Ricerc@Sapienza

Metabolites, cofactors and nucleotides cross the compartmentalized mitochondria organelle by specific transporters located in the highly impermeable mitochondrial inner membrane. The flux of those molecules is catalyzed mainly by a superfamily of nuclear-coded proteins known as Mitochondrial Carrier Family [MCF](1). Mitochondrial carriers [MCs] are highly conserved and widely distributed in all eukaryotes. MCs share a common structure consisting of three tandemly related sequences of about 100 amino acids, each containing two hydrophobic motifs and two membrane spanning domains. Alterations of MCs cause metabolic diseases which are directly related to oxidative phosphorylation defects or due to alterations in functions other than oxidative phosphorylation and, in particular, in intermediary metabolism.
Drosophila genome harbors 46 MCs, which share high identity (25%-86%) with their human counterparts. We have previously found that the function of one of these, Scheggia (Sea), the SLC25A1 citrate carrier ortholog, is also required for global histone acetylation and chromosome integrity thus providing compelling evidence of an unanticipated link between metabolite transport and epigenetic control of genome maintenance (10). We plan to use Drosophila melanogaster as model to analyze the role of DmPiC, the Drosophila ortholog of the human phosphate mitochondrial carrier SLC25A3/PiC, which is involved in the mitochondrial phosphate-carrier deficiency disorder. Our preliminary data indicate that DmPiC regulates ATP synthesis and cell proliferation during Drosophila development.
In this proposal I will exploit the power of Drosophila genetics to functionally characterize DmPiC by examining: (1) its function in intracellular metabolism and cell cycle progression (2) its role in mitochondria homeostasis (3) its interaction with Nbs1 which highlights an unanticipated role of Nbs1 in the regulation of mitochondria.
References are in the last section.