title: Cardiolipin's propensity for phase transition and its reorganization by dynamin-related protein 1 form a basis for mitochondrial membrane fission.
abstract: Cardiolipin (CL) is an atypical, dimeric phospholipid essential for mitochondrial dynamics in eukaryotic cells. Dynamin-related protein 1 (Drp1), a cytosolic member of the dynamin superfamily of large GTPases, interacts with CL and functions to sustain the balance of mitochondrial division and fusion by catalyzing mitochondrial fission. Although recent studies have indicated a role for CL in stimulating Drp1 self-assembly and GTPase activity at the membrane surface, the mechanism by which CL functions in membrane fission, if at all, remains unclear. Here, using a variety of fluorescence spectroscopic and imaging approaches together with model membranes, we demonstrate that Drp1 and CL function cooperatively in effecting membrane constriction toward fission in three distinct steps. These involve 1) the preferential association of Drp1 with CL localized at a high spatial density in the membrane bilayer, 2) the reorganization of unconstrained, fluid-phase CL molecules in concert with Drp1 self-assembly, and 3) the increased propensity of CL to transition from a lamellar, bilayer arrangement to an inverted hexagonal, nonbilayer configuration in the presence of Drp1 and GTP, resulting in the creation of localized membrane constrictions that are primed for fission. Thus we propose that Drp1 and CL function in concert to catalyze mitochondrial division.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Natalia
authors.initials: N
authors.lastname: Stepanyants
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Macdonald
authors.affiliation: Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Cleveland Center for Membrane and Structural Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Francy
authors.affiliation: Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Cleveland Center for Membrane and Structural Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Mears
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106 Cleveland Center for Membrane and Structural Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 rxr275@case.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramachandran
mesh_terms: D002308:Cardiolipins / Q000378:metabolism*; D048749:Cytokinesis; D003600:Cytosol / Q000378:metabolism; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D044367:Phase Transition; D017434:Protein Structure, Tertiary
chemical_list: D002308:Cardiolipins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins