TY - JOUR
T1 - A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission
AU - Macdonald, Patrick J.
AU - Stepanyants, Natalia
AU - Mehrotra, Niharika
AU - Mears, Jason A.
AU - Qi, Xin
AU - Sesaki, Hiromi
AU - Ramachandran, Rajesh
PY - 2014/6/15
Y1 - 2014/6/15
N2 - The GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial division, but the mechanisms remain poorly understood. Much of what is attributed to Drp1's mecha nism of action in mitochondrial membrane fission parallels that of prototypical dynamin in endocytic vesicle scission. Unlike the case for dynamin, however, no lipid target for Drp1 activation at the mitochondria has been identified. In addition, the oligomerization properties of Drp1 have not been well established. We show that the mitochondria-specific lipid cardiolipin is a potent stimulator of Drp1 GTPase activity, as well as of membrane tubulation. We establish further that under physiological conditions, Drp1 coexists as two morphologically distinct polymeric species, one nucleotide bound in solution and the other membrane associated, which equilibrate via a dimeric assembly intermediate. With two mutations, C300A and C505A, that shift Drp1 polymerization equilibria in opposite directions, we demonstrate that dimers, and not multimers, potentiate the reassembly and reorganization of Drp1 for mitochondrial membrane remodeling both in vitro and in vivo.
AB - The GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial division, but the mechanisms remain poorly understood. Much of what is attributed to Drp1's mecha nism of action in mitochondrial membrane fission parallels that of prototypical dynamin in endocytic vesicle scission. Unlike the case for dynamin, however, no lipid target for Drp1 activation at the mitochondria has been identified. In addition, the oligomerization properties of Drp1 have not been well established. We show that the mitochondria-specific lipid cardiolipin is a potent stimulator of Drp1 GTPase activity, as well as of membrane tubulation. We establish further that under physiological conditions, Drp1 coexists as two morphologically distinct polymeric species, one nucleotide bound in solution and the other membrane associated, which equilibrate via a dimeric assembly intermediate. With two mutations, C300A and C505A, that shift Drp1 polymerization equilibria in opposite directions, we demonstrate that dimers, and not multimers, potentiate the reassembly and reorganization of Drp1 for mitochondrial membrane remodeling both in vitro and in vivo.
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U2 - 10.1091/mbc.E14-02-0728
DO - 10.1091/mbc.E14-02-0728
M3 - Article
C2 - 24790094
AN - SCOPUS:84902682341
SN - 1059-1524
VL - 25
SP - 1905
EP - 1915
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 12
ER -