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
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.