Discovery of bioactive lipids and lipid pathways in cell death and disease

Abstract

Apoptosis is an intricately regulated cellular process required for the health and homeostasis of living systems. The mitochondrial apoptotic pathway depends on the BCL-2 family of pro- and anti-apoptotic members whose interactions regulate cell fate. BAX and BAK are key pro-apoptotic proteins required for mitochondrial permeabilization during apoptosis. While the mitochondrial death program relies heavily on its protein components, evidences support equally crucial roles for lipids and lipid metabolism in promoting or hindering apoptosis at the mitochondria. To gain insight into the interplay between lipids and BCL-2 proteins we used a liquid chromatography (LC)-mass spectrometry (MS)-based comparative lipidomics approach to uncover lipid changes in the absence of BAX and/or BAK. Our analysis revealed novel functions for BAX and BAK in inflammation and ceramide metabolism. A targeted LC-MS workflow was also developed for characterization of a novel lipid class involved in type 2 diabetes. Targeted LC-MS revealed altered oxysterol metabolism following perturbation of the Sonic hedgehog pathway. Taken together, our findings demonstrate interesting connections among lipids, cell death and disease.