Molecular mechanisms of crosstalk between apoptotic and metabolic regulation

Apoptosis is a genetically encoded pathway allowing cells to undergo a highly regulated form of cell death in response to pro-apoptotic stimuli. Apoptosis requires integrated signaling from a number of cellular regulator circuits which controls a core set of genes dedicated to cell death execution. Here we describe two independent strategies designed to better understand how apoptotic regulation is linked with other cellular signaling pathways.;In order to identify novel regulatory mechanisms for apoptotic activation, we performed a high-throughput RNAi screen in Drosophila melanogaster KC cells for genes required for DNA damage-induced cell death. We were able to identify 10 genes that appear to function as general regulators of apoptotic cell death. Remarkably, half of these genes are known to be required for cellular metabolism, demonstrating that the threshold for caspase activation is in part determined by the metabolic state of the cell. Our discovery that BNIP3 regulates mitochondrial metabolism together with our identification of metabolic genes required for caspase activation provides clear evidence that crosstalk between apoptotic and metabolic regulatory pathways underlies life and death decisions in the cell.;We demonstrate that BNIP3, a protein first characterized as a pro-apoptotic BH3-only family member, is required for starvation-induced autophagy in pancreatic beta cells. Autophagy is a cellular pathway of self-digestion induced to provide energy during stress. The involvement of BNIP3 in autophagic induction suggests that it may in fact be acting as a pro-survival molecule in this context. We also provide evidence that BNIP3 induces autophagy through the regulation of mitochondrial respiration, demonstrating a mechanism of direct crosstalk between the apoptotic machinery and metabolic regulation. Finally, we identify GSK33 as an activator of BNIP3, tying BNIP3 to a kinase known to regulate metabolic signaling.