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.

中文翻译：

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通过使用MITO-Porter的全身性给药，辅酶Q10的线粒体递送可防止小鼠肝脏缺血/再灌注损伤

我们在此报告了基于MITO-Porter的抗氧化剂将辅酶Q ₁₀（CoQ ₁₀）传递至体内线粒体的线粒体治疗效果，MITO-Porter是一种通过膜融合起作用的基于脂质体的线粒体传递系统。为了评估效果，我们使用了小鼠肝缺血/再灌注损伤（I / R损伤）模型，其中线粒体活性氧种类过表达。我们将辅酶Q ₁₀包装在MITO-Porter的脂质相中，并优化了线粒体融合活性以生产辅酶Q ₁₀-MITO-Porter。通过共聚焦激光扫描显微镜对肝脏中的载体进行组织学观察，并且在肝脏中放射性同位素标记的载体的积累证实了CoQ ₁₀ -MITO-Porter通过全身注射被递送至肝线粒体。这些分析结果使我们能够优化CoQ ₁₀ -MITO-Porter的成分，从而使其能够有效地在小鼠肝线粒体中积累。最后，我们通过尾静脉注射将优化的辅酶Q ₁₀ -MITO-Porter应用于小鼠，然后诱导肝I / R损伤，然后测量血清丙氨酸氨基转移酶（ALT）水平，这是肝损伤的标志。我们确认使用CoQ ₁₀-MITO-Porter导致血清ALT水平显着降低，表明通过MITO-Porter的体内线粒体CoQ ₁₀递送可预防小鼠肝脏的I / R损伤。这证明了这种递送系统在线粒体疗法中的潜在用途。