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A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease

Lookup NU author(s): Holly Baines, Dr Craig Stamp, Dr Laura Greaves, Dr Jim StewartORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials.

Publication metadata

Author(s): Kauppila JHK, Baines HL, Bratic A, Simard ML, Freyer C, Mourier A, Stamp C, Filograna R, Larsson NG, Greaves LC, Stewart JB

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2016

Volume: 16

Issue: 11

Pages: 2980-2990

Online publication date: 13/09/2016

Acceptance date: 11/08/2016

Date deposited: 24/10/2016

ISSN (electronic): 2211-1247

Publisher: Elsevier


DOI: 10.1016/j.celrep.2016.08.037


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Funder referenceFunder name
Knut and Alice Wallenberg Foundation
13-053RUnited Mitochondrial Disease Foundation
2015-00418Swedish Research Council
367990950Ake-Wiberg foundation
G0700718Newcastle University Centre for Ageing and Vitality (Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, and Medical Research Council)
G096919Wellcome Trust Centre for Mitochondrial Research
G0700718Medical Research Council (MRC)