Mouse model for mitochondrial diseases

Mutations in the mitochondrial DNA (mtDNA) affect mitochondrial function essential for the oxidative phosphorylation system, the aerobic respiration and the efficient production of cellular energy. The resultant devastating mitochondrial disorders are not only involved in encephalomyophathies, especially brain and muscle diseases due to their high-energy requirement but also in a variety of age-associated human diseases. Despite the realization that mitochondrial disease is a relatively common genetic disorder, treatment is still very limited.
The lack of appropriate animal models carrying pathogenic mtDNA mutations, recreating human disease phenotypes, is a big obstacle for in vivo testing of novel treatments. Despite enormous efforts, direct manipulation and stable transfection of mtDNA are still not possible. Currently used, indirect methods of mtDNA manipulation do not allow to obtain the hallmark of mtDNA-related diseases, the heteroplasmy, observed as a mosaic pattern of cells mixture of the mutant, dysfunctional and wildtype versions.

Our researchers developed a transgenic, heteroplasmic mouse with stable pathogenic mutation in the tRNA^ALA gene of mtDNA, displaying symptoms as observed in human patients with disease-causing mutation in the same mitochondrial gene. The allele segregation with high levels of mutation behaves similar to common mitochondrial disorder alleles observed in MELAS and MERRF diseases. In addition, the mice have decreasing body mass after 20 weeks and increased expression levels of atrial natriuretic factor, consistent with the development of cardiomyopathy. As in humans, the observed mitochondrial disorder in mice is progressive, showing after 60 weeks widespread mitochondrial dysfunction in the heart, skeletal muscle and the smooth muscle cells of the colon.
Taken together, the developed transgenic mouse model has high clinical relevance to test a variety of novel treatments against mitochondrial dysfunction and this know-how is available for licensing.

1. Johanna H.K. Kauppila, Holly L. Baines, Ana Bratic, Marie-Lune Simard, Christoph Freyer, Arnaud Mourier, Craig Stamp, Roberta Filograna, Nils-Goran Larsson, Laura C. Greaves, James B. Stewart (2016): A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease. Cell Reports. 16, 2980–2990.
2. James M. Ross, James B. Stewart, Erik Hagström, Stefan Brené, Arnaud Mourier, Giuseppe Coppotelli, Christoph Freyer, Marie Lagouge, Barry J. Hoffer, Lars Olson and Nils-Göran Larsson (2013) Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501: 412-416.
3. James Bruce Stewart, Christoph Freyer, Joanna L. Elson, Anna Wredenberg, Zekiye Cansu, Aleksandra Trifunovic and Nils-Göran Larsson (2008) Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biology 6: 63-71.