Apoptosis has a central role during development and tissue homeostasis, and stress-induced apoptosis functions through mitochondria. Besides the involvement of the key regulatory B-cell lymphoma 2 (Bcl-2) protein family, a role for lipids in the regulation of cell death has also been described. In particular, ceramides, which are synthesised in the endoplasmic reticulum (ER), are implicated in mitochondrial apoptosis, but their actual contribution to the apoptotic response in living cells is unclear. Now (p. 360), Joost Holthuis and colleagues investigate the consequence of targeting newly synthesised ceramides to mitochondria, and, to that end, localise the ceramide transfer protein (CERT) to the outer mitochondrial membrane (OMM). The resulting mitoCERT protein is still capable of interacting with ER-resident VAMP-associated proteins (VAPs) and acts as an ER–mitochondria tether. The authors show that mitoCERT-expression activates mitochondrial apoptosis, as indicated by caspase 9 activation and cytochrome c translocation into the cytoplasm. Furthermore, mitoCERT-induced apoptosis is dependent on the Bcl-2 protein Bax, requires ongoing ceramide biosynthesis and can be abolished by removing the ceramide transfer domain of mitoCERT or impairing its interaction with VAPs in the ER. Together, these data provide direct evidence that ER ceramides are authentic transducers of apoptosis signalling and that their arrival in mitochondria is a critical step in committing cells to death.
