title: Treatment of human cells derived from MERRF syndrome by peptide-mediated mitochondrial delivery.
abstract: OBJECTIVE
  The feasibility of delivering mitochondria using the cell-penetrating peptide Pep-1 for the treatment of MERRF (myoclonic epilepsy with ragged red fibers) syndrome, which is caused by point mutations in the transfer RNA genes of mitochondrial DNA, is examined further using cellular models derived from patients with MERRF syndrome.
  
  
  METHODS
  Homogenesis of mitochondria (wild-type mitochondria) isolated from normal donor cells with about 83.5% preserved activity were delivered into MERRF fibroblasts by Pep-1 conjugation (Pep-1-Mito).
  
  
  RESULTS
  Delivered doses of 52.5 μg and 105 μg Pep-1-Mito had better delivered efficiency and mitochondrial biogenesis after 15 days of treatment. The recovery of mitochondrial function in deficient cells receiving 3 days of treatment with peptide-mediated mitochondrial delivery was comprehensively demonstrated by restoration of oxidative phosphorylation subunits (complex I, III and IV), mitochondrial membrane potential, adenosine triphosphate synthesis and reduction of reactive oxygen species production. The benefits of enhanced mitochondrial regulation depended on the function of foreign mitochondria and not the existence of mitochondrial DNA and can be maintained for at least 21 days with dramatically elongated mitochondrial morphology. In contrast to delivery of wild-type mitochondria, the specific regulation of Pep-1-Mito during MERRF syndrome progression in cells treated with mutant mitochondria was reflected by the opposite performance, with increase in reactive oxygen species production and matrix metalloproteinase activity.
  
  
  CONCLUSIONS
  The present study further illustrates the feasibility of mitochondrial intervention therapy using the novel approach of peptide-mediated mitochondrial delivery and the benefit resulting from mitochondria-organelle manipulation.
authors.affiliation: Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Jui-Chih
authors.initials: JC
authors.lastname: Chang
authors.forename: Ko-Hung
authors.initials: KH
authors.lastname: Liu
authors.forename: Chieh-Sen
authors.initials: CS
authors.lastname: Chuang
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Su
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
authors.forename: Shou-Jen
authors.initials: SJ
authors.lastname: Kuo
authors.forename: Chin-San
authors.initials: CS
authors.lastname: Liu
mesh_terms: D002478:Cells, Cultured; D003543:Cysteamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004272:DNA, Mitochondrial / Q000235:genetics; D042967:Electron Transport Complex I / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D017243:MERRF Syndrome / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010455:Peptides / Q000008:administration & dosage*; D017382:Reactive Oxygen Species
chemical_list: D004272:DNA, Mitochondrial; C503924:Pep-1 peptide; D010455:Peptides; D017382:Reactive Oxygen Species; D003543:Cysteamine; D042967:Electron Transport Complex I
keywords: MERRF syndrome; Pep-1; metalloproteinases; mitochondrial delivery; mitochondrial function