Mitochondrial DNA heteroplasmy in disease and targeted nuclease-based therapeutic approaches.
gene editing
heteroplasmy
mitochondrial DNA
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
04 03 2020
04 03 2020
Historique:
received:
06
11
2019
revised:
11
12
2019
accepted:
29
01
2020
pubmed:
20
2
2020
medline:
28
4
2021
entrez:
20
2
2020
Statut:
ppublish
Résumé
Mitochondrial DNA (mtDNA) encodes a subset of the genes which are responsible for oxidative phosphorylation. Pathogenic mutations in the human mtDNA are often heteroplasmic, where wild-type mtDNA species co-exist with the pathogenic mtDNA and a bioenergetic defect is only seen when the pathogenic mtDNA percentage surpasses a threshold for biochemical manifestations. mtDNA segregation during germline development can explain some of the extreme variation in heteroplasmy from one generation to the next. Patients with high heteroplasmy for deleterious mtDNA species will likely suffer from bona-fide mitochondrial diseases, which currently have no cure. Shifting mtDNA heteroplasmy toward the wild-type mtDNA species could provide a therapeutic option to patients. Mitochondrially targeted engineered nucleases, such as mitoTALENs and mitoZFNs, have been used in vitro in human cells harboring pathogenic patient-derived mtDNA mutations and more recently in vivo in a mouse model of a pathogenic mtDNA point mutation. These gene therapy tools for shifting mtDNA heteroplasmy can also be used in conjunction with other therapies aimed at eliminating and/or preventing the transfer of pathogenic mtDNA from mother to child.
Identifiants
pubmed: 32073748
doi: 10.15252/embr.201949612
pmc: PMC7054667
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
e49612Subventions
Organisme : NEI NIH HHS
ID : R01 EY010804
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS079965
Pays : United States
Organisme : HHS|NIH|National Eye Institute (NEI)
ID : 5R01EY0108041
Pays : International
Organisme : Muscular Dystrophy Association (MDA)
Pays : International
Organisme : HHS|NIH|National Institute of Neurological Disorders and Stroke (NINDS)
ID : 1R01NS079965
Pays : International
Organisme : HHS|NIH|National Institute on Aging (NIA)
ID : 1R01AG036871
Pays : International
Organisme : NIA NIH HHS
ID : R01 AG036871
Pays : United States
Organisme : HHS|NIH|National Institute of Environmental Health Sciences (NIEHS)
ID : 1R33ES025673
Pays : International
Organisme : NIEHS NIH HHS
ID : R33 ES025673
Pays : United States
Informations de copyright
© 2020 The Authors.
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