A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease.
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.
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
Johanna H K
JHK
Kauppila
Newcastle University LLHW Centre for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Holly L
HL
Baines
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
Ana
A
Bratic
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
Marie-Lune
ML
Simard
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.
Christoph
C
Freyer
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
Arnaud
A
Mourier
Newcastle University LLHW Centre for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Craig
C
Stamp
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden.
Roberta
R
Filograna
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden. Electronic address: larsson@age.mpg.de.
Nils-Göran
NG
Larsson
Newcastle University LLHW Centre for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Laura C
LC
Greaves
Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany. Electronic address: jstewart@age.mpg.de.
James B
JB
Stewart
D000818:Animals; D001947:Breeding; D009202:Cardiomyopathies / Q000235:genetics / Q000503:physiopathology; D002999:Clone Cells; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D008810:Mice, Inbred C57BL; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D014176:Protein Biosynthesis; D012344:RNA, Transfer, Ala / Q000235:genetics
D004272:DNA, Mitochondrial; D012344:RNA, Transfer, Ala