Inter-organellar communication with mitochondria regulates both the intrinsic and extrinsic pathways of apoptosis

One of our major research interests is to define BCL-2 family function in the cellular decision to induce mitochondrial outer membrane permeabilization and apoptosis. Curiosity in BCL-2 family - mitochondrial interactions led to the identification that the sphingolipid pathway plays a crucial role in BCL-2 family function. For approximately 20 years, sphingolipid biology and apoptotic mechanisms have criss-crossed, but remained distinct, as neither literature could explain the observable interplay between these pathways. We recently identified that two products within the sphingolipid pathway, sphingosine-1-PO4 and hexadecenal, directly regulate BAK and BAX activation, respectively. Furthermore, our work suggests that mitochondrial communication with heterotypic membrane and/or organelles may be an important regulatory mechanism for apoptotic sensitivity.