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

Patrick J. Macdonald, Natalia Stepanyants, Niharika Mehrotra, Jason A. Mears, Xin Qi, Hiromi Sesaki, Rajesh Ramachandran

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)1905-1915
Number of pages11
JournalMolecular biology of the cell
Volume25
Issue number12
DOIs
StatePublished - Jun 15 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Macdonald, P. J., Stepanyants, N., Mehrotra, N., Mears, J. A., Qi, X., Sesaki, H., & Ramachandran, R. (2014). A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission. Molecular biology of the cell, 25(12), 1905-1915. https://doi.org/10.1091/mbc.E14-02-0728