Sex, drugs and mitochondria

Abstract

In mammals, mitochondrial DNA (mtDNA) is transmitted through the maternal germ line, and is preceded by a bottlenecking process that effectively results in the transmission of only a small number of founder molecules. Under these circumstances, it has been suggested that only the fittest mtDNA should be transmitted, thus compensating for the absence of the sexual cycle. It is therefore a mystery why deleterious, disease-causing mtDNA mutations are passed on from mother to child, sometimes with a significant increase in mutant-gene dosage and disease severity.A major problem in attacking this question has been the absence of an animal model owing to the fact that direct mtDNA transformation has not been achieved in mammals. However, Marchington et al.1xTransmitochondrial mice carrying resistance to chloramphenicol on mitochondrial DNA: developing the first mouse model of mitochondrial DNA disease. Marchington, D.R. and Poulton, J. Nat. Med. 1999; 5: 957–960Crossref | PubMed | Scopus (46)See all References1 have now devised an ingenious way around this by combining transmitochondrial cybrid fusion with blastocyst injection, using donor mtDNA from 3T3 cells that carry a deleterious but also selectable mutation (chloramphenicol resistance, CAPr). Cybrid fusion was used to generate a heteroplasmic embryonic stem (ES) cell line containing CAPr mtDNA, which was injected into blastocysts to yield chimeric transmitochondrial mice that carried a proportion of CAPr mtDNA.The CAPr mutation (mapping to the 16S rRNA gene) causes defective mitochondrial translation and entrains a respiratory chain insufficiency. Although an analogous mutation has not been found in humans, the majority of mitochondrial disease mutations do affect the translation system, thus the CAPr mouse might offer a useful model. In the absence of any imposed selection, there was considerable tissue variation in the relative amount of CAPr mtDNA, with preferential accumulation in oxidative tissues such as the heart and diaphragm. This paradoxical finding also reflects the behaviour of mutant molecules in mtDNA disease, suggesting that a similar mechanism is at work.It remains to be seen whether the CAPr mtDNA can be transmitted through the female germ line. Even if CAPr mtDNA is systematically excluded from oocytes, this will be an important clue that disease-causing mtDNA mutations are transmissible as a result of some, as yet unknown, positive selective advantage they confer, in spite of phenotypic counter-selection. Plainly, we still have much to learn about mitochondrial sex.