The Drosophila Bcl-2 protein, Buffy, modulates metabolic stress possibly through calcium signaling

Bcl-2 proteins are classically known as apoptotic proteins that signal cell death for a variety of reasons, including cellular stress. It is known that mammalian Bcl-2 proteins perturb the mitochondrion when signaling apoptosis. However, apoptosis in Drosophila does not always incorporate the mitochondrion, relieving the Drosophila Bcl-2 protein, Buffy, from this apoptotic duty.;In this study, we generated a null mutant in the Drosophila Bcl-2 homolog buffy. We observed no defects in developmental apoptosis but did observe many unique phenotypes that coalesced into an underlying theme: a metabolic derailment due to stress. Stress can be defined as any environmental factor that reduces the fitness of an organism. A prime example of stress is nutrient deprivation. Larvae lacking the Drosophila Bcl-2 protein Buffy demonstrate an array of defective metabolic responses to nutrient deprivation. The buffy mutant is particularly defective in the autophagic response, lipid metabolism and ATP generation during periods of nutrient withdrawal. Thus, Bcl-2 proteins in the fly evolved to help the organism withstand periods of starvation by adjusting the animal's metabolic state. Additionally, mutant larvae demonstrated heightened cytosolic levels of Ca2+ which is indicative of ER leakage. Since it is known that calcium efflux from the ER can influence metabolic processes, we propose that in the starved mutant the metabolic derailment is due to a defect in levels of intracellular calcium.;Similar observations have been made in mammalian cells demonstrating an extra-apoptotic role for mammalian Bcl-2 proteins, however many of these reports are conflicting. It is therefore likely that we are studying the ancestral role of the Bcl-2 family, in the fly. Changing the perception of Bcl-2 proteins as "stress proteins" rather than "apoptotic proteins" may aid in a better interpretation of the data gathered regarding the basic function of Bcl-2 proteins in the cell. Thus, the fly model serves as an ideal system for studying the alternate faces of Bcl-2 function that are often shadowed by their major apoptotic role in mammals.