Tissue-specific differences impacts therapeutic outcomes of mitochondrial transplantation through regulation of bioenergetics in metabolic syndrome.

Abstract

Mitochondria transplantation is an emerging therapeutic strategy with remarkable potential in treating various diseases associated with mitochondrial dysfunction. Despite the known differences in tissue-specific mitochondria, the therapeutic outcomes of mitochondria isolated from various sources, after their transplantation in a specific disease model has remained elusive. In this study, we investigated the tissue-dependent therapeutic differences after transplantation of mitochondria isolated from heart, muscle, and liver tissues in a high-fat diet and streptozotocin, 35 mg/Kg (HFD + STZ) induced metabolic syndrome (MetS) in Wistar rats. We found striking differences in lowering of blood glucose levels, blood pressure, cholesterol, ALT, and AST levels in MetS after transplantation of mitochondria obtained from heart, muscle, and liver tissues (P < 0.01). Liver mitochondria transplantation demonstrated the most effective upregulation of mitochondrial complex activities, enhanced anti-oxidant enzyme levels in recipient liver tissues (P < 0.01). It also upregulated gene expression of genes associated with mitochondrial biogenesis and bioenergetics and reduced apoptosis and inflammation associated genes in HFD + STZ rats. In addition, GC-MS metabolite analysis revealed differential blood serum concentrations of key tri-carboxylic acid metabolites such as succinic acid, malic acid, alpha-ketoglutarate, citric acid, and pyruvate after mitochondrial transplantation in HFD + STZ rats. This study supports the idea that mitochondria source tissue should be considered to provide better clinical outcomes for mitochondrial transplantation.