Journal article
A Calcineurin Docking Motif (LXVP) in Dynamin-related Protein 1 Contributes to Mitochondrial Fragmentation and Ischemic Neuronal Injury
The Journal of biological chemistry, Vol.288(17), pp.12353-12365
04/26/2013
DOI: 10.1074/jbc.M113.459677
PMCID: PMC3636919
PMID: 23486469
Abstract
Background:
The mitochondrial fission enzyme dynamin-related protein 1 (Drp1) is regulated via reversible phosphorylation of Ser-656.
Results:
The Drp1 L
X
VP motif mediates dephosphorylation and activation by calcineurin (CaN), which influences mitochondrial morphology and survival post-injury in neurons.
Conclusion:
The CaN-Drp1 signaling axis can be detrimental to injured neurons.
Significance:
The CaN-Drp1 complex may be a target for neuroprotective therapeutic intervention.
Fission and fusion events dynamically control the shape and function of mitochondria. The activity of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) is finely tuned by several post-translational modifications. Phosphorylation of Ser-656 by cAMP-dependent protein kinase (PKA) inhibits Drp1, whereas dephosphorylation by a mitochondrial protein phosphatase 2A isoform and the calcium-calmodulin-dependent phosphatase calcineurin (CaN) activates Drp1. Here, we identify a conserved CaN docking site on Drp1, an L
X
VP motif, which mediates the interaction between the phosphatase and mechanoenzyme. We mutated the L
X
VP motif in Drp1 to either increase or decrease similarity to the prototypical L
X
VP motif in the transcription factor NFAT, and assessed stability of the mutant Drp1-CaN complexes by affinity precipitation and isothermal titration calorimetry. Furthermore, we quantified effects of L
X
VP mutations on Drp1 dephosphorylation kinetics
in vitro
and in intact cells. With tools for bidirectional control of the CaN-Drp1 signaling axis in hand, we demonstrate that the Drp1 L
X
VP motif shapes mitochondria in neuronal and non-neuronal cells, and that CaN-mediated Drp1 dephosphorylation promotes neuronal death following oxygen-glucose deprivation. These results point to the CaN-Drp1 complex as a potential target for neuroprotective therapy of ischemic stroke.
Details
- Title: Subtitle
- A Calcineurin Docking Motif (LXVP) in Dynamin-related Protein 1 Contributes to Mitochondrial Fragmentation and Ischemic Neuronal Injury
- Creators
- Andrew M Slupe - From the Departments ofRonald A Merrill - From the Departments ofKyle H Flippo - From the Departments ofMark A Lobas - Biology, andJon C. D Houtman - Microbiology, University of Iowa, Iowa City, Iowa 52242Stefan Strack - From the Departments of
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.288(17), pp.12353-12365
- DOI
- 10.1074/jbc.M113.459677
- PMID
- 23486469
- PMCID
- PMC3636919
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- NS056244; NS057714; CA136729 / National Institutes of Health
- Alternative title
- Calcineurin-Drp1 Docking in Neuronal Injury
- Language
- English
- Date published
- 04/26/2013
- Academic Unit
- Microbiology and Immunology; Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040263702771
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