Power of mitochondrial drug delivery systems to produce innovative nanomedicines
Graphical abstract
Introduction
Mitochondria carry out vital and lethal functions for cells that are relevant to the pathophysiology of diseases. Mitochondria are responsible for providing a significant portion of cellular energy in the form of adenosine triphosphate (ATP), for controlling the level of reactive oxygen species (ROS), buffering cytosolic calcium levels, and regulating programmed cell death (apoptosis) [1]. To support their functions, mitochondria are supplied by several proteins that are encoded either by mitochondrial DNA (mtDNA) or nuclear DNA. Fig. 1 is shown to summarize our current understanding of mitochondrial structure and their various functions [2]. The mitochondrion possesses a double membrane consisting of an outer membrane, which includes important proteins related to apoptosis regulation, and an inner membrane containing the mitochondrial oxidative phosphorylation system, including proteins related to the electron transport chain and ATP synthase. The very inner space, the matrix, contains pooled mtDNA and major metabolic pathways, including the tricarboxylic acid (TCA) cycle, the urea cycle and fatty acid oxidation (β-oxidation). Thus, by delivering target molecules to mitochondria, it would be possible, in theory, to control the functions of cells and living organisms, which could be useful for our fundamental understanding of life phenomena.
It has often been reported that mitochondrial dysfunction can cause a variety of human disorders, including neurodegenerative and neuromuscular diseases, heart failure, ischemia/reperfusion (I/R) injuries, cancer and a variety of inherited mitochondrial diseases [[3], [4], [5], [6]]. For example, inherited mitochondrial diseases are caused by mutations and defects of mtDNA. Thus, if it were possible to deliver therapeutic compounds to the mitochondrial matrix where the mtDNA is located, the condition caused by such mutations and defects of mtDNA in mitochondria in diseased cells could be improved. While, the mitochondrial delivery of compounds that are toxic to mitochondria and destroy them, the energy plant of cancer cells could be destroyed. Such a mitochondrial targeting strategy would be useful for cancer therapy [7].
Based on the above information, mitochondria would be expected to be promising organelles for targeting. The technology of delivering the target molecule to mitochondria should have a substantial impact on our understanding of life processes. Moreover, delivering therapeutic molecules to mitochondria for the treatment of a variety of human disorders promises to be a useful innovative therapeutic strategy. It should be noted here that the transport system of naïve mitochondria is strictly controlled as shown in Fig. 2 [2]. The outer membrane is only permeable to small molecules with molecular weights of less than 5 kDa, with passage through a membrane-spanning protein, namely porin. Macromolecules, such as proteins, are taken up by mitochondria via a protein transport machinery by a special route. The mitochondrial protein import machinery is involved in mitochondrial transport of a variety of proteins linked with mitochondrial targeting signal peptide (MTS). Specific compounds reach the matrix space via a number of transport proteins that are imbedded within the inner membrane—each of which is responsible for the transport of a specific ligand.
For the treatment of a mitochondrial disease, the molecular mechanism and pathway of mitochondrial diseases needs to be elucidated and a drug delivery system (DDS) for mitochondria in diseased cells is required. First, methodology for encapsulating drugs in nanocarriers independent of the physicochemical characteristics of the drugs are needed. Second, the nanocarriers should be internalized into the target cells of a diseased tissue. Finally, the precise control of the intracellular trafficking of a nanocarrier is required to deliver the cargo to the mitochondria. Therefore, the development of DDS technology for delivering cargoes to mitochondrial sites, irrespective of the size and type of molecule, would be highly desirable. To date, several mitochondrial DDS developments have been reported [2,8,9], but a generalized DDS leading to therapy targeting mitochondria has not been established. The mitochondrial delivery of macromolecules such as nucleic acids and proteins is particularly difficult using the currently available technology for targeting mitochondria.
This review focuses on mitochondria-targeted therapeutic strategies including antioxidant therapy, cancer therapy, mitochondrial gene therapy and cell transplantation therapy based on mitochondrial DDS. In particular, we discuss nanocarriers for mitochondrial delivery to achieve mitochondria-targeting therapy. In the section on antioxidant therapy targeting mitochondria, we summarize the current state of knowledge of mitochondrial delivery of anti-oxidant molecules, including chemicals, peptides. The discussion of cancer therapy includes the mitochondrial delivery of anticancer drugs and mitochondrial targeted photodynamic therapy (PDT). In the section of mitochondrial gene therapy, we summarize current therapeutic methods that are available for the treatment of mitochondrial inherited diseases and discuss the mitochondrial delivery of small nucleic acids and circular DNA for an innovative mitochondrial gene therapy. Finally, we introduce cell plantation therapy using mitochondria activated cells. This review also summarizes our current efforts regarding a liposome-based carrier for mitochondrial delivery, MITO-Porter that delivers cargoes to mitochondria via a membrane fusion mechanism.
Section snippets
Antioxidant therapy using mitochondrial DDS
In this section, research related to antioxidant therapy targeting mitochondria is described. Current reports of the use of mitochondrial DDS in antioxidant therapy are mainly classified into three groups: mitochondrial delivery via triphenylphosphonium (TPP), Szeto-Schiller (SS)-peptides, and mitochondrial targeting nanocarriers (Fig. 3).
Cancer therapy targeting mitochondria
In the early 19th century, a German physiologist and Nobel laureate, Otto Heinrich Warburg hypothesized the existence of a close relationship between defects in mitochondrial function with tumorigenesis [53]. He observed that tumors rely on aerobic glycolysis, even in an oxygen-rich environment, by taking up more glucose and secreting increased levels of lactate to the tumor microenvironment (termed the Warburg effect). In current studies, Chandel et al. proposed that aerobic glycolysis is
Mitochondrial diseases and an attempt toward mitochondrial gene therapy
Mitochondrial diseases are defined as a group of genetic disorders that are characterized by defects in oxidative phosphorylation, which are caused by genetic mutations in the both the mtDNA and nuclear DNA that encode mitochondrial proteins or proteins that are related to mitochondrial function [129]. Mitochondrial diseases have wide heterogeneities and can occur at any age, resulting in various manifestations with a broad range of clinical phenotypes [129]. Mitochondrial diseases can occur in
Cell transplantation therapy and mitochondrial activation
The use of stem cell therapy for the treatment of mitochondrial diseases has been reported [196]. Hematopoietic stem cell transplantation therapy to maintain thymidine phosphorylase activity was found to lower the levels of thymidine and deoxyuridine in patient's blood and lead to improvements in the clinical symptoms in the patients suffering from the MNGIE syndrome. Unfortunately, more than 50% therapy-related deaths have been reported [196]. Cell transplantation therapy and the relationship
Conclusions
Research on mitochondria with various functions have been carried out around the world for a long time, and controlling the functions of this organelle is expected to be studied deeply in attempts to understand the life sciences and develop innovative therapeutic strategies. To achieve such an innovative research and mitochondrial therapy, a mitochondrial DDS will be required. At the beginning of the 2000s, when we started our own research to develop a mitochondrial DDS, there were only a few
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
This research was funded by Grants-in-Aid for Scientific Research (B) (17H02094 to Y.Y.) from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government (MEXT), a grant from the Special Education and Research Expenses of the MEXT, a grant from the Uehara Memorial Foundation (to Y.Y.), a grant from the KOSE Cosmetology Research Foundation (to Y.Y.) and a grant from the Takeda Science Foundation (to Y.Y.). We wish to thank Dr. Milton Feather for his helpful advice
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