Journal
CELL
Volume 161, Issue 3, Pages 459-469Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.03.051
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Funding
- Leona M. and Harry B. Helmsley Charitable Trust
- NIH Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship
- National Basic Research Program of China (973 Program) [2015CB964800, 2014CB964600]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA01020312]
- National Natural Science Foundation of China (NSFC) [81271266, 31222039, 31201111, 81371342]
- NIH [5R01EY010804, 1R01AG036871]
- JDM Fund
- Muscular Dystrophy Association
- United Mitochondrial Disease Foundation
- Florida Department of Health [3KN09]
- G. Harold and Leila Y. Mathers Charitable Foundation
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
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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 trans-generational transmission of human mitochondrial diseases caused by mutations in mtDNA.
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