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Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules

Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously u...

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Detalles Bibliográficos
Autores principales: Strack, Stefan, Wilson, Theodore J., Cribbs, J. Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691453/
https://www.ncbi.nlm.nih.gov/pubmed/23798729
http://dx.doi.org/10.1083/jcb.201210045
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author Strack, Stefan
Wilson, Theodore J.
Cribbs, J. Thomas
author_facet Strack, Stefan
Wilson, Theodore J.
Cribbs, J. Thomas
author_sort Strack, Stefan
collection PubMed
description Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1-x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form–specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin-dependent kinase signaling.
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spelling pubmed-36914532013-12-24 Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules Strack, Stefan Wilson, Theodore J. Cribbs, J. Thomas J Cell Biol Research Articles Fission and fusion reactions determine mitochondrial morphology and function. Dynamin-related protein 1 (Drp1) is a guanosine triphosphate–hydrolyzing mechanoenzyme important for mitochondrial fission and programmed cell death. Drp1 is subject to alternative splicing of three exons with previously unknown functional significance. Here, we report that splice variants including the third but excluding the second alternative exon (x01) localized to and copurified with microtubule bundles as dynamic polymers that resemble fission complexes on mitochondria. A major isoform in immune cells, Drp1-x01 required oligomeric assembly and Arg residues in alternative exon 3 for microtubule targeting. Drp1-x01 stabilized and bundled microtubules and attenuated staurosporine-induced mitochondrial fragmentation and apoptosis. Phosphorylation of a conserved Ser residue adjacent to the microtubule-binding exon released Drp1-x01 from microtubules and promoted mitochondrial fragmentation in a splice form–specific manner. Phosphorylation by Cdk1 contributed to dissociation of Drp1-x01 from mitotic microtubules, whereas Cdk5-mediated phosphorylation modulated Drp1-x01 targeting to interphase microtubules. Thus, alternative splicing generates a latent, cytoskeletal pool of Drp1 that is selectively mobilized by cyclin-dependent kinase signaling. The Rockefeller University Press 2013-06-24 /pmc/articles/PMC3691453/ /pubmed/23798729 http://dx.doi.org/10.1083/jcb.201210045 Text en © 2013 Strack et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Strack, Stefan
Wilson, Theodore J.
Cribbs, J. Thomas
Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
title Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
title_full Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
title_fullStr Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
title_full_unstemmed Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
title_short Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
title_sort cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691453/
https://www.ncbi.nlm.nih.gov/pubmed/23798729
http://dx.doi.org/10.1083/jcb.201210045
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