Mitochondrial drug delivery and mitochondrial disease therapy – An approach to liposome-based delivery targeted to mitochondria

Abstract

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. Yamada, Y., et al 3 Keywords:Mitochondrial drug delivery; Mitochondrial protein therapy; Mitochondrial gene therapy; Transferrin and GALA system; multifunctional envelope-type nano device (MEND);Regulation of intramitochondrial trafficking. Yamada, Y., et al 4

Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model

“…Liposomebased carriers can import hybrid molecules into mitochondria of whole cells, but this approach suffers from low efficiency and high cytotoxicity (8,25,39). Mutated mtDNA can be removed from the germ line by transfer of the spindle-chromosomal complex from one egg to another that is enucleated and depleted of its mitochondria (40).…”

“…Still, there is some recent evidence for recombination between mtDNA molecules (22), which could enable gene replacement. Although a natural DNA mitochondrial import has been reported in isolated rat liver mitochondria (23) and in plants (24), exogenous DNA cannot be transfected into mitochondria by conventional techniques (25,26). Therefore, the most important challenge at present is the development of procedures for introducing DNA into mitochondria, ideally in intact cells or living tissues.…”

Enhancement in selective mitochondrial association by direct modification of a mitochondrial targeting signal peptide on a liposomal based nanocarrier

“…Mitochondrial dysfunction is implicated in a variety of human diseases, including mitochondrial inherited diseases, neurodegenerative disorders, diabetes mellitus and cancer (Chan, 2006;Reeve et al, 2008;Schapira, 2006;Wallace, 2005), therefore, mitochondria would be expected to be the target organelle for these diseases (Armstrong, 2007;Du and Yan, 2010;Fulda et al, 2010;Giorgi et al, 2012;Gogvadze et al, 2009;Yamada et al, 2007).…”

Delivery of drugs and macromolecules to mitochondria☆

“…During the past few years a number of outstanding review articles have been published that discussed various ways to bring drugs or chemicals into mitochondria [2][3][4][5][6]. This review.article will summarize various unique features of mitochondria and then review how others suggested that those might be exploited to permit compounds to enter it.…”