Fig. 4

Advanced mitochondrial therapies for neurological diseases and mitochondrial diseases. a Mitochondrial transplantation via injection of isolated mitochondria, mitochondria-containing vesicles and mitochondria-loaded stem cells is promising for the treatment of brain diseases. b Mitochondrial replacement therapy is conducted by pronuclear transfer or spindle transfer. For pronuclear transfer, a zygote is generated by fertilization and then pronuclei of the zygote containing mutated mtDNA are transferred to the donor’s enucleated zygote. For spindle transfer, the spindle of the oocyte with mtDNA mutation is transferred to the donor’s enucleated oocyte, followed by fertilization. c Mitochondrial genome editing is conducted by editing the nuclease systems using the ZFNs, the TALENs and the CRISPR/Cas9 systems. mtTALENs and mtZFNs are mitochondria-targeted DNA nucleases and promote the degradation of mutant mtDNA for heteroplasmic shifting of mutant mtDNA. Mitochondrial base editing is achievable by DdCBEs, TALED, ZFD and mitoBEs to effectively correct the homoplasmic mtDNA mutation. The mito-Cas9 system enables successful knockin of exogenous DNA into mtDNA, which is promising for manipulating more types of mtDNA base editing. CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-associated Cas9; DdCBE: bacterial cytidine deaminase fused with mitochondrial TALE-linked deaminases; mitoBEs: mtDNA base editors; MRT, mitochondrial replacement therapy; TALEN: transcription activator-like effector nuclease; ZFDs: zinc-finger deaminases; ZFNs: zinc finger nucleases