Mitochondrial Targeting of Farnesyl Diphosphate Synthase is a Widespread Phenomenon in Eukaryotes

The isoprenoid pathway is responsible for the generation of a wide range of products that are crucial for cellular processes; namely, cholesterol synthesis, protein glycosylation, growth control and synthesis of several hormones. Farnesyl diphosphate synthase (FPS), a key enzyme in this pathway, is usually considered to be cytosolic/peroxisomal. However, significant enzymatic activity has also been detected in rat liver mitochondria, although none of the mammalian FPS genes characterized to date contain sequences coding for mitochondrial transit peptides. Here, we describe the genomic organization of the human FPS gene and demonstrate that one of the two mRNAs expressed from this gene encodes an isoform with a 66 amino acid N-terminal extension containing a peptide that targets it to mitochondria. Previous studies suggested that the N-terminal extension of FPS in the plant Arabidopsis thaliana contains a mitochondrial targeting sequence. In this study, database analysis reveals that this is also the case in a number of mammals and insects. Finally, we provide functional proofs that the N-terminal sequence of Drosophila melanogaster FPS targets the protein to mitochondria. Taken together, these data suggest that mitochondrial targeting of FPS may be widespread among eukaryotes.