Cell
Volume 161, Issue 3, 23 April 2015, Pages 459-469
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Article
Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing

https://doi.org/10.1016/j.cell.2015.03.051Get rights and content
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Highlights

  • Mitochondria-targeted nucleases selectively reduce mtDNA haplotypes in germline

  • Germline heteroplasmy shift prevents transmission of mtDNA haplotypes to offspring

  • Human mutated mtDNA can be reduced in oocytes by mitochondria-targeted nucleases

Summary

Mitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber’s hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA.

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