Mitochondrial protein import and human health and disease
James A. MacKenzie
, R. Mark Payne
Department of Biological Sciences, 133 Piez Hall, State University of New York at Oswego, Oswego, NY 13126, USA
Department of Pediatrics and Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Received 26 July 2006; received in revised form 6 December 2006; accepted 7 December 2006Available online 9 December 2006
The targeting and assembly of nuclear-encoded mitochondrial proteins are essential processes because the energy supply of humans isdependent upon the proper functioning of mitochondria. Defective import of mitochondrial proteins can arise from mutations in the targetingsignals within precursor proteins, from mutations that disrupt the proper functioning of the import machinery, or from deficiencies in thechaperones involved in the proper folding and assembly of proteins once they are imported. Defects in these steps of import have been shown tolead to oxidative stress, neurodegenerative diseases, and metabolic disorders. In addition, protein import into mitochondria has been found to be adynamically regulated process that varies in response to conditions such as oxidative stress, aging, drug treatment, and exercise. This reviewfocuses on how mitochondrial protein import affects human health and disease.© 2006 Elsevier B.V. All rights reserved.
Mitochondria; Protein targeting; Protein translocation; Human health and disease
Proteins act as hormones, receptors, enzymes, channels, andstructural components within the cell, and although most aresynthesized by the same set of cytosolic ribosomes, each proteinhas a specific subcellular location in which it resides andfunctions properly. Blobel and colleagues first postulated the
, which predicted that proteins contain
within their amino acid sequences that determine their subcellular location[1,2]. The importance of this hypothesiswas supported by the finding that preproinsulin from twodifferent fish species could be efficiently imported into dog pancreas microsomal vesicles, confirming that the system of protein targeting is evolutionarily conserved throughout nature. In addition to specific targeting and compartmentalizationwithin the cell, proteins also undergo post-translationalmodifications such as processing, folding, and oligomerization.Errorsinanyofthestepsthatproteinsmustgothroughbeforethey become fully active in their proper location can result indisease. While a great deal of attention has been focused on howabnormaltargetingandfoldingofproteinscausehumandiseases(e.g., cystic fibrosis, hypercholesterolemia, Alzheimer's),there has been little focus on how problems in mitochondrial protein import contribute to human health and disease. Thisreview addresses how errors in the molecular mechanisms of import can lead to human disease, and also how mitochondrial protein import is variable and can be altered by variousconditions. In order to appreciate the complexity of mitochon-drialproteinimportandhowitrelatestodisease,webeginwitha brief overview of the import mechanisms.
2. Mitochondrial protein import
The targeting and import of mitochondrial proteins involve aseries of receptors, import pores, and molecular machineslocated in the four intra-mitochondrial locations; the outer andinner mitochondrial membranes, the intermembrane space(IMS), and the matrix[5,6]. Most mitochondrial proteins aresynthesized by free cytosolic ribosomes and are imported post-translationally (Fig. 1). All nuclearly-encoded mitochondrial proteins initially enter mitochondria via the protein translocasemachinery of the outer membrane (TOM complex). From there,they are sorted to their final destination by the combined actions
Biochimica et Biophysica Acta 1772 (2007) 509
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