Mitochondrial Dna: a Genetic Pandora’s Box

For stealing fire from the gods, Prometheus was bound to a rock on Caucasus, a vulture forever to consume his liver. As an additional punishment, the mortals were sent, by the gods, a beautiful and gifted woman, Pandora, whose only weakness was curiosity. Pandora was entrusted with a box, which she was sworn never to open. Alas, she did, and all evils flew out of the box and around the world. Thus, to compare mitochondrial DNA (mtDNA) to Pandora’s box seems fitting not only because of the myriad diseases that are potentially harbored within the mtDNA circle, but also because Pandora’s box was brought by a woman, just as mtDNA is given to us by our mothers. Lest this mythological parable exposes me to the accusation of sexism, let me hasten to point out the positive side of the s t o r y. Prometheus, a male giant, had given humans the wonderful gift of external fire, a source of heat and light, but Pandora, a god-given woman, gave humans their internal fire, their source of intracellular energ y. Although mitochondrial DNA (mtDNA) was discovered in 1963 (1), pathogenic mutations in the mitochondrial genome were not reported until 1988, when Holt et al. described l a rge-scale deletions in patients with mitochondrial myopathy (2), and Wallace et al. described a point mutation in the gene encoding subunit 4 of complex I (ND4) in a family with Leber’s hereditary optic neuropathy (LHON) (3). These two papers marked the opening of the genetic Pandor a ’s box to which I referred: in the past 12 years, the “morbidity map” of mtDNA has grown from one point mutation (1988) to the 115 point mutations listed in January 2001 (4) (Fig. 1, see over). To this, of course, must be added the innumerable mtDNA rearrangements (deletions, duplications, or both together) first identified by the group of the late Anita Harding (2), and quickly associated with various forms of progressive external ophthalmoplegia by our group (5,6). The aim of this lecture is not to review the variety of clinical presentations associated with mutations in mtDNA, but rather to ask the question, “Is Pandora’s box empty?” – have we ex-