M.P. King

Increasing numbers of patients are being identified as suffering from mitochondrial diseases. Such diseases display great diversity in clinical symptoms and morphological and biochemical characteristics. Although mtDNA mutations have been identified in many patients, there are presently no effective treatments. A number of human diseases result from mutations in mtDNA-encoded proteins, a group of proteins that are hydrophobic and have multiple membrane-spanning regions. One method which has great potential for overcoming the pathogenic consequences of these mutations is to place a wild-type copy of the affected gene in the nucleus, and target the expressed protein to the mitochondrion to function in place of the defective mitochondrial protein. The Chlorophytic algae Chlamydomonas reinhardtii and Polytomella sp. have several specific respiratory chain subunit genes encoded in their nuclear DNA, that in humans are encoded in the mtDNA. Analysis of these genes has revealed adaptations that facilitated their transfer from the mitochondrion to the nucleus. The proteins exhibited diminished physical constraints for import as compared to mtDNA-encoded homologs. The diminished hydrophobicity is greater in those regions of the proteins that are not involved in subunit-subunit interactions or the enzymatic reactions of the proteins. In addition, they contain unusually large mitochondrial targeting sequences. Information derived from these studies should be applicable towards the development of genetic therapies for human diseases resulting from mutations in mtDNA-encoded polypeptide genes.

Keywords (Optional): 
respiratory chain
mitochondrial disease