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In vitro supplementation with deoxynucleoside monophosphates rescues mitochondrial DNA depletion

Lookup NU author(s): Dr Brendan PayneORCiD, Professor Hanns Lochmuller, Professor Patrick Chinnery, Professor Rita HorvathORCiD


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Mitochondrial DNA depletion syndromes are a genetically heterogeneous group of often severe diseases, characterized by reduced cellular mitochondrial DNA content. Investigation of potential therapeutic strategies for mitochondrial DNA depletion syndromes will be dependent on good model systems. We have previously suggested that myotubes may be the optimal model system for such studies. Here we firstly validate this technique in a diverse range of cells of patients with mitochondrial DNA depletion syndromes, showing contrasting effects in cell lines from genetically and phenotypically differing patients. Secondly, we developed a putative therapeutic approach using variable combinations of deoxynucleoside monophosphates in different types of mitochondrial DNA depletion syndromes, showing near normalization of mitochondrial DNA content in many cases. Furthermore, we used nucleoside reverse transcriptase inhibitors to precisely titrate mtDNA depletion in vitro. In this manner we can unmask a physiological defect in mitochondrial depletion syndrome cell lines which is also ameliorated by deoxynucleoside monophosphate supplementation. Finally, we have extended this model to study fibroblasts after myogenic transdifferentiation by MyoD transfection, which similar to primary myotubes also showed deoxynucleoside monophosphate responsive mitochondria! DNA depletion in vitro, thus providing a more convenient method for deriving future models of mitochondrial DNA depletion. Our results suggest that using different combinations of deoxynucleoside monophosphates depending on the primary gene defect and molecular mechanism may be a possible therapeutic approach for many patients with mitochondrial DNA depletion syndromes and is worthy of further clinical investigation. (c) 2012 Elsevier Inc. All rights reserved.

Publication metadata

Author(s): Bulst S, Holinski-Feder E, Payne B, Abicht A, Krause S, Lochmuller H, Chinnery PF, Walter MC, Horvath R

Publication type: Article

Publication status: Published

Journal: Molecular Genetics and Metabolism

Year: 2012

Volume: 107

Issue: 1-2

Pages: 95-103

Print publication date: 03/05/2012

ISSN (print): 1096-7192

ISSN (electronic): 1096-7206

Publisher: Academic Press


DOI: 10.1016/j.ymgme.2012.04.022


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Funder referenceFunder name
Parkinson's Disease Society (UK)
UK NIHR Biomedical Research Centre in Ageing and Age related disease
Medical Research Council Translational Muscle Centre
BH090164Academy of Medical Sciences (UK)
G1000848MRC (UK)