Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane

How cytochrome C is released from the mitochondria to the cytosol via Bax oligomeric pores, a process which is required for apoptosis, is still a mystery. Based on experimentally measured residue-residue distances, we recently solved the first atomic model for Bax oligomeric pores at the membranes using computational approaches. Here, we investigate the mechanism at the microsecond time- and nanometer space- scale using MD simulations. Our free energy landscape depicts a low barrier for the permeation of cytochrome C into the Bax C-terminal mouth, with the pathway proceeding to the inner cavity and exiting via the N-terminal mouth. Release is guided by organized charged/hydrophilic surfaces. The hydrophilicity and negative charge of the pore surface gradually increase along the release pathway from the pore entry to the exit opening. Rather than inert passing of the cytochrome C through a rigid pore, the flexible pore may selectively aid the cytochrome C passage. Once the Bax pore is formed in the membrane, with a low energy barrier, the release of cytochrome C may be readily achieved through energy fluctuations. Collectively, our work provides mechanistic insight in atomic detail into the release of cytochrome C through Bax oligomeric pores.