Metabolic reprogramming of human cells in response to oxidative stress: implications in the pathophysiology and therapy of mitochondrial diseases.
Metabolic reprogramming of human cells in response to oxidative stress: implications in the pathophysiology and therapy of mitochondrial diseases.
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DOI：
10.2174/1381612820666140306103401
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发表时间：
2014-09
影响因子：
3.1
通讯作者：
Yu-Ting Wu;Shi-Bei Wu;Yau-Huei Wei
中科院分区：
文献类型：
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作者：
Yu-Ting Wu;Shi-Bei Wu;Yau-Huei Wei
线粒体是产生大部分能量的细胞器，在人类细胞的各种生化功能中发挥重要作用。线粒体缺陷可导致ATP缺乏和活性氧的过度产生，这是线粒体疾病的主要标志。大量证据表明，线粒体功能障碍引起的氧化应激在线粒体疾病的发病和进展中起重要作用。线粒体可以通过逆行信号对能量缺乏做出反应，从而触发许多分子事件，帮助人体细胞科普生理或环境变化。在这篇文章中，我们首先描述了氧化应激诱导的细胞反应，包括代谢适应，线粒体生物合成的代偿性增加，抗氧化酶的上调，以及线粒体功能障碍的人类细胞中蛋白质乙酰化的改变。在这方面，我们回顾了最近的研究结果，以阐明人类细胞激励其线粒体和抗氧化防御系统响应能量缺乏和氧化应激，这有助于线粒体疾病的适应性代谢重编程的机制。此外，我们强调AMPK，Sirt 1和Sirt 3的激活在携带线粒体DNA突变的人类细胞的代谢适应中的关键作用。近年来的研究表明，AMPK和sirtuins介导的信号通路参与了线粒体功能障碍细胞的代谢重编程，而这一过程是通过上调抗氧化防御系统和线粒体蛋白乙酰化来实现的。最后，我们讨论了几个潜在的生物能量功能的调节剂，如辅酶Q10，靶向抗氧化剂，白藜芦醇，和L-肉碱的基础上，从人类细胞和动物模型的线粒体疾病的研究最近的发现。阐明这种线粒体功能障碍引发的氧化应激适应性反应的信号通路，可能使我们能够更深入地了解线粒体和细胞核之间的通信，并指导我们开发新的治疗药物，以有效治疗线粒体疾病。
Mitochondria are the organelles producing most of the energy and play important roles in a variety of biochemical functions in human cells. Mitochondrial defects can cause ATP deficiency and overproduction of reactive oxygen species, which are the major hallmarks of mitochondrial diseases. Abundant evidence has suggested that mitochondrial dysfunction-elicited oxidative stress can play an important role in the pathogenesis and progression of mitochondrial diseases. Mitochondria can respond to energy deficiency by the retrograde 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 mitochondrial biogenesis, upregulation of antioxidant enzymes, and alteration of protein acetylation in human cells with mitochondrial dysfunction. In this regard, we review recent findings to elucidate the mechanisms by which human cells motivate their mitochondria and the antioxidant defense system to respond to energy deficiency and oxidative stress, which contribute to the adaptive metabolic reprogramming in mitochondrial diseases. In addition, we emphasize the critical role of the activation of AMPK, Sirt1 and Sirt3 in the metabolic adaptation of human cells harboring mitochondrial DNA mutations. Recent studies have revealed that AMPK and sirtuins-mediated signaling pathways are involved in metabolic reprogramming, which is effected by upregulation of antioxidant defense system and mitochondrial protein acetylation, in human cells with mitochondrial dysfunction. Finally, we discuss several potential modulators of bioenergetic function such as coenzyme Q10, mitochondria-targeting antioxidants, resveratrol, and L-carnitine based on recent findings from studies on human cells and animal models of mitochondrial diseases. Elucidation of the signaling pathway of this adaptive response to oxidative stress triggered by mitochondrial dysfunction may enable us to gain a deeper insight into the communication between mitochondria and the nucleus and guide us to develop novel therapeutic agents for effective treatment of mitochondrial diseases.