A feat that has eluded researchers for some time-the creation of an animal model of human mitochondrial DNA (mtDNA) diseases-has finally been accomplished. Japanese researchers report that they have created mutant mice with a large-scale mtDNA deletion and that many of these mice suffer from disease phenotypes similar to the human mtDNA disorders.

Mitochondria, descended from bacteria that were incorporated into what became eukaryotic cells, carry their own DNA around with them. This tiny ring, dwarfed by the immense nuclear genome, codes for some of the proteins (or protein subunits) involved in the respiratory chain. Of special interest to Alzheimer's researchers it the fact that mtDNA is inherited almost exclusively from the mother, because the embryo derives virtually all its cytoplasm, and therefore its mitochondria, from the egg, as opposed to the sperm. There is a suspicion that some component of susceptibilty to Alzheimer's involves the mitochondrial genome, since studies have shown that having a mother with Alzheimer's confers a greater risk for the disease than having a father with Alzheimer's. There is also considerable evidence that Alzheimer's disease involves a disruption of energy metabolism.

Defects in the mtDNA lead to a clinically diverse group of diseases called the encephalomyopathies. Efforts to study these diseases in animal models has been stymied by the instability of mutagenized mtDNA. Jun-Ichi Hayashi and his collaborators found a clever solution, using naturally occurring deletion mutations in aging mice. The aged, mutant mtDNA was sealed inside mouse synaptosomes (cytoplasmic vesicles) and introduced to a cell line depleted of mtDNA. When the researchers finally got a cell repopulated with a high proportion of mutant mtDNA, they enucleated it, fused it to a mouse embryo, and implanted it in female mice. They were then able to propagate the mutant mtDNA through three generations. The mice display respiratory chain deficiencies, most prominently in heart and muscle tissue, as is characteristic of the human diseases. Unlike humans, however, most of the mice died of kidney failure.

The great hope is that this method will allow researchers to also introduce point mutations into the mtDNA, writes Eric Shoubridge of McGill University, Montreal, in an accompanying News and Views, "but isolating the appropriate mutations at levels sufficient to create heteroplasmic embryos will be difficult. The holy grail of mammalian mitochondrial genetics, the transformation of mtDNA, remains an important goal."—Hakon Heimer


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Primary Papers

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  2. . Immunology. Agrin--a bridge between the nervous and immune systems. Science. 2001 Jun 1;292(5522):1667-8. PubMed.