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

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...

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Autores principales: Macdonald, Patrick J., Stepanyants, Natalia, Mehrotra, Niharika, Mears, Jason A., Qi, Xin, Sesaki, Hiromi, Ramachandran, Rajesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055269/
https://www.ncbi.nlm.nih.gov/pubmed/24790094
http://dx.doi.org/10.1091/mbc.E14-02-0728
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author Macdonald, Patrick J.
Stepanyants, Natalia
Mehrotra, Niharika
Mears, Jason A.
Qi, Xin
Sesaki, Hiromi
Ramachandran, Rajesh
author_facet Macdonald, Patrick J.
Stepanyants, Natalia
Mehrotra, Niharika
Mears, Jason A.
Qi, Xin
Sesaki, Hiromi
Ramachandran, Rajesh
author_sort Macdonald, Patrick J.
collection PubMed
description 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.
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spelling pubmed-40552692014-08-30 A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission Macdonald, Patrick J. Stepanyants, Natalia Mehrotra, Niharika Mears, Jason A. Qi, Xin Sesaki, Hiromi Ramachandran, Rajesh Mol Biol Cell Articles 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. The American Society for Cell Biology 2014-06-15 /pmc/articles/PMC4055269/ /pubmed/24790094 http://dx.doi.org/10.1091/mbc.E14-02-0728 Text en © 2014 Macdonald, Stepanyants, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Macdonald, Patrick J.
Stepanyants, Natalia
Mehrotra, Niharika
Mears, Jason A.
Qi, Xin
Sesaki, Hiromi
Ramachandran, Rajesh
A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission
title A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission
title_full A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission
title_fullStr A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission
title_full_unstemmed A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission
title_short A dimeric equilibrium intermediate nucleates Drp1 reassembly on mitochondrial membranes for fission
title_sort dimeric equilibrium intermediate nucleates drp1 reassembly on mitochondrial membranes for fission
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055269/
https://www.ncbi.nlm.nih.gov/pubmed/24790094
http://dx.doi.org/10.1091/mbc.E14-02-0728
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