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Mitochondria maintain a biochemical environment that cooperates with BH3–only proteins (e.g., BIM) to potentiate BAX activation, the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate metabolite 2-trans-hexadecenal (2t–hexadecenal) is one such component described to support BAX activation, but molecular mechanisms remain largely unknown. Here, we utilize complementary biochemical and biophysical techniques to reveal that 2t-hexadecenal non-covalently interacts with BAX, and cooperates with BIM to stimulate early-activation steps of monomeric BAX. Integrated structural and computational approaches reveal 2t–hexadecenal binds an undefined region – a hydrophobic cavity formed by core-facing residues of α5, α6, and gated by α8 – we now term the “BAX actuating funnel” (BAF). We define alkenal length and α8 mobility as critical determinants for 2t–hexadecenal synergy with BIM and BAX, and demonstrate that proline 168 allosterically regulates BAF function. Collectively, this work imparts detailed molecular insights advancing our fundamental knowledge of BAX regulation and identifies a regulatory region with implications for biological and therapeutic opportunities. 

The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondria crosstalk with numerous regulated cell death (RCD) pathways to control the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD, that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery; as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die.