Over-expression of Tfam improves the mitochondrial disease phenotypes in a mouse model system.
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.
Nishiyama
Satoshi
S
Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki 305-8572, Japan.
Shitara
Hiroshi
H
Nakada
Kazuto
K
Ono
Tomio
T
Sato
Akitsugu
A
Suzuki
Hidenori
H
Ogawa
Tetsuhiro
T
Masaki
Haruhiko
H
Hayashi
Jun-Ichi
J
Yonekawa
Hiromichi
H
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*
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D003576:Electron Transport Complex IV