Targeting proteins to mitochondria: a current overview.

Abstract

Correct targeting of nuclear-encoded, cytoplasmicallysynthesized proteins to mitochondria is one facet of a diverse pattern of intracellular traffic of nascent polypeptides that occurs within all eukaryotic cells. The complex internal organization of cells necessitates that organellar or secreted polypeptides, initially formed in the cytoplasm, must be delivered efficiently across one or more internal membranes before reaching their final intracellular or extracellular destinations. Specific diseases can arise when polypeptides are 'addressed' incorrectly and subsequently directed to the wrong compartment. In the case of lysosomal storage diseases, degradative enzymes are secreted erroneously into the bloodstream, resulting in the accumulation of undegraded products in the lysosomal compartment, e.g. glycosaminoglycans or glycolipids in the case of I-cell disease [1,2]. Recently, it has been recognised also that primary hyperoxaluria in some patients may be the result of a targeting defect in which the peroxisomal enzyme, L-alanine: glyoxylate aminotransferase aberrantly assumes a mitochondrial location. The molecular basis for this phenomenon appears to be a point mutation in the 5'-flanking region of the gene which contains a cryptic mitochondrial presequence. This mutation permits initiation of translation at a new upstream AUG site, resulting in the synthesis of an altered form of the enzyme with additional polypeptide sequence at the N-terminus, exhibiting the properties of a mitochondrial targeting signal [3]. The last decade has seen rapid progress in our understanding of how the cell achieves this remarkable feat of traffic management. Advances in recombinant DNA technology combined with elegant research from many major laboratories have been responsible for elucidating the basic mechanisms underlying these processes and have now begun to unravel the complex sequence of molecular events involved in the translocation of newly-formed proteins across membranes. A series of excellent, comprehensive reviews and three books have appeared from the major contributors to this research in recent years [4-10], so the purpose of this article is to provide a broad perspective on developments, with particular emphasis on mitochondrial targeting.