Mixing mitochondrial DNA bad for physiology

Oct 16 2012

By Eleanor McDermid, Senior medwireNews Reporter

Mice with mitochondrial (mt) DNA from two sources have abnormal physiology and cognition, researchers report in Cell.

This could explain why almost all animals inherit mtDNA only from their mothers, say Douglas Wallace (Children's Hospital of Philadelphia, Pennsylvania) and co-workers.

The team generated female mice that had "roughly equal" proportions of mtDNA from the 129S6 and NZB mouse strains and crossbred them with males from the C57BL/6J strain.

The resultant mice had a "dramatic reduction" in their activity levels when kept in darkness, relative to mice with the same nuclear genome (C57BL/6J) but only 129S6 or NZB mtDNA, and they had significantly reduced food intake and metabolic rates. They also had abnormal responses to stressful situations, being less prone to "behavioral despair" in a forced swim test, and more willing to explore open, exposed environments than the mice with a single mtDNA source.

"Yet the increased activity was tempered by a decreased capacity to learn and remember," say Wallace et al.

They found that mice with both 129S6 and NZB mtDNA were less able to escape from a maze than mice with a single mtDNA source, due to having poorer spatial memory retention.

This suggests that the apparently small differences between mtDNA from different strains of the same species "may not be neutral," says the team, and may in fact be sufficiently deleterious to drive unilateral inheritance of mtDNA.

Indeed, when mice with both 129S6 and NZB mtDNA were allowed to breed, the NZB mtDNA almost completely disappeared within two generations, whereas it took more than 10 generations of selective breeding for the researchers to produce mice that were nearly homogenous for NZB mtDNA. However, mice selectively lost NZB mtDNA only if it initially accounted for more than 10% of the total mtDNA.

Wallace and team say that a slight decrease in oxidative phosphorylation capacity caused by interaction between the two mtDNAs could place an organ such as the liver under chronic stress, because it lacks any reserve capacity. This could drive the loss of one mtDNA during normal tissue aging; indeed, during their lifetimes, mice selectively lost 129S6 mtDNA from the liver and kidneys, and lost NZB mtDNAs from the spleen and pancreas.

Other organs, such as the brain, have reserve oxidative phosphorylation capacity, so the drive to lose one mtDNA would be less. But this capacity would be exhausted under the stress of new situations, and would manifest as cognitive impairment, as the team found.

"The physiological mechanism by which one 'normal' mtDNA can be distinguished from another remains a mystery," observe Wallace and team.

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