LOCKING THE FLY MITOCHONDRIA: CONTROL OF BODY SIZE THROUGH THE MODULATION OF THE 2-OXOGLUTARATE TRANSPORTER PAMPERO

SERGIO H. SIMONETTA; NURIA M. ROMERO; PABLO WAPPNER

Buenos Aires

Congreso; Latinoamerican Society of Developmental Biology; 2008

LOCKING THE FLY MITOCHONDRIA: CONTROL OF BODY SIZE THROUGH THE MODULATION OF THE 2-OXOGLUTARATE TRANSPORTER PAMPERO.     Simonetta SH, Romero NM, Wappner P Fundación Instituto Leloir. Buenos Aires. Argentina ssimonetta@leloir.org.ar In Drosophila, nutrient availability and oxygen levels modulate growth and developmental timing through Insulin and TOR pathways. However, it is still unclear which molecules are actually sensed by the cells that report the nutritional status of the organism, to convey a signal that results in growth regulation. In this regard, the tricarboxylic acid intermediate 2-oxoglutarate is a good candidate molecule. 2-oxoglutarate is a substrate of the HIF-prolyl-4-hydroxylases that operate as oxygen sensors (PHDs), which have been recently involved in growth control. It is a precursor for amino acid synthesis, and its cytoplasmic levels are known to correlate with the nutritional state of the cell. This mitochondrial keto acid is exported to the cytoplasm by specific mitochondrial inner membrane transporters, some of which have been identified in the fly genome. In this work, we have experimentally decreased cytosolic 2-oxoglutarate levels through RNAi mediated silencing of one of such transporters, which we have named Pampero (Pmp). Ubiquitous RNAi-mediated silencing of pmp expression led to consistent reduction of body size, correlating with delayed pupariation.  The Drosophila HIF-prolyl-4-hydroxylase Fatiga (Fga) utilizes 2-oxoglutarate as a co-substrate for catalysis and therefore, it is possible that Fga mediates the effect of 2-oxoglutarate on growth regulation. Consistent with this possibility, fga loss of function mutants are smaller than their wild type siblings and pupariation is delayed. We are currently performing genetic interaction experiments in order to assess the pathways involved in 2-oxoglutarate-dependent growth regulation. Our results suggest that 2-oxoglutarate might play a role in the mechanism of nutrient sensing involved in regulation of animal growth.