseases and conclude with a discussion on the specific roles of UPRmt and mitohormesis as a novel therapeutic strategy for the treatment of obesity and insulin resistance.
线粒体作为细胞和全身能量稳态的关键细胞器，以及作为信号枢纽，发挥着至关重要的作用，它们协调核转录反应以适应细胞内和细胞外环境。包括糖尿病、肥胖症、脂肪肝疾病和与衰老相关的退行性疾病在内的复杂人类疾病与线粒体氧化磷酸化（OxPhos）功能的改变有关。然而，最近在动物模型中的一系列研究表明，对可耐受的线粒体应激的综合反应似乎使细胞对随后的衰老过程和代谢应激的敏感性降低，这是mitohormesis 的一个关键特征。线粒体未折叠蛋白反应（UPRmt）是 mitohormetic 反应的核心部分，是一种逆行信号通路，利用线粒体到细胞核的通讯网络。我们对 UPRmt 的理解有助于阐明线粒体在代谢适应和寿命调节中的作用。在这篇综述中，我们讨论并整合了来自文献中的最新数据，这些数据涉及代谢疾病发展过程中线粒体 OxPhos 功能的现状，这些数据依赖于来自人类和其他动物研究的证据，这些证据表明线粒体功能的改变是调节代谢疾病的关键因素，并讨论了 UPRmt 和 mitohormesis 的特定作用，作为治疗肥胖症和胰岛素抵抗的一种新的治疗策略。
