Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes

Abstract

Mice carrying mitochondrial DNA (mtDNA) with pathogenic mutations would provide a system in which to study how mutant mtDNAs are transmitted and distributed in tissues, resulting in expression of mitochondrial diseases. However, no effective procedures are available for the generation of these mice. Isolation of mouse cells without mtDNA (rho0) enabled us to trap mutant mtDNA that had accumulated in somatic tissues into rho0 cells repopulated with mtDNA (cybrids). We isolated respiration-deficient cybrids with mtDNA carrying a deletion and introduced this mtDNA into fertilized eggs. The mutant mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues. Moreover, most of these mice died because of renal failure, suggesting the involvement of mtDNA mutations in the pathogeneses of new diseases.

Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

“…The ⌬mtDNA mice had high levels of a single mtDNA deletion in most tissues already at birth (17), resulting in respiratory chain deficiency in heart, skeletal muscle, and kidney and making it a good model for an early onset multisystem mitochondrial disease. The ⌬mtDNA mice died at 6 months of age due to renal failure.…”

“…Mouse models with mitochondrial dysfunction have been generated (15)(16)(17)(18), but their severe disease course resembled that of childhood diseases and no models for chronic late-onset disease have been available. We examined the consequences of dominant Twinkle-PEO mutations in transgenic mice.…”

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

“…mtDNA mutations can be introduced into mouse germ cells (Inoue et al, 2000), or they can be induced to occur as a consequence of a proofreading-deficient DNA polymerase gamma (Kauppila et al, 2016). However, the generated mouse models cannot recapitulate the heteroplasmy or tissue specificity of mtDNA disorders.…”

The mitochondrial theory of aging: dead or alive?

“…This should create a model for mtDNA rearrangements analogous to the POLG mutator for point mutations. A starting point is provided by mice already generated, that begin life with a substantial load of rearranged mtDNA (Inoue et al ., 2000). Mice with predominantly rearranged mtDNA do die prematurely, but as a result of renal failure.…”