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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: 7.86). 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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    • "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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    The Journal of Physiology 12/2014; 593. DOI:10.1113/jphysiol.2014.282459 · 4.54 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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    • "Treatment of the cells with PKCd siRNA, roscovitine or both attenuated A/R-induced increases of mitochondria fission and increased aspect ratio and form factor values compared to A/R alone group ( ⁄ P < 0.05 vs. Ctrl, # P < 0.05 vs. A/R, n = 3). (G) PKCd siRNA or Cdk1 inhibitor roscovitine significantly attenuated LDH release in cardiomyocytes during A/R ( ⁄ P < 0.001 vs. Ctrl, # P < 0.05 vs. A/R, n = 3). of mitochondrial fission through changes in phosphorylation status of Drp1 in adult murine heart [7]. In the present study, we had similar observation showing that the A/R-induced cardiomyocyte was accompanied with the increased mitochondrial fission (Fig. 1). "
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