Cardiolipin provides specificity for _targeting of tBid to mitochondria

Abstract

Recent evidence supports the theory that mitochondrial homeostasis is the key regulatory step in apoptosis through the actions of members of the Bcl-2 family^1,2,3. Pro-apoptotic members of the family, such as Bax, Bad and Bid, can induce the loss of outer-membrane integrity with subsequent redistribution of pro-apoptotic proteins such as cytochrome c that are normally located in the intermembrane spaces of mitochondria². The anti-apoptotic members of the family, such as Bcl-2 and Bcl-X_L, protect the integrity of the mitochondrion and prevent the release of death-inducing factors^1,2,3. Bid normally exists in an inactive state in the cytosol, but after cleavage by caspase 8, the carboxy-terminal portion (tBid) moves from cytosol to mitochondria, where it induces release of cytochrome c^4,5. Here we address the question of what mediates specific _targeting of tBid to the mitochondria. We provide evidence that cardiolipin, which is present in mitochondrial membranes, mediates the _targeting of tBid to mitochondria through a previously unkown three-helix domain in tBid. These findings implicate cardiolipin in the pathway for cytochrome c release.