title: Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells.
abstract: Many incurable mitochondrial disorders result from mutant mitochondrial DNA (mtDNA) and impaired respiration. Leigh's syndrome (LS) is a fatal neurodegenerative disorder of infants, and Leber's hereditary optic neuropathy (LHON) causes blindness in young adults. Treatment of LHON and LS cells harboring G11778A and T8993G mutant mtDNA, respectively, by >90%, with healthy donor mtDNA complexed with recombinant human mitochondrial transcription factor A (rhTFAM), improved mitochondrial respiration by ∼1.2-fold in LHON cells and restored >50% ATP synthase function in LS cells. Mitochondrial replication, transcription, and translation of key respiratory genes and proteins were increased in the short term. Increased NRF1, TFAMB1, and TFAMA expression alluded to the activation of mitochondrial biogenesis as a mechanism for improving mitochondrial respiration. These results represent the development of a therapeutic approach for LHON and LS patients in the near future.
authors.affiliation: Center for the Study of Biological Complexity, Life Sciences, Virginia Commonwealth University, Richmond, VA 23284-3020, USA. siyer@vcu.edu
authors.forename: Shilpa
authors.initials: S
authors.lastname: Iyer
authors.forename: Kristen
authors.initials: K
authors.lastname: Bergquist
authors.forename: Kisha
authors.initials: K
authors.lastname: Young
authors.forename: Erich
authors.initials: E
authors.lastname: Gnaiger
authors.forename: Raj R
authors.initials: RR
authors.lastname: Rao
authors.forename: James P
authors.initials: JP
authors.lastname: Bennett
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D050259:Genes, Mitochondrial / Q000235:genetics; D015316:Genetic Therapy; D006801:Humans; D007888:Leigh Disease / Q000235:genetics / Q000628:therapy*; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics / Q000628:therapy*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A