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Mol Biol Cell. 2014 Jun 15;25(12):1905-15. doi: 10.1091/mbc.E14-02-0728. Epub 2014 Apr 30.

A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission.

Author information

1
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
2
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
3
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106Center for Mitochondrial Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
4
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106 rxr275@case.edu.

Abstract

The GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial division, but the mechanisms remain poorly understood. Much of what is attributed to Drp1's mechanism 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.

PMID:
24790094
PMCID:
PMC4055269
DOI:
10.1091/mbc.E14-02-0728
[Indexed for MEDLINE]
Free PMC Article

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