Current progress with mammalian models of mitochondrialDNAdisease

Abstract

Mitochondrial disorders make up a large class of heritable diseases that cause a broad array of different human pathologies. They can affect many different organ systems, or display very specific tissue presentation, and can lead to illness either in childhood or later in life. While the over 1200 genes encoded in the nuclear DNA play an important role in human mitochondrial disease, it has been known for over 30 years that mutations of the mitochondria's own small, multicopy DNA chromosome (mtDNA) can lead to heritable human diseases. Unfortunately, animal mtDNA has resisted transgenic and directed genome editing technologies until quite recently. As such, animal models to aid in our understanding of these diseases, and to explore preclinical therapeutic research have been quite rare. This review will discuss the unusual properties of animal mitochondria that have hindered the generation of animal models. It will also discuss the existing mammalian models of human mtDNA disease, describe the methods employed in their generation, and will discuss recent advances in the targeting of DNA‐manipulating enzymes to the mitochondria and how these may be employed to generate new models.

The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

“…In addition to the great advantages of the yeast model, it should be noted that some limitations exist: (i) yeast cannot be used to model a disease at the scale of an organ or an intact complex multicellular organism; (ii) yeast does not allow to assess tissue specificity and disease progression; (iii) some functions fulfilled by human mitochondria do not exist in S. cerevisiae such as the respiratory complex I which, however, is present in the yeast Yarrowia lipolytica , used to model mutations related to this complex [ 271 ]. Moreover, cell division and mitochondrial replication in human development could lead to much greater variation in the relative levels of the mtDNA mutation in a largely stochastic system [ 23 ]. This could induce compensatory biogenesis mechanisms to maintain the cell’s mitochondrial function, an effect not observable in yeast where the heteroplasmic condition is rapidly lost.…”

“…Model systems (yeast, Caenorhabditis elegans , Drosophila, zebrafish, mouse) have proved their usefulness to validate the pathogenicity of variants, to assess the disease progression and the mechanisms associated with mitochondrial dysfunction. They therefore represent a powerful tool to study new disease genes, in particular when the gene function is unknown, when there is only a single patient, patient samples cannot be obtained or when cell lines, derived from patient fibroblasts, are aphenotypic (see for recent review [ 1 , 20 , 23 ]). The yeast Saccharomyces cerevisiae is the organism that more than any other has contributed to our understanding of mitochondria functionality.…”

Potential of Mitochondrial Genome Editing for Human Fertility Health

“…Additionally, the generation of animal models is an important and indispensable approach for the exploration of the mitochondrial genome. To date, mouse models of mtDNA disease have either been generated by introducing pathogenic mtDNA mutations within mitochondria into mouse embryos and importing them into embryo stem (ES) cells that are implanted into embryos or by the generation and selection of mtDNA mutations produced by mtDNA mutator mice ( Stewart, 2020 ). Novel MGE technologies offer the possibility of a more precise and efficient strategy to create animal models with certain mtDNA mutations and further give hope for the treatment of mitochondrial diseases.…”

Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

“…Moreover, given the difficulties in manipulating mtDNA, very few animal models with mtDNA pathogenic mutations are available ( 11 ), preventing the possibility to study the affected tissues and organs and test therapeutic options.…”