title: Over-expression of Tfam improves the mitochondrial disease phenotypes in a mouse model system.
abstract: The phenotypes of mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) have been proposed to be strictly regulated by the proportion of wild-type and pathogenically mutated mtDNAs. More specifically, it is thought that the onset of the disease phenotype occurs when cells cannot maintain the proper mitochondrial function because of an over-abundance of pathological mtDNA. Therapies that cause a decrease in the pathogenic mtDNA population have been proposed as a treatment for mitochondrial diseases, but these therapies are difficult to apply in practice. In this report, we present a novel concept: to improve mitochondrial disease phenotypes via an increase in the absolute copy number of the wild-type mtDNA population in pathogenic cells even when the relative proportion of mtDNA genotypes remains unchanged. We have succeeded in ameliorating the typical symptoms of mitochondrial disease in a model mouse line by the over-expression of the mitochondrial transcription factor A (Tfam) followed by an increase of the mtDNA copy number. This new concept should lead to the development of a novel therapeutic treatment for mitochondrial diseases.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shitara
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.forename: Tomio
authors.initials: T
authors.lastname: Ono
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Sato
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Ogawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Masaki
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hayashi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D024101:Mitochondrial Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D003576:Electron Transport Complex IV