Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver

Abstract

We herein report on a mitochondrial therapeutic effect based on the delivery of coenzyme Q10 (CoQ10), an anti-oxidant, to in vivo mitochondria using a MITO-Porter, a liposome-based mitochondrial delivery system that functions via membrane fusion. To evaluate the effects, we used a mouse liver ischemia/reperfusion injury (I/R injury) model, in which mitochondrial reactive oxygen species are overexpressed. We packaged CoQ10 in the lipid phase of a MITO-Porter and optimized the mitochondrial fusogenic activities to produce the CoQ10-MITO-Porter. A histological observation of the carriers in the liver by confocal laser scanning microscopy was done and the accumulation of the carrier labeled with a radio isotope in the liver confirmed that the CoQ10-MITO-Porter was delivered to liver mitochondria via systemic injection. These analytical results permitted us to optimize the compositions of the CoQ10-MITO-Porter so as to permit it to efficiently accumulate in mouse liver mitochondria.Finally, we applied the optimized CoQ10-MITO-Porter to mice via tail vein injection, and hepatic I/R injury was then induced, followed by measuring serum alanine aminotransferase (ALT) levels, a marker of liver injury. We confirmed that the use of the CoQ10-MITO-Porter resulted in a significant decrease in serum ALT levels, indicating that in vivo mitochondrial delivery of the CoQ10 via MITO-Porter prevents I/R injury in mice livers. This provides a demonstration of the potential use of such a delivery system in mitochondrial therapies.

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…PLGA-CoQ 10 NPs of <100 nm were successfully prepared by an emulsion-diffusion-evaporation method, which demonstrated enhanced oral bioavailability and anti-inflammatory activity compared to free CoQ 10 (Figure 11) (162). Recently, Yamada et al reported Co Q 10 delivery using MITO-Porter, a liposomal delivery system, to target mitochondria for preventing IR injury (163). The CoQ 10 -MITO-Porter was intravenously injected in the hepatic IR injury mice model.…”

Packaging of the Coenzyme Q₁₀ into a Liposome for Mitochondrial Delivery and the Intracellular Observation in Patient Derived Mitochondrial Disease Cells

“…14) Lipid, CoQ 10 and DMG-PEG2000 stock solutions were prepared in ethanol and stored at −20°C until used. A 100% (v/v) EtOH solution containing 2.75 mM lipids [DOPE/SM/DMG-PEG2000 (9/2/0.33, molar ratio)] was prepared.…”

“…14) Since liposomes that are prepared using different methods can result in significant differences in drug encapsulation efficiency and the physiochemical characteristics of the carrier, liposomes prepared using the three methods as shown in Fig. 1 were compared.…”

“…We previously reported on the preparation of a MITO-Porter, a mitochondrial-targeted liposome, 12,13) and the fact that it can be used to deliver some mitochondrial functional molecules, including CoQ 10 , to mitochondria and that excellent pharmaceutical effects, both in vitro and in vivo were observed. 13,14) Because of its highly mitochondrial fusogenic lipid components, it is taken up by mitochondria via membrane fusion, thus permitting its cargo to be released into the mitochondrial membrane. CoQ 10 can then exert its pharmaceutical effect on the mitochondrial membrane, where endogenous CoQ 10 functions as an important functional molecule.…”

“…[14][15][16][17][18] However, while it has been reported that the method used to prepare such liposomes had an influence on CoQ 10 encapsulation efficiency, attempts to optimize CoQ 10 encapsulation by varying the initial CoQ 10 concentration have not been reported. In addition, a comparison of the characteristics of CoQ 10 encapsulated liposomes among different packaging methods have not been reported, which is important information, in terms of establishing the optimal method for packaging CoQ 10 in liposomes.…”