Article ID Journal Published Year Pages File Type
1931225 Biochemical and Biophysical Research Communications 2010 6 Pages PDF
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.

Research highlights► Over-expression of Tfam in mito-mice prolonged the life span. ► Disease phenotypes were improved in Tfam over-expressing mito-mice. ► Over-expression of Tfam increases the amount of mtDNA. ► Increased wild-type mtDNA provides normal RNAs and proteins in mito-mice. ► Sufficient levels of mitochondrial factors prevent cells from respiration deficiency.

Related Topics
Life Sciences Biochemistry, Genetics and Molecular Biology Biochemistry
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