Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death

J Thomas Cribbs; Stefan Strack

doi:10.1038/sj.embor.7401062

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Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death

Journal article

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Peer reviewed

Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death

J Thomas Cribbs and Stefan Strack

EMBO reports, Vol.8(10), pp.939-944

10/2007

DOI: 10.1038/sj.embor.7401062

PMCID: PMC2002551

PMID: 17721437

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Abstract

Opposing mitochondrial fission and fusion reactions determine the shape and interconnectivity of mitochondria. Dynamin-related protein 1 (Drp1) is an ancient mechanoenzyme that uses GTP hydrolysis to power the constriction and division of mitochondria. Although Drp1-mediated mitochondrial fragmentation is recognized as an early event in the apoptotic programme, acute regulation of Drp1 activity is poorly understood. Here, we identify a crucial phosphorylation site that is conserved in all metazoan Drp1 orthologues. Ser 656 is phosphorylated by cyclic AMP-dependent protein kinase and dephosphorylated by calcineurin, and its phosphorylation state is controlled by sympathetic tone, calcium levels and cell viability. Pseudophosphorylation of Drp1 by mutation of Ser 656 to aspartic acid leads to the elongation of mitochondria and confers resistance to various pro-apoptotic insults. Conversely, the constitutively dephosphorylated Ser656Ala mutant Drp1 promotes mitochondrial fragmentation and increases cell vulnerability. Thus, Drp1 phosphorylation at Ser 656 provides a mechanism for the integration of cAMP and calcium signals in the control of mitochondrial shape, apoptosis and other aspects of mitochondrial function.

dynamin-related protein 1

apoptosis

cAMP-dependent protein kinase

calcineurin

mitochondria

Scientific Report

Details

Title: Subtitle: Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death
Creators: J Thomas Cribbs - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Stefan Strack - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Resource Type: Journal article
Publication Details: EMBO reports, Vol.8(10), pp.939-944
DOI: 10.1038/sj.embor.7401062
PMID: 17721437
PMCID: PMC2002551
NLM abbreviation: EMBO Rep
ISSN: 1469-221X
eISSN: 1469-3178
Publisher: Nature Publishing Group
Language: English
Date published: 10/2007
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Ophthalmology and Visual Sciences
Record Identifier: 9984040372302771

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