Mechanisms for multiple intracellular localization of human mitochondrial proteins

There is an increasing number of reports that some single gene products function in more than one cellular compartment. This review lists and categorizes the targeting mechanisms of 31 human mitochondrial proteins that have multiple localizations. Further, genetic disorders based on mislocalization are described, and prediction algorithms for multi-localized proteins are proposed. A high diversity of experimentally verified targeting mechanisms ranging from single protein to multi-protein mechanisms exists, with a combination of multiple transcription starting points and alternative splicing being the most frequent. This observation stresses the individuality of the evolutionary histories of such mechanisms. We did not find specific localization strategies to cluster with certain protein functions. There was also no bias with respect to the evolutionary origin of the multi-compartmentalized mitochondrial proteins. Both, genes of bacterial and eukaryotic origin show multiple localization, which does not corroborate the hypothesis that the development of multiple targeting is coupled predominantly with the recruitment of nuclear eukaryotic genes for novel mitochondrial functions.