Journal
NEUROSIGNALS
Volume 21, Issue 3-4, Pages 160-173Publisher
KARGER
DOI: 10.1159/000341981
Keywords
Cell-penetrating peptide; Mitochondrial delivery; Myoclonic epilepsy with ragged-red fibres syndrome; Mitochondrial functions; Mitochondrial biogenesis; Mitochondrial fusion/fission proteins
Funding
- Changhua Christian Hospital [99-ICO-01]
- National Science Council [NSC 100-2314-B-371-003]
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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 (Mito rho degrees). Forty-eight hours later, translocation of Pep-1-labelled mitochondria into the mitochondrial regions of MitoB2 and Mito rho degrees 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 Mito rho degrees 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. Copyright (c) 2012 S. Karger AG, Basel
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