Cardiolipin Reorganization and Phase Transition Induced by Dynamin-Related Protein 1 Facilitates Mitochondrial Membrane Fission

Abstract

Cardiolipin (CL) is a unique, dimeric phospholipid essential for mitochondrial dynamics in eukaryotic cells. Dynamin-related protein 1 (Drp1), a member of the dynamin superfamily of large GTPases, maintains the balance of mitochondrial division and fusion by rapidly catalyzing mitochondrial fission. Although recent studies have indicated a role for CL in stimulating Drp1 self-assembly as well as GTPase activity on the mitochondrial surface, the exact mechanism by which CL functions in membrane fission remains unclear. Here we use a variety of fluorescence spectroscopic and imaging approaches, together with model membranes, to demonstrate that Drp1 and CL function cooperatively in effecting membrane fission in three distinct steps: (i) Drp1's preferential association with unconstrained, fluid-phase CL molecules located at a high spatial density in the membrane bilayer, (ii) CL's reorganization in concert with Drp1 self-assembly, and (iii) CL's rapid phase transition from a lamellar, bilayer structure to an inverted hexagonal, non-bilayer configuration in the presence of Drp1 and GTP, resulting in the creation of localized membrane constrictions that are primed for fission. We propose that Drp1 thus catalyzes mitochondrial division.