A basic study for mitochondria-targeting liposome vector using human mitochondrial fusiogenic protein.

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The mitochondria are organelle in the cell and have the proper DNA different from the nuclear genome. The development of the new way of introducing a material into the mitochondria, which is different from the usual gene therapy to the nuclear target, is necessary for the fundamental treatment of the mitochondrial disease based on the mitochondrial DNA. In this research, it aims at the fundamental development of new liposome vector that peculiarly targets the mitochondria, using the mitochondrial fusiogenc factor as an effective component. Such a vector will make it possible that not only normal mitochondrial DNA but also the drug adjusting the mitochondrial function and/or the exogenous ribozyme regulating the mitochondrial transcripts are introduced into the mitochondria. The development of such a vector would become applied for a new drug delivery system for many diseases with dysfunction of the mitochondria in the future.We identified a mitochondrial fusiogenic protein, a human Fzo homolog, and analyzed the domain of the protein necessary for membrane fusiogenic activity. We also produced the recombinant protein of the domain, reconstituted the proteoliposome using the protein, and proved the membrane fusiogenic activity of the liposome in vitro. On the other hand, we examined the OPA1 protein which has the mitochondrial fusiogenic activity, and showed the differential sublocalization of OPA1 isoform in the human cell. This factor is one of the assistant factors of the mitochondrial fusiogenic device, which will be important for improvement for the efficiency of the liposome vector. Next step requires an examination whether the mitochondrial DNA-embedded liposome, introduced in the cell by microinjection, actually targets the mitochondria in vivo. This research is the first step to establish the fundamental technology of the gene therapy of mitochondrial diseases.