Experimental assessment of bioenergetic differences caused by the common European mitochondrial DNA haplogroups H and T
Taku Amoa, Nagendra Yadavab, Richard Ohb, David G. Nichollsb and Martin D. Brand
Studies of both survival after sepsis and sperm motility in human populations have shown significant associations with common European mitochondrial DNA haplogroups, and have led to proposals that mitochondria bearing haplogroup H have different bioenergetic capacities than those bearing haplogroup T. However, the validity of such associations assumes that there are no non-random influences of nuclear genes or other factors. Here, we removed the effect of any differences in nuclear genes by constructing transmitochondrial cybrids harbouring mitochondria with either haplogroup H or haplogroup T in cultured A549 human lung carcinoma cells with identical nuclear backgrounds. We compared the bioenergetic capacities and coupling efficiencies of mitochondria isolated from these cells, and of mitochondria retained within the cells, as a critical experimental test of the hypothesis that these haplogroups affect mitochondrial bioenergetics. We found that there were no functionally-important bioenergetic differences between mitochondria bearing these haplogroups, using either isolated mitochondria or mitochondria within cells.
There are published associations between mitochondrial haplogroups H and T and phenotypes that might be expected to have a strong bioenergetic component. However, our results show no significant bioenergetic differences in mitochondria with H or T-haplogroup mtDNAs in a constant nuclear background, at either the mitochondrial or the cellular level. We have previously shown that our methodology can pick up 10% differences in respiratory chain activity (Amo and Brand, 2007), so if haplogroup does affect mitochondrial bioenergetics, any effects must be very small. The lack of effect of haplogroup on mitochondrial coupling efficiency in intact cybrids shows that even if haplogroup affects mitochondrial proliferation or retrograde signalling, such changes do not affect coupling efficiency in the cells under basal conditions.
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Our results fail to provide support for the hypothesis that the common European mitochondrial haplogroups H and T have significant effects on bioenergetics that cause the associations with survival after sepsis and sperm motility that have been reported. If such associations stand up to further scrutiny, they presumably operate through more subtle mechanisms than respiratory rates, mitochondrial coupling efficiencies or ATP supply.