Animal models of human mitochondrial DNA mutations

Abstract

Background Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic states in human patients. Development of animal models harboring mtDNA mutations is crucial to elucidating pathways of disease and as models for preclinical assessment of therapeutic interventions. Scope of Review This review covers the knowledge gained through animal models of mtDNA mutations and the strategies used to produce them. Animals derived from spontaneous mtDNA mutations, somatic cell nuclear transfer (SCNT), nuclear translocation of mitochondrial genes followed by mitochondrial protein targeting (allotopic expression), mutations in mitochondrial DNA polymerase gamma, direct microinjection of exogenous mitochondria, and cytoplasmic hybrid (cybrid) embryonic stem cells (ES cells) containing exogenous mitochondria (transmitochondrial cells) are considered. Major Conclusions A wide range of strategies have been developed and utilized in attempts to mimic human mtDNA mutation in animal models. Use of these animals in research studies has shed light on mechanisms of pathogenesis in mitochondrial disorders, yet methods for engineering specific mtDNA sequences are still in development. General Significance Research animals containing mtDNA mutations are important for studies of the mechanisms of mitochondrial disease and are useful for development of clinical therapies.

Mitochondria functionality and sperm quality

“…To this extent, mtDNA defects have been associated with a range of human disorders (including neurodegenerative diseases and cancer), as well as with ageing (for recent reviews, see Greaves et al (2012) and Schon et al (2012)). The development of animal models harbouring mtDNA mutations corroborated this association and contributed to the elucidation of mitochondrial disease mechanisms (Dunn et al 2012).…”

Gene Editing

“…While gene knockout/knock-in strategies involving embryonic stem (ES) cell approaches are standard in mouse laboratories, these techniques have until recently been restricted exclusively to mice (Dunn et al, 2005(Dunn et al, , 2012Martin et al, 2010). Alternative methods for ablating specific gene function or knocking in alternative genetic sequences in other species, when available, are labor intensive and inefficient.…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…Transgenic mice with a conditional knockout of the NDUFS4 gene presented with a fatal progressive encephalopathy similar to human patients, regardless of whether the knockout was global or exclusive to the central nervous system (CNS), suggesting that NDUFS4 function is of particular relevance to the CNS. Although generating animal models mutant for nuclear-encoded components of OXPHOS is feasible, few models exist thus far [47,49,50] ( Table 1). Given the conserved nature of many OXPHOS components, in many cases conditional models will be required to overcome embryonic lethality associated with global mutants.…”