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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of cell biology 2013-06, Vol.201 (7), p.1037-1051
Main Authors: Strack, Stefan, Wilson, Theodore J, Cribbs, J Thomas
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Apoptosis
Cell Cycle - physiology
Cells
Cyclin-Dependent Kinases
GTP Phosphohydrolases - metabolism
HeLa Cells
Humans
Mice
Microtubule-Associated Proteins - metabolism
Microtubules - metabolism
Mitochondria
Mitochondria - metabolism
Mitochondria - ultrastructure
Mitochondrial Proteins - metabolism
Phosphorylation
Protein Transport - physiology
Proteins
Rats
Signal Transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Request full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201210045