Yamada Yuma, Akita Hidetaka, Kogure Kentaro, Kamiya Hiroyuki, Harashima Hideyoshi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan.
Mitochondrion. 2007 Feb-Apr;7(1-2):63-71. doi: 10.1016/j.mito.2006.12.003. Epub 2006 Dec 13.
Recent progress in genetics and molecular biology has provided useful information regarding the molecular mechanisms associated with the mitochondrial diseases. Genetic approaches were initiated in the late 1980s to clarify the gene responsible for various mitochondrial diseases, and information concerning genetic mutations is currently used in the diagnosis of mitochondrial diseases. Moreover, it was also revealed that mitochondria play a central role in apoptosis, or programmed cell death, which is closely related to the loss of physiological functions of tissues. Therefore, drug therapies targeted to the mitochondria would be highly desirable. In spite of the huge amount of mechanism-based studies of mitochondrial diseases, effective therapies have not yet been established mainly because of the lack of an adequate delivery system. To date, numerous investigators have attempted to establish a mitochondrial drug delivery system. However, many problems remain to be overcome before a clinical application can be achieved. To fulfill a drug delivery targeted to mitochondria, we first need to establish a method to encapsulate various drugs, proteins, peptides, and genes into a drug carrier depending on their physical characteristics. Second, we need to target it to a specific cell. Finally, multi-processes of intracellular trafficking should be sophisticatedly regulated so as to release a drug carrier from the endosome to the cytosol, and thereafter to deliver to the mitochondria. In this review, we describe the current state of the development of mitochondrial drug delivery systems, and discuss the advantage and disadvantage of each system. Our current efforts to develop an efficient method for the packaging of macromolecules and regulating intracellular trafficking are also summarized. Furthermore, novel concept of "Regulation of intramitochondrial trafficking" is proposed herein as a future challenge to the development of a mitochondrial drug delivery system.
遗传学和分子生物学的最新进展为线粒体疾病相关的分子机制提供了有用信息。20世纪80年代末开始采用遗传学方法来阐明导致各种线粒体疾病的基因，目前有关基因突变的信息已用于线粒体疾病的诊断。此外，还发现线粒体在细胞凋亡（即程序性细胞死亡）中起核心作用，而细胞凋亡与组织生理功能丧失密切相关。因此，针对线粒体的药物治疗将非常受欢迎。尽管对线粒体疾病进行了大量基于机制的研究，但主要由于缺乏合适的递送系统，尚未建立有效的治疗方法。迄今为止，众多研究人员试图建立线粒体药物递送系统。然而，在实现临床应用之前，仍有许多问题有待克服。为了实现靶向线粒体的药物递送，我们首先需要建立一种根据各种药物、蛋白质、肽和基因的物理特性将它们封装到药物载体中的方法。其次，我们需要将其靶向特定细胞。最后，应精细调节细胞内运输的多个过程，以便将药物载体从内体释放到细胞质中，然后递送至线粒体。在这篇综述中，我们描述了线粒体药物递送系统的发展现状，并讨论了每种系统的优缺点。我们目前开发高效大分子包装和调节细胞内运输方法的努力也进行了总结。此外，本文提出了“线粒体内运输调节”这一新概念，作为线粒体药物递送系统未来发展的挑战。
