title: Selective elimination of mitochondrial mutations in the germline by genome editing.
abstract: 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. PAPERCLIP.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ocampo
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Jinping
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Bacman
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Sion L
authors.initials: SL
authors.lastname: Williams
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugawara
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Daiji
authors.initials: D
authors.lastname: Okamura
authors.affiliation: Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tsunekawa
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lam
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Xiong
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Pluripotent Stem Cells and Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Montserrat
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Concepcion Rodriguez
authors.initials: CR
authors.lastname: Esteban
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China; Beijing Institute for Brain Disorders, Beijing100069, China.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Liu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sancho-Martinez
authors.affiliation: Institut Clínic of Gynecology, Obstetrics and Neonatology (ICGON), Hospital Clinic, University of Barcelona, Barcelona 08036, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Manau
authors.affiliation: Institut Clínic of Gynecology, Obstetrics and Neonatology (ICGON), Hospital Clinic, University of Barcelona, Barcelona 08036, Spain.
authors.forename: Salva
authors.initials: S
authors.lastname: Civico
authors.affiliation: Mitochondrial Research Laboratory, IDIBAPS/CIBER on Rare Diseases, University of Barcelona and Internal Medicine Department, Hospital Clínic, University of Barcelona, Barcelona 08036, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Cardellach
authors.affiliation: Neuropediatric Department/CIBERER, Hospital Universitari Sant Joan de Déu, Esplugues de Llobregat 08950, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Del Mar O'Callaghan
authors.affiliation: Neuropediatric Department/CIBERER, Hospital Universitari Sant Joan de Déu, Esplugues de Llobregat 08950, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Campistol
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Renal Division, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona 08036, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
authors.affiliation: Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: belmonte@salk.edu.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D000818:Animals; D002459:Cell Fusion; D004272:DNA, Mitochondrial; D004622:Embryo, Mammalian / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000517:prevention & control; D009154:Mutation; D009865:Oocytes / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004720:Endonucleases