Metabolic Reprogramming of Human Cells in Response to Oxidative Stress: Implications in the Pathophysiology and Therapy of Mitochondrial Diseases

Mitochondria are the organelles producing most of the energy and play important roles in a variety of biochemical functions inhuman cells. Mitochondrial defects can cause ATP deficiency and overproduction of reactive oxygen species, which are the major hall-marks of mitochondrial diseases. Abundant evidence has suggested that mitochondrial dysfunction-elicited oxidative stress can play animportant role in the pathogenesis and progression of mitochondrial diseases. Mitochondria can respond to energy deficiency by the ret-rograde signaling to trigger a number of molecular events to help the human cells to cope with physiological or environmental changes.In this article, we first describe oxidative stress-induced cellular responses including metabolic adaptation, compensatory increase of mi-tochondrial biogenesis, upregulation of antioxidant enzymes, and alteration of protein acetylation in human cells with mitochondrial dys-function. In this regard, we review recent findings to elucidate the mechanisms by which human cells motivate their mitochondria and theantioxidant defense system to respond to energy deficiency and oxidative stress, which contribute to the adaptive metabolic reprogram-ming in mitochondrial diseases. In addition, we emphasize the critical role of the activation of AMPK, Sirt1 and Sirt3 in the metabolicadaptation of human cells harboring mitochondrial DNA mutations. Recent studies have revealed that AMPK and sirtuins-mediated sig-naling pathways are involved in metabolic reprogramming, which is effected by upregulation of antioxidant defense system and mito-chondrial protein acetylation, in human cells with mitochondrial dysfunction. Finally, we discuss several potential modulators of bio-energetic function such as coenzyme Q 10 , mitochondria-targeting antioxidants, resveratrol, and L-carnitine based on recent findings fromstudies on human cells and animal models of mitochondrial diseases. Elucidation of the signaling pathway of this adaptive response tooxidative stress triggered by mitochondrial dysfunction may enable us to gain a deeper insight into the communication between mito-chondria and the nucleus and guide us to develop novel therapeutic agents for effective treatment of mitochondrial diseases.

线粒体是为人类细胞产生绝大多数能量的细胞器，并在各类生化功能中发挥关键作用。线粒体功能缺陷可引发ATP缺乏与活性氧（reactive oxygen species, ROS）过度生成，这正是线粒体疾病的主要标志性特征。大量研究证据表明，线粒体功能障碍引发的氧化应激，在线粒体疾病的发病机制与病程进展中扮演重要角色。线粒体可通过逆行信号通路响应能量匮乏，触发一系列分子事件，帮助人类细胞应对生理或环境变化。本文首先阐述线粒体功能障碍的人类细胞中，氧化应激诱导的细胞应答反应，包括代谢适应、线粒体生物发生的代偿性增加、抗氧化酶的上调以及蛋白质乙酰化的改变。据此，本文综述了近期研究成果，以阐明人类细胞如何激活线粒体与抗氧化防御系统，从而响应能量匮乏与氧化应激——这一过程有助于线粒体疾病中的适应性代谢重编程。此外，本文着重探讨了腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）、沉默信息调节因子1（Sirtuin 1, Sirt1）与沉默信息调节因子3（Sirtuin 3, Sirt3）的激活，在携带线粒体DNA突变的人类细胞代谢适应过程中的关键作用。近期研究表明，在线粒体功能障碍的人类细胞中，AMPK与沉默信息调节因子家族（sirtuins）介导的信号通路参与代谢重编程，该过程通过上调抗氧化防御系统以及调控线粒体蛋白质乙酰化水平得以实现。最后，基于人类细胞与线粒体疾病动物模型的最新研究成果，本文探讨了辅酶Q₁₀、线粒体靶向抗氧化剂、白藜芦醇与L-肉碱等多种潜在的生物能功能调节剂。阐明线粒体功能障碍引发的氧化应激适应性应答的信号通路，将有助于我们更深入地理解线粒体与细胞核之间的信号交流，并为开发用于线粒体疾病有效治疗的新型治疗药物提供指导。