Selective elimination of mitochondrial mutations in the germline by genome editing

Pradeep Reddy, Alejandro Ocampo, Keiichiro Suzuki, Jinping Luo, Sandra R. Bacman, Sion L. Williams, Atsushi Sugawara, Daiji Okamura, Yuji Tsunekawa, Jun Wu, David Lam, Xiong Xiong, Nuria Montserrat, Concepcion Rodriguez Esteban, Guang Hui Liu, Ignacio Sancho-Martinez, Dolors Manau, Salva Civico, Francesc Cardellach, Maria Del Mar O'CallaghanJaime Campistol, Huimin Zhao, Josep M. Campistol, Carlos T. Moraes, Juan Carlos Izpisua Belmonte*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

195 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)459-469
Number of pages11
Issue number3
StatePublished - Apr 23 2015

Bibliographical note

Funding Information:
We thank M. Schwarz for administrative support. We thank S. Heinz and M.M. Ku from H.A. and Mary K. Chapman Charitable Foundations Genomic Sequencing Core at the Salk Institute for help with sequencing analysis. We thank M. Chang from the Integrative Genomics and Bioinformatics Core at the Salk Institute for sequencing data analysis. We thank C.B. Farrokhi from the Behavioral Testing Core at the Salk Institute for help with behavioral studies. We thank Eric Shoubridge from McGill University, Montreal, Canada for sharing with us the NZB/BALB/c heteroplasmic mice. We thank Julio Montoya Villarroya from the University of Zaragoza, Zaragoza, Spain, and M a Ángeles Ruiz Gómez from the Hospital de Son Espases, Palma de Mallorca, Spain. Financial support: M.M. Ku and S. Heinz are supported by the Leona M. and Harry B. Helmsley Charitable Trust. A.O. was partially supported by an NIH Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship. G.-H.L. was supported by National Basic Research Program of China (973 Program, 2015CB964800; 2014CB964600), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01020312), National Natural Science Foundation of China (NSFC: 81271266; 31222039; 31201111; 81371342). C.T.M. was supported by NIH grants 5R01EY010804, 1R01AG036871, the JDM Fund, the Muscular Dystrophy Association and the United Mitochondrial Disease Foundation. S.L.W. is supported by Florida Department of Health Grant 3KN09. Work in the laboratory of J.C.I.B. was supported by the G. Harold and Leila Y. Mathers Charitable Foundation and the Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002).

Publisher Copyright:
© 2015 Elsevier Inc.

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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