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

Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
EMBO Reports (Impact Factor: 9.06). 11/2007; 8(10):939-44. DOI: 10.1038/sj.embor.7401062
Source: PubMed

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.

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    • "If the lack of phosphorylation is determined by different topology or subcellular localization of Mfn2 is unknown, but worth testing, especially in the light of the functional difference between the two Mfns. While DRP1 post-translational modifications are well established players in apoptosis (Cribbs and Strack, 2007), necrosis (Wang et al., 2012), and autophagy (Gomes et al., 2011), our knowledge of how mitochondrial fusion is modulated during cell death is scarcer. Fusion inhibition is an established consequence of apoptosis induction, and it occurs around the time of BAX activation (Karbowski et al., 2004). "
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    ABSTRACT: Controlled changes in mitochondrial morphology participate in cellular signaling cascades. However, the molecular mechanisms modifying mitochondrial shape are largely unknown. Here we show that the mitogen-activated protein (MAP) kinase cascade member extracellular-signal-regulated kinase (ERK) phosphorylates the pro-fusion protein mitofusin (MFN) 1, modulating its participation in apoptosis and mitochondrial fusion. Phosphoproteomic and biochemical analyses revealed that MFN1 is phosphorylated at an atypical ERK site in its heptad repeat (HR) 1 domain. This site proved essential to mediate MFN1-dependent mitochondrial elongation and apoptosis regulation by the MEK/ERK cascade. A mutant mimicking constitutive MFN1 phosphorylation was less efficient in oligomerizing and mitochondria tethering but bound more avidly to the proapoptotic BCL-2 family member BAK, facilitating its activation and cell death. Moreover, neuronal apoptosis following oxygen glucose deprivation and MEK/ERK activation required an intact MFN1(T562). Our data identify MFN1 as an ERK target to modulate mitochondrial shape and apoptosis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Molecular cell 03/2015; 104(2). DOI:10.1016/j.molcel.2015.02.021 · 14.02 Impact Factor
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    • "Neuronal activity enhances mitochondrial Ca 2+ uptake , which stimulates ATP production and increases mitochondrial NAD ( P ) H levels ( Jonas , 2014 ) . Ca 2+ also influences mitochondrial function by promoting fragmentation of mitochondria triggered by calcineurin - mediated dephosphorylation of Drp1 ( Cribbs & Strack , 2007 ; Cereghetti et al . 2008 ; Wang et al . "
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    ABSTRACT: The classical view of mitochondria as housekeeping organelles acting in the background to simply maintain cellular energy demands has been shaken by mounting evidence of their direct and active participation in synaptic plasticity in neurons. Time-lapse imaging has revealed that mitochondria are motile in dendrites, with their localization and fusion and fission events regulated by synaptic activity. The positioning of mitochondria directly influences function of nearby synapses through multiple pathways including control over local concentrations of ATP, Ca+2, and reactive oxygen species. Recent studies have also shown that mitochondrial protein cascades classically associated with apoptosis are involved in neural plasticity in healthy cells. These findings link mitochondria to the plasticity- and metaplasticity-associated activity-dependent transcription factor MEF2 further repositioning mitochondria as potential command centers for regulation of synaptic plasticity. Intriguingly, MEF2 and mitochondrial functions appear to be intricately intertwined, as MEF2 is a target of mitochondrial apoptotic caspases and in turn, MEF2 regulates mitochondrial genome transcription essential for production of superoxidase and hydrogen peroxidase. Here, we review evidence supporting mitochondria as central organelles controlling the spatiotemporal expression of neuronal plasticity, and attempt to disentangle the MEF2-mitochondria relationship mediating these functions.This article is protected by copyright. All rights reserved
    The Journal of Physiology 12/2014; 593(16). DOI:10.1113/jphysiol.2014.282459 · 5.04 Impact Factor
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    • "At the onset of mitosis, Drp1 is phosphorylated by Cdk1/ Cyclin B at Ser585, which increases Drp1 GTPase activity [26]. In contrast, reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase (PKA) and its dephosphorylation by phosphatase calcineurin at Ser656 leads to elongated mitochondria [27]. In addition, the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5), dephosphorylates Drp1 at Ser637 and recruits Drp1 to mitochondria to induce mitochondrial fragmentation. "
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    ABSTRACT: Mitochondria are cellular energy powerhouses that play important roles in maintaining cell survival, cell death and cellular metabolic homeostasis. Timely removal of damaged mitochondria via autophagy (mitophagy) is thus critical for cellular homeostasis and function. Mitochondria are reticular organelles that have high plasticity for their dynamic structures and constantly undergo fission and fusion as well as movement through the cytoskeleton. In this review, we discuss the most recent progress on the molecular mechanisms and roles of mitochondrial fission/fusion and mitochondrial motility in mitophagy. We also discuss multiple pathways leading to the quality control of mitochondria in addition to the traditional mitophagy pathway under different conditions. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
    11/2014; 4C:6-13. DOI:10.1016/j.redox.2014.11.006
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