Reverse Genetic Studies on Mammalian Mitochondrial DNA with Pathogenic Mutations

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  • Nakada Kazuto
    Faculty of Life and Environmental Sciences, University of Tsukuba

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  • 病原性突然変異型ミトコンドリアDNAのマウス逆遺伝学

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Abstract

<p>　It has been well documented that mitochondrial DNA（mtDNA）mutations induce mitochondrial respiration defects, when certain pathogenic mtDNA mutations accumulate predominantly in the affected tissues and cells. These pathogenic mtDNA mutations include large-scale deletions and point mutations. The resultant mitochondrial respiration defects manifest as a variety of mitochondrial diseases with varying clinical outcomes. Accumulation of mutations in mtDNA is observed not only in patients with mitochondrial disease, but also in patients with diabetes, neurodegenerative disease, infertility, cancer, and in aged subjects. Cell and animal models carrying mtDNA mutations are powerful tools for understanding the pathophysiological mechanism underlying mitochondrial diseases. However, to our knowledge, no methodology is currently available for transfection of mutagenized mammalian whole mtDNA into mitochondria of living cells or isolated mitochondria. Using the cell fusion technique, we have successfully generated a mouse model, named “mito-mice”, carrying pathogenic mtDNA mutations. We transfected mitochondria carrying pathogenic mutations in the mtDNA into mouse zygotes and mouse embryonic stem cells. In this review, the pathogenicity of mtDNA mutations and the associated phenotypes in mito-mice is discussed.</p>

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