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Mitochondrial mutations: When the cell's 2 genomes collide
Date:2/5/2013

power plant.

Once the team, including lead author Meiklejohn, had a bona fide mitochondrial-nuclear incompatibility to study, they could then begin looking for exactly where the problem lay and how it was causing disease. In the paper, they describe the genetic and biochemical experiments they conducted to find out.

Brown graduate student Marissa Holmbeck, the paper's second author, measured the productivity of several enzymes in the mitochondria's power generation process. Two enzymes that are derived entirely from nuclear genes ran just as well in the sick flies as in healthy ones, but three enzymes that are jointly managed by mitochondrial and nuclear genes lagged behind in activity.

"The different complexes that are jointly encoded by the mitochondrial and nuclear subunits, those are the ones where we are seeing the defect in activity," Holmbeck said.

Each mutation alone, in fact, does little or no harm to flies. It is only when both are present that the flies fall ill.

Meanwhile, Meiklejohn and Montooth tracked those mutations to just two altered nucleotide letters one in each genome. In the mitochondrial genome, a G to U mutation in an RNA suggested a problem with protein production inside the mitochondria. This was confirmed when they discovered an A to V mutation in the nuclear protein that adds an amino acid to this same mitochondrial RNA.

The biochemical and genetic evidence pointed to flaws in how fast the mitochondria of the sick flies could produce proteins needed to promote growth.

"The specifics of this paper are tracking that down to the individual nucleotide," Rand said, "But the more general lesson is that this coevolution of mitochondrial and nuclear genes has been going on for millions of years in millions of organisms and is going on in human populations today."

In human beings, a well-known mitochondrial disease, for example, is an aversion to exercise that is due to a mu
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Contact: David Orenstein
david_orenstein@brown.edu
401-863-1862
Brown University
Source:Eurekalert  

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