Cell type-targeted mitochondrial transplantation rescues cell degeneration

A number of currently untreatable diseases, including neurodegenerative disorders, optic nerve atrophy, and heart failure, are associated with mitochondrial dysfunction. Transplantation of healthy mitochondria has been proposed as a potential therapeutic strategy. However, the lack of methods to target donor mitochondria to disease-affected cell types limits treatment specificity and efficacy. Here, we developed 'MitoCatch' as a system to deliver mitochondria to specific cell types using different types of protein binders. Donor mitochondria are captured by target cells, either by cell surface-displayed monospecific binders, by mitochondria-displayed monospecific binders, or by bispecific binders linking mitochondria to target cells. Using MitoCatch, we show that donor mitochondria are efficiently internalized, exposed to the cytosol, move, and undergo fusion and fission inside target cells. By engineering binders with different affinities, we tune the efficiency of mitochondria delivery. We demonstrate targeted mitochondrial transplantation to retinal cell types, neurons, cardiac, endothelial and immune cells in humans or mice. Transplanted mitochondria promoted the survival of damaged neurons from a human subject with optic nerve atrophy in vitro and after neuronal injury in mice in vivo. MitoCatch is a universal strategy to efficiently target disease-affected cell types with mitochondria in organs affected by diseases associated with mitochondrial dysfunction.