Transmitochondrial mice: Proof of principle and promises

Since the initial identification of pathogenic mutations in 1988, more than 100 point mutations and numerous large-scale deletions of human mtDNA have been associated with a wide range of clinical phenotypes (1). The development, by King and Attardi, of cells in culture called cybrids (cytoplasmic hybrids) provided an in vitro method to study mtDNA mutations against a uniform nuclear (nDNA) background (2). Although cybrid technology has been very useful in defining some pathogenic effects of mtDNA mutations, until this year, researchers have been hindered by the lack of animal models with mtDNA mutations. By contrast, manipulation of mouse embryonic stem (ES) cells has already produced a few lines of mice with defects of nDNA-encoded mitochondrial proteins (3, 4).

In a recent issue of PNAS, Sligh et al. describe how they have succeeded in producing transmitochondrial mice by transferring exogenous mtDNA into embryo (5). These are the first mice with a transmitochondrial mtDNA point mutation to express an abnormal phenotype, a mitochondrial disease. This exciting work and the recent report by Inoue et al. of a transmitochondrial mouse harboring a pathogenic mtDNA deletion (6) are likely to be the harbingers of a new wave of research with animal models of human mitochondrial disorders. Curiously, these developments mirror the sequence in which human mutations were reported: large-scale deletions first, followed shortly thereafter by a pathogenic point mutation.

Mitochondria are vital organelles that provide most of the cellular energy in the form of ATP. This process requires the transfer of reducing equivalents through enzyme complexes of the respiratory chain, thereby generating a proton gradient across the inner mitochondrial membrane, which, in turn, drives oxidative phosphorylation to produce ATP. Four of the five respiratory chain complexes are under dual genetic control because some of their structural subunits are encoded by mtDNA …