This week's Nature had a news feature by Nick Lane about mitochondrial disease. I found it interesting because it focuses not only on disorders associated with mtDNA alterations, but broadly on all those disorders of energy metabolism, most of which result from changes to DNA transferred long ago from the mitochondria to the nucleus:
[M]itochondrial genomes did not start out so small -- they probably once contained at least a few thousand genes, inherited from the free-living ancestor of mitochondria1. Exactly what happened to most of these genes is a moot point, but the evolution of a stable symbiotic relationship within eukaryotic cells led to hundreds, perhaps even thousands, being simply transferred to the cell's main genome in its nucleus. These transfers meant that mitochondria became dependent on the host cell for virtually all their functions. Today, some 99% of human mitochondrial proteins are encoded in the nucleus; all the proteins and other molecules required to build mitochondria are synthesized in the main body of the cell, then imported into the organelle. Only a fraction of these genes has been identified; the rest lie hidden in the vast code of the nucleus's genome.
This enigmatic 99% is now the focus of intense scrutiny. There are good reasons to believe that genes affecting the mitochondria could play a central role in human health and disease. Most of the genes that have remained in the mitochondrion have been linked to a series of devastating diseases, indicating the importance of fully functional mitochondria to human health.
This is far from comforting:
[David] Thorburn, however, estimates that as much as a tenth of the population may be carrying genetic disorders that could affect mitochondrial function. This is based on estimates of the number of mitochondrial genes in the nuclear genome and the incidence of recessive genetic disorders. He echoes a favourite catchphrase of mitochondriacs: "Mitochondrial deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age, and with any mode of inheritance."
Of course, all of this is on top of the normal climate-related variation in mitochondrial metabolism. People ought to be pretty widely variable in mitochondrial output, and disease variants are just the most extreme manifestation of this variability.
Other, more complex degenerative conditions, such as Parkinson's disease, progressive-blindness diseases and other nervous-system conditions also involve mutations in mitochondrial proteins4. Even cancer can be caused by mutations in nuclear genes encoding mitochondrial proteins. Examples are now cropping up almost every year, and together they are beginning to focus attention on the central role of mitochondria in disease.
These examples have all unexpectedly turned out to be 'mitochondrial', after years of tracking down candidate genes for the diseases. But new tools are letting scientists turn the old approach on its head. Rather than starting with an inherited condition and trying to track down the genes responsible, researchers are starting off with the mitochondria themselves, and attempting to hunt down the proteins needed to build them.
Knowledge of function begets hypotheses about etiology. It will soon be time to add the evolutionary element -- how much do any of these things contribute to fitness, for example?