Uncoupling proteins and aging in Drosophila

Dietary caloric restriction (CR) has long been known to reduce metabolism and extend lifespan. Furthermore, single gene mutations that extend lifespan, by and large, are involved in metabolic pathways. A reduction in the generation of reactive oxygen species (ROS) is widely assumed to be the root cause of lifespan extension. Despite metabolism being a major focus in aging research, little is known about the role of mitochondrial uncoupling proteins (UCPs) in the process of aging. UCPs are hypothesized to reduce the production of ROS generated during aerobic metabolism by allowing the free flow of protons into the mitochondrial matrix and reducing mitochondrial membrane potential. The present work studies the role of UCPs in fly survival by initially identifying and characterizing all previously unstudied UCP family members in Drosophila melanogaster. Of the novel homologous UCP genes identified in Drosophila, only CG6492 was found to have definitive uncoupling activity. Expression of the gene CG6492, i.e. DmUCP4A, decreases mitochondrial membrane potential while increasing cellular and mitochondrial oxygen consumption in a GDP-regulated manner. Furthermore, heterologous expression of DmUCP4A in yeast culture limits yeast growth rates and reduces cellular ATP without decreasing cell viability. ^ Transgenic flies made by P-element insertion of a DmUCP4A transgene were used to study the effects of uncoupling protein expression on fly survival. Expression of DmUCP4A in the nervous system of transgenic flies increases survival under conditions known to accelerate mortality: starvation, paraquat stress, and a high calorie diet. Analysis for enhanced survival under these conditions shows a reduced mortality rate. There were no compensatory changes found in body mass or spontaneous locomotor activity. We conclude that CG6492 is a bona fide uncoupling protein and that expression of this gene results in increased survival and stress resistance in the fly.