The yeast mitochondrial carrier Leu5p and its human homologue Graves' disease protein are required for accumulation of coenzyme A in the matrix

Citation
C. Prohl et al., The yeast mitochondrial carrier Leu5p and its human homologue Graves' disease protein are required for accumulation of coenzyme A in the matrix, MOL CELL B, 21(4), 2001, pp. 1089-1097
Citations number
69
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MOLECULAR AND CELLULAR BIOLOGY
ISSN journal
02707306 → ACNP
Volume
21
Issue
4
Year of publication
2001
Pages
1089 - 1097
Database
ISI
SICI code
0270-7306(200102)21:4<1089:TYMCLA>2.0.ZU;2-0
Abstract
The transport of metabolites, coenzymes, and ions across the mitochondrial inner membrane is still poorly understood. In most cases, membrane transpor t is facilitated by the so-called mitochondrial carrier proteins. The yeast Saccharomyces cerevisiae contains 35 members of the carrier family, but a function has been identified for only 13 proteins. Here, we investigated th e yeast carrier Leu5p (encoded by the gene YHR002w) and its close human hom ologue Graves' disease protein. Leu5p is inserted into the mitochondrial in ner membrane along the specialized import pathway used by carrier proteins. Deletion of LEU5 (strain Delta leu5) was accompanied by a 15-fold reductio n of mitochondrial coenzyme A (CoA) levels but did not affect the cytosolic CoA content. As a consequence, the activities of several mitochondrial CoA -dependent enzymes were strongly decreased in Delta leu5 cells. Our in vitr o and in vivo analyses assign a function to Leu5p in the accumulation of Co A in mitochondria, presumably by serving as a transporter of CoA or a precu rsor thereof. Expression of the Graves' disease protein in Delta leu5 cells can replace the function of Leu5p, demonstrating that the human protein re presents the orthologue of yeast Leu5p. The function of the human protein m ight not be directly linked to the disease, as antisera derived from patien ts with active Graves' disease do not recognize the protein after expressio n in yeast, suggesting that it does not represent a major autoantigen. The two carrier proteins characterized herein are the first components for whic h a role in the subcellular distribution of CoA has been identified.