Engineering the mammalian mitochondrial genome, and movement of mitochondria between cells

Recent evidence from a number of labs suggests that mitochondria can move between cells. With respect to the nervous system in particular, there is evidence that mitochondria can move from astrocytes to neurons following stroke and that this promotes neuroprotection. Other observations suggest that infusion of healthy mitochondria can be cardioprotective. Conversely, transfer of healthy mitochondria from surrounding cells to tumors may also promote cancer. The idea that mitochondria might move between cells in physiological contexts is quite exciting but essentially unexplored in terms of how, when, where and kinds of regulation. Transferred mitochondria could provide a localized source of energy production in the recipient cell. They could also be involved in a number of other local mitochondria-based metabolic activities. Finally, because mitochondria carry their own genome, such movement would also be associated with the long-term movement of self-replicating information between cells. Given the high frequency of pathogenic mutations noted above, it becomes interesting to determine the contexts in which mitochondria move between cells of the nervous system and other tissues, and whether this acts to promote normal function and/or spread pathology.

In order to address these questions we need to be able to create populations of mitochondria that can be distinguished from each other for long periods. To this end we are working to create transgenic mitochondria, which express a fluorescent protein from an otherwise wildtype mitochondrial genome. Success in this project constitutes the first step in longer-term program that would create a mouse carrying a transgenic mitochondrial genome in which expression of a mtDNA-based reporter is induced in response to condition-dependent expression of a site-specific recombinase from the nuclear genome. In parallel, the fate of reporter-expressing mitochondria, prepared from the transgenic cell population and infused directly into the circulation or specific tissues of non-transgenic mice can also be evaluated.