Role of TOR Signaling in Mitochondrial Metabolism

University Of California-Davis, Davis CA

Investigators

Abstract

The primary objective of the proposed research is to further our understanding of the mechanisms by which the highly conserved TOR (Target Of Rapamycin) signaling pathway regulates cell growth in eukaryotic organisms. This pathway was discovered by the action of the antibiotic rapamycin, a potent immune suppressor, which targets the large, evolutionarily conserved TOR kinase. Insight into the function of this pathway has come from recent studies of the simple eukaryote, S. cerevisiae, where it has been shown that TOR controls the expression of genes involved in several essential nutrient-responsive biosynthetic pathways. In particular, TOR regulates the expression of a concise cluster of genes (termed RTG-target genes) that encode mitochondrial and peroxisomal enzymes whose activities are required for the de novo biosynthesis of glutamate and glutamine. The RTG-target genes are also regulated by a mitochondria-to-nucleus signaling pathway, termed the retrograde response pathway, that is induced when mitochondrial respiratory function is impaired. The aims of this project are three-fold. First, the pathway by which TOR regulates RTG target gene expression will be elucidated. Research underlying this project has determined that TOR acts in part by regulating the nucleocytoplasmic localization of a transcription factor complex, composed of the Rtg1 and Rtg3 proteins. Thus, the research will examine a number of proteins that may provide a link between TOR and this important regulatory step. Second, functional genomic approaches will be used to determine the extent of cross talk and/or overlap between TOR and retrograde signaling. Third, novel regulators of RTG target gene expression will be identified and partitioned into the TOR and/or retrograde branches of this signaling pathway. Together, these studies will help elucidate the molecular mechanisms by which TOR regulates the activity of an essential metabolic pathway. Moreover, we will learn how TOR collaborates with another important intracellular signaling mechanism to maintain the normal metabolic behavior of cells.