mitoTev-TALE: a monomeric DNA editing enzyme to reduce mutant mitochondrial DNA levels

EMBO Molecular Medicine
Claudia V PereiraCarlos T Moraes

Abstract

Pathogenic mitochondrial DNA (mtDNA) mutations often co-exist with wild-type molecules (mtDNA heteroplasmy). Phenotypes manifest when the percentage of mutant mtDNA is high (70-90%). Previously, our laboratory showed that mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) can eliminate mutant mtDNA from heteroplasmic cells. However, mitoTALENs are dimeric and relatively large, making it difficult to package their coding genes into viral vectors, limiting their clinical application. The smaller monomeric GIY-YIG homing nuclease from T4 phage (I-TevI) provides a potential alternative. We tested whether molecular hybrids (mitoTev-TALEs) could specifically bind and cleave mtDNA of patient-derived cybrids harboring different levels of the m.8344A>G mtDNA point mutation, associated with myoclonic epilepsy with ragged-red fibers (MERRF). We tested two mitoTev-TALE designs, one of which robustly shifted the mtDNA ratio toward the wild type. When this mitoTev-TALE was tested in a clone with high levels of the MERRF mutation (91% mutant), the shift in heteroplasmy resulted in an improvement of oxidative phosphorylation function. mitoTev-TALE provides an effective architecture for mtDNA editing that could f...Continue Reading

References

Nov 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·R E GilesD C Wallace
Apr 9, 1981·Nature·S AndersonI G Young
Nov 1, 1993·Archives of Neurology·S DiMauro, C T Moraes
Sep 2, 1998·Proceedings of the National Academy of Sciences of the United States of America·J BitinaiteI Schildkraut
Dec 7, 2002·The Biochemical Journal·Rodrigue RossignolThierry Letellier
Sep 24, 2005·Proceedings of the National Academy of Sciences of the United States of America·Maria Pilar Bayona-BafaluyCarlos T Moraes
Dec 16, 2006·Proceedings of the National Academy of Sciences of the United States of America·Michal MinczukAaron Klug
Oct 3, 2009·Mitochondrion·Douglas C Wallace, Weiwei Fan
May 28, 2010·Journal of Inherited Metabolic Disease·Paul M Smith, Robert N Lightowlers
Jan 24, 2012·Seminars in Neurology·Ryan L Davis, Carolyn M Sue
May 9, 2012·Proceedings of the National Academy of Sciences of the United States of America·Benjamin P KleinstiverDavid R Edgell
Nov 17, 2012·Nature Reviews. Genetics·Eric A SchonMichio Hirano
Apr 25, 2013·Nature Communications·Marine BeurdeleyGeorge H Silva
Nov 5, 2013·Cold Spring Harbor Perspectives in Biology·Douglas C Wallace, Dimitra Chalkia
Apr 18, 2014·G3 : Genes - Genomes - Genetics·Benjamin P KleinstiverDavid R Edgell
Apr 25, 2015·Cell·Pradeep ReddyJuan Carlos Izpisua Belmonte
Jul 15, 2015·Molecular Therapy : the Journal of the American Society of Gene Therapy·Masami HashimotoCarlos T Moraes
Aug 19, 2015·Nature Reviews. Genetics·James B Stewart, Patrick F Chinnery
Nov 29, 2017·Trends in Genetics : TIG·Payam A GammageMichal Minczuk

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Citations

Jul 2, 2019·Human Molecular Genetics·Mansur M NaeemNeal Sondheimer
Dec 4, 2019·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Christopher P WallisOliver Rackham
Dec 4, 2019·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Anna Klucnika, Hansong Ma
Mar 17, 2020·Journal of Internal Medicine·U ZekonyteC T Moraes
Sep 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yoon-Ha Jang, Kwang-Il Lim
Feb 12, 2019·Frontiers in Genetics·Juvid AryamanNick S Jones
Dec 14, 2018·Cancer Metastasis Reviews·Thomas C BeadnellDanny R Welch
Oct 26, 2020·Journal of Inherited Metabolic Disease·James Bruce Stewart
Jan 28, 2021·Life·Elvira G ZakirovaKonstantin E Orishchenko
Oct 17, 2020·The Journal of Biological Chemistry·David L ProleNick S Jones
Jan 13, 2021·Neural Regeneration Research·Isaac G OnyangoGorazd B Stokin
Dec 31, 2020·Molecular Therapy. Methods & Clinical Development·Naoki YahataRyuji Hata
Jan 18, 2021·The Journal of Biological Chemistry·David L ProleNick S Jones
Mar 14, 2021·Reproductive Sciences·Zhixin Jiang, Huan Shen
Mar 19, 2021·Science Advances·Priyanka NandakumarNeal Sondheimer
Mar 30, 2020·Cell·Oliver M RussellDoug M Turnbull
May 30, 2021·Nature Communications·Ugne ZekonyteCarlos T Moraes
Feb 18, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Marina Villanueva-PazJosé A Sánchez-Alcázar
Jun 12, 2021·Disease Models & Mechanisms·Marlies P RossmannLeonard I Zon
Jul 1, 2021·Computational and Structural Biotechnology Journal·Xingbo YangYaozu Xiang
Aug 7, 2021·Frontiers in Genetics·Lin FuYang Yu
Jun 2, 2020·Molecular Therapy. Methods & Clinical Development·Pedro Silva-PinheiroCarlo Viscomi
Dec 4, 2021·Nature Reviews. Genetics·Pedro Silva-Pinheiro, Michal Minczuk
Jan 4, 2022·ACS Biomaterials Science & Engineering·Naoto Yoshinaga, Keiji Numata

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Methods Mentioned

BETA
transfection
Fluorescence microscopy
transfections
PCR
FACS
aminoacylation
protein assay
electrophoresis

Software Mentioned

mitoTALENs
OptiQuant
Wave Software
Image laboratory
Image
mitoTALEN
GraphPad Prism

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