Atm1p, a mitochondrial half-type ATP-binding cassette (ABC) protein in Saccharomyces cerevisiae, transports a precursor of the iron-sulfur (Fe/S) cluster from mitochondria to the cytosol. We have identified a novel half-type human ABC protein, designating it MTABC3 (mammalian mitochondrial ABC protein 3). MTABC3 mRNA is ubiquitously expressed in all of the rat and human tissues examined. MTABC3 protein is shown to be present in the mitochondria, as assessed by immunoblot analysis and confocal microscopic analysis of subcellular fractions of Chinese hamster ovary cells stably expressing MTABC3. Accumulation of iron in the mitochondria, mitochondrial DNA damage, and respiratory dysfunction in the yeast ATM1 mutant strain (atm1-1 mutant cells) were almost fully reversed by expressing MTABC3 in these mutant cells. These results indicate that MTABC3 is a novel ortholog of the yeast and suggest an important role in mitochondrial function. Interestingly, the human MTABC3 gene has been mapped to chromosome 2q36, a region within the candidate locus for lethal neonatal metabolic syndrome, a disorder of the mitochondrial function associated with iron metabolism, indicating that MTABC3 is a candidate gene for this disorder.
ATP-binding cassette (ABC)1 proteins constitute one of the largest superfamily of membrane proteins in both prokaryotic and eukaryotic organisms, and their general structures are well conserved in evolution (1, 2). In eukaryotes, most of the members of the ABC protein family function as ATP-dependent active transporters in the plasma membranes and the membranes of intracellular organelle, including the endoplasmic reticulum, vacuoles, peroxisome, and mitochondria (3-7). Some ABC proteins, however, function as ion channels or regulators of ion channels (2,8,9). Recently, mutations of ABC proteins have been shown to be responsible for various genetic diseases in man (10). Mitochondria provide cells with energy for many biological functions by oxidative phosphorylation. Reactive oxygen species are by-products of respiration. Their interaction with free iron in mitochondria through the Fenton reaction could lead to oxidative damage to lipids, proteins, and DNA in mitochondria (11,12), suggesting that iron homeostasis is crucial in the maintenance of mitochondrial function.Atm1p was the first member of the ABC protein family identified in mitochondria (7), and it plays an important role in normal cellular growth and iron homeostasis (11, 13). Further analysis of Atm1p has shown that it transports the precursor of the Fe/S cluster from mitochondria to the cytosol (14). Because mutation of ATM1 results in mitochondrial dysfunction (11), mutations of human mitochondrial ABC proteins could be associated with various diseases. Although the complete genomic sequences of Saccharomyces cerevisiae and Escherichia coli predict the existence of 29 and 79 members of the ABC protein family, respectively (15, 16), only a few mitochondrial ABC proteins have been identified to date.In the course of our search for human ABC p...
