title: Functional recovery of human cells harbouring the mitochondrial DNA mutation MERRF A8344G via peptide-mediated mitochondrial delivery.
abstract: We explored the feasibility of mitochondrial therapy using the cell-penetrating peptide Pep-1 to transfer mitochondrial DNA (mtDNA) between cells and rescue a cybrid cell model of the mitochondrial disease myoclonic epilepsy with ragged-red fibres (MERRF) syndrome. Pep-1-conjugated wild-type mitochondria isolated from parent cybrid cells incorporating a mitochondria-specific tag were used as donors for mitochondrial delivery into MERRF cybrid cells (MitoB2) and mtDNA-depleted Rho-zero cells (Mitoρ°). Forty-eight hours later, translocation of Pep-1-labelled mitochondria into the mitochondrial regions of MitoB2 and Mitoρ° host cells was observed (delivery efficiencies of 77.48 and 82.96%, respectively). These internalized mitochondria were maintained for at least 15 days in both cell types and were accompanied by mitochondrial function recovery and cell survival by preventing mitochondria-dependent cell death. Mitochondrial homeostasis analyses showed that peptide-mediated mitochondrial delivery (PMD) also increased mitochondrial biogenesis in both cell types, but through distinct regulatory pathways involving mitochondrial dynamics. Dramatic decreases in mitofusin-2 (MFN2) and dynamin-related protein 1/fission 1 were observed in MitoB2 cells, while Mitoρ° cells showed a significant increase in optic atrophy 1 and MFN2. These findings suggest that PMD can be used as a potential therapeutic intervention for mitochondrial disorders.
authors.affiliation: Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan, ROC.
authors.forename: Jui-Chih
authors.initials: JC
authors.lastname: Chang
authors.forename: Ko-Hung
authors.initials: KH
authors.lastname: Liu
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Li
authors.forename: Shou-Jen
authors.initials: SJ
authors.lastname: Kou
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
authors.forename: Chieh-Sen
authors.initials: CS
authors.lastname: Chuang
authors.forename: Mingli
authors.initials: M
authors.lastname: Hsieh
authors.forename: Chin-San
authors.initials: CS
authors.lastname: Liu
mesh_terms: D057846:Cell-Penetrating Peptides; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D017243:MERRF Syndrome / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D004272:DNA, Mitochondrial