Membrane fusion as a pathway to fission

Remodeling of biological membranes, such as fusion and fission, is involved in a variety of basic, cellular processes. This work investigates the mechanisms and pathways for the fission of phospholipid membranes, in particular double-membrane fission as it occurs in mitochondrial division. We employ self-consistent field theory and utilize the string method to find the Minimum Free Energy Path (MFEP) in order to determine the most likely pathway for the transition. The complex landscape of possible rearrangements gives rise to multiple possible mechanisms for double membrane fission. The simplest pathway involves the local constriction, hemifusion and fission of the inner membrane, without contact with the outer membrane. Intriguingly, we also uncover a new mechanism whereby local fusion contact between the inner and outer membrane can catalyze the fission of the inner membrane. Not only does the new mechanism have a lower total free energy barrier, but also an intermediate metastable state, allowing the system to ratchet its way up the rate-limiting step.