Most (78%) mitochondrial genomes in the studied mutant strain of Drosophila subobscura have undergone a large-scale deletion (5 kb) in the coding region. This mutation is stable, and is transmitted intact to the offspring. This animal model of major rearrangements of mitochondrial genomes can be used to analyse the involvement of the nuclear genome in the production and maintenance of these rearrangements. Successive backcrosses between mutant strain females and wild-type males yield a biphasic change in heteroplasmy level: (a) a 5% decrease in mutated genomes per generation (from 78 to 55%), until the nuclear genome is virtually replaced by the wild-type genome (seven to eight crosses); and (b) a continuous decrease of 0.5% per generation when the nuclear context is completely wild-type. In parallel with these changes, NADH dehydrogenase activity, which is halved in the mutant strain (five subunits of this complex are affected by the mutation), gradually increases and stabilizes near the wild-type activity. A return to a nuclear context is accompanied by the opposite phenomena: progressive increase in heteroplasmy level and stabilization at the value seen in the wild-type strain and a decrease in the activity of complex I. These results indicate that the nuclear genome plays an important role in the control of heteroplasmy level and probably in the production of rearranged genomes.Keywords: deletion; heteroplasmy; mitochondria; nuclear control; respiratory complexes.Various mutations of the mitochondrial genomes have been correlated with human diseases, first affecting the high energy-consuming tissues such as muscles and the nervous system [1][2][3]. These mutations generally do not affect all of the mitochondrial genomes, and intact and mutated mitochondrial (mt)DNA can coexist (heteroplasmy) in a given cell or mitochondrial matrix. Disease severity is often greater when the proportion of mutated genomes is higher [3]. These mutations may be point mutations, as in the case of the diseases MERRF (myoclonus epilepsy with ragged red fibers) and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) [4,5], or concern larger regions (duplications and/or deletions) as in Kearns-Sayre syndrome and Pearson syndrome [6][7][8][9]. In these cases of substantial rearrangements, the mutations are usually sporadic. However, in certain well-described diseases (adPEO), the mutation is hereditary, autosomal and dominant [10,11]. Several different loci have been identified [11,12]. Various genes are therefore probably involved in the genesis or maintenance of the multiple deletions [13,14]; however, the mechanisms of these involvements are not yet fully understood.To date, no mammalian model of mitochondrial genome rearrangement has been elucidated, but different heteroplasmic mice have recently been obtained by transgenesis [15] or by directly introducing mitochondria into fertilized eggs [16].We have studied a mutant strain of Drosophila (D. subobscura) which is an animal model of these subs...
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