Treatment of acetaminophen-induced liver injury with exogenous mitochondria in mice.

Drug-induced liver injury shares a common feature of mitochondrial dysfunction. Mitochondrial therapy (mitotherapy), which replaces malfunctional mitochondria with functional exogenous mitochondria, may be a fundamental approach for treating drug-mediated hepatotoxicity. Here, we suggested that mitochondria isolated from human hepatoma cell could be used to treat acetaminophen (APAP)-induced liver injury in mice. When the mitochondria were added into the cell media, they could enter primarily cultured mouse hepatocyte. When the mitochondria were intravenously injected into mice, they distribute in several tissues, including liver. In the model mice of APAP-induced liver injury, mitochondria treatment increased hepatocyte energy supply, reduced oxidation stress, and consequently ameliorated tissue injury. The study suggests that exogenous mitochondria could be an effective therapeutic strategy in treating APAP-induced liver injury.

Mitotherapy for Fatty Liver by Intravenous Administration of Exogenous Mitochondria in Male Mice.

Mitochondrial dysfunction is a major and common mechanism in developing non-alcoholic fatty liver disease (NAFLD). Replacement of dysfunctional mitochondria by functional exogenous mitochondria may attenuate intrahepatic excessive lipid and recover hepatocyte function. However, no data shows that mitochondria can be systemically administrated to animals to date. Here we suggest that mitochondria isolated from hepatoma cells are used as a mitotherapy agent to treat mouse fatty liver induced by high-fat diets. When the mitochondria were intravenously injected into the mice, serum aminotransferase activity and cholesterol level decreased in a dose-dependent manner. Also, the mitotherapy reduced lipid accumulation and oxidation injury of the fatty liver mice, improved energy production, and consequently restored hepatocyte function. The mitotherapy strategy offers a new potential therapeutic approach for treating NAFLD.

Intravenous administration of mitochondria for treating experimental Parkinson's disease.

Mitochondrial dysfunction is associated with a large number of human diseases, including neurological and muscular degeneration, cardiovascular disorders, obesity, diabetes, aging and rare mitochondrial diseases. Replacement of dysfunctional mitochondria with functional exogenous mitochondria is proposed as a general principle to treat these diseases. Here we found that mitochondria isolated from human hepatoma cell could naturally enter human neuroblastoma SH-SY5Y cell line, and when the mitochondria were intravenously injected into mice, all of the mice were survived and no obvious abnormality appeared. The results of in vivo distribution suggested that the exogenous mitochondria distributed in various tissues including brain, liver, kidney, muscle and heart, which would benefit for multi-systemically mitochondrial diseases. In normal mice, mitochondrial supplement improved their endurance by increase of energy production in forced swimming test; and in experimental Parkinson's disease (PD) model mice induced by respiratory chain inhibitor MPTP, mitochondrial replacement prevented experimental PD progress through increasing the activity of electron transport chain, decreasing reactive oxygen species level, and preventing cell apoptosis and necrosis. Since effective drugs remain elusive to date for mitochondrial diseases, the strategy of mitochondrial replacement would provide an essential and innovative approach as mitochondrial therapy.