Factors that might affect the allotopic replacement of a damaged mitochondrial DNA-encoded protein





S.J. Zullo J.M. Eisenstadt, C.R. Merril, H. Weiner

Department of Biochemistry, Purdue University, 175 South University Street, West Lafayette, Indiana 47907, USA



We recently demonstrated that by changing codons of an oligomycin-resistant mutant mitochondrial DNA (mtDNA)-encoded ATPase 6 gene, it was possible to express it from the nucleus. Further, if constructed with a mitochondrial-targeting leader sequence, this protein was transported into mitochondria of CHO cells and conferred oligomycin resistance to a cell line that possessed a normal mtDNA ATPase 6 gene sequence (Zullo et al. Rejuvenation Research 8, 18-28, 2005). In principle then, any mtDNA-encoded gene could be altered so it could be expressed from the nucleus (known as allotopic expression) and should be able to compensate for a defective mtDNA-encoded gene product.

For this to occur, the newly synthesized protein needs to be accessible to chaperon proteins and/or not fold or aggregate prior to import; the leader would most likely need to be removed prior to the protein being inserted into the membrane-associated complex (all mtDNA-encoded proteins are membrane-associated proteins). If the complex possessed a mutated but stable form of a damaged protein, the pre-existing protein in the complex would need to be displaced; alternatively, the newly imported protein could be inserted into nascent complexes, which would need to replace the existing complex. It has not been established that all these events could occur so the generality of the events in our initial report has not yet been determined.

Lastly, we recently found a bacterial leader that could bring proteins into HeLa cell mitochondria. It is not known if this event occurs in nature.

The relevance of this finding and other factors that might influence the ability of normally mtDNA-encoded genes to be allotopically expressed from the nucleus will be discussed.




Key words: Allotopic, mitochondria, protein import, mtDNA







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