Cardiolipin's propensity for phase transition and its reorganization by dynamin-related protein 1 form a basis for mitochondrial membrane fission

被引:124
作者
Stepanyants, Natalia [1 ]
Macdonald, Patrick J. [1 ]
Francy, Christopher A. [2 ,3 ,4 ]
Mears, Jason A. [2 ,3 ,4 ]
Qi, Xin [1 ,2 ]
Ramachandran, Rajesh [1 ,4 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Ctr Mitochondrial Dis, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA
[4] Case Western Reserve Univ, Sch Med, Cleveland Ctr Membrane & Struct Biol, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
CONFORMATIONAL-CHANGES; GTPASE ACTIVITY; BARTH-SYNDROME; DOMAIN; LIPIDS; DIVISION; FUSION; MICRODOMAINS; LAMELLAR; OLIGOMERIZATION;
D O I
10.1091/mbc.E15-06-0330
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:3104 / 3116
页数:13
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