Conformational change-dependent formation of active BAX complexes in mammalian cells

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The pro-apoptotic BCL-2 protein BAX permeabilizes the outer mitochondrial membrane (OMM) and initiates the caspase cascade after surpassing the cellular threshold of apoptotic stress. Active BAX forms multi-MDa complexes with large cytosolic fractions that are difficult to reconcile with a function in membrane permeabilization. Our recent results show that active BAX accumulates either in discrete membrane-integral complexes or in large membrane-associated structures. This duality of BAX complexes corresponds to two independent pro-apoptotic functions: (I) membrane-associated BAX complexes directly bind and activate caspase-9, (II) whereas smaller, discrete BAX complexes release cytochrome c from mitochondria, initiating activation of caspases by the apoptosome. Our results show that membrane permeabilization in cells lacking large BAX complexes results in significantly lower caspase activity despite cytochrome c release, whereas large BAX complexes alone induce caspase activity with reduced membrane permeabilization. BAX complexes and apoptosomes together ensure complete caspase activation and therefore prevent genomic instability resulting from partial caspase activation. This project will clarify the extent to which the formation of the two active BAX complex species is conserved in mammalian cells. Furthermore, we will investigate whether differences exist in the formation of both complexes in different mammalian cells. We will analyze the common principle of conformational change-induced selective formation of functionally different complexes and the effect of different complex formation on the cell stress response. Differential apoptosis regulation in different mammals could underlie the significant differences in tumor formation and stress resistance in different mammalian species. This project will clarify the extent to which BAX regulation is conserved in mammals and the processes that enable differential apoptosis regulation.