Generation of Somatic Mitochondrial DNA-Replaced Cells for Mitochondrial Dysfunction Treatment

Abstract

Mitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed over the long term, even inducing the production of pluripotent stem cells from the mitochondrial DNA-replaced cells to maintain the genotype without a reversion to the original. Both mitochondrial disease patient-derived and aged fibroblasts could regain respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. The mitochondrial DNA-replaced cells could be a resource for transplantation to treat not only mitochondrial diseases, but also senescence-related diseases.