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

Cribbs, J. Thomas; Strack, Stefan

doi:10.1038/sj.embor.7401062

Cited by 908 publications

(969 citation statements)

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“…In healthy mammalian cells, endogenous Drp1 is predominantly localized in the cytosol and can be translocated into mitochondria during apoptosis. Overexpression of dominant negative Drp1 protein results in dramatic increase of mitochondrial connectivity (Smirnova et al, 2001), while overexpression of Drp1 promotes mitochondrial fission and increases cell vulnerability (Cribbs and Strack, 2007). In contrast to Drp1, Fis1 is exclusively localized to mitochondria and overexpression of Fis1 in HeLa cells can promote extensive mitochondrial fragmentation (Jofuku et al, 2005).…”

Section: Mitochondria Fission and Fusionmentioning

confidence: 99%

Mitochondrial network in the heart

Zhou

Gao

et al. 2012

Protein Cell

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Mitochondria are subcellular organelles that provide energy for the cell. They form a dynamic tubular network and play an important role in maintaining the cell function and integrity. Heart is a powerful organ that supplies the motivation for circulation, thereby requiring large amounts of energy. Thus, the healthiness of cardiomyocytes and mitochondria is necessary for the normal cardiac function. Mitochondria not only lie in the center of the cell apoptotic pathway, but also are the major source of reactive oxygen species (ROS) generation. Mitochondrial morphological change includes fission and fusion that are regulated by a large number of proteins. In this review we discuss the regulators of mitochondrial fission/fusion and their association with cell apoptosis, autophagy and ROS production in the heart.

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Section: Mitochondria Fission and Fusionmentioning

confidence: 99%

Mitochondrial network in the heart

Zhou

Gao

et al. 2012

Protein Cell

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“…Cellular stress increases Drp1 shuttling, which leads to fragmented mitochondrial networks, whereas prolonged or severe insult promotes stabilization of Drp1 to the mitochondria, which increases the likelihood of progression to apoptotic cell death (7,8,(11)(12)(13). Phosphorylation of Drp1-S637 prevents translocation to mitochondria, whereas overexpression of Drp1 K38A (a dominant-negative mutation lacking GTPase activity) prevents Drp1 translocation, attenuates a fragmented mitochondrial phenotype, and decreases cell death (4,14). Collectively, these observations suggest that Drp1 phosphorylation increases cell viability via inhibition of mitochondrial fission.…”

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confidence: 99%

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Din

Mason

Völkers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

121

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Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-S637 , and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pimdominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis-dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.

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“…During mitosis, Drp1 is activated by CDK1/cyclinB phosphorylation of Ser618 (human Drp1; 585 in rat Drp1), resulting in mitochondrial fragmentation (Taguchi et al 2007). Conversely, Drp1 GTPase activity is inactivated by phosphorylation at Ser637 (human Drp1; Ser656 in rat Drp1) within the GTPase effector domain (GED) mediated by cAMP-dependent protein kinase A (PKA), resulting in mitochondrial fusion (Chang and Blackstone 2007;Cribbs and Strack 2007). Thus, Drp1 activity can be positively and negatively regulated by kinases.…”

Section: Post-translational Modification Of Drp1 and Mfn2mentioning

confidence: 99%

“…Expression of a phosphomimetic mutant Drp1 S656D in cells leads to mitochondrial elongation and increased resistance to staurosporine-and etoposide-mediated apoptosis (Cribbs and Strack 2007). On the other hand, elimination of the conserved PKA phosphorylation site with an S656A mutation in Drp1 results in increased mitochondrial fragmentation and a higher sensitivity to apoptotic stimuli (Cribbs and Strack 2007).…”

Section: Post-translational Modification Of Drp1 Regulates Its Role Imentioning

confidence: 99%

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Mitochondrial Dynamics and Apoptosis

Cleland

Youle

2011

Mitochondrial Dynamics and Neurodegeneration

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In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.Apoptosis mediates the catabolism of eukaryotic cells that is crucial for metazoan development, adult tissue turnover, host defense pathways, and protection from cancer. All pathways of apoptosis converge upon the activation of caspases, proteases that orchestrate the efficient and noninflammatory demolition of cells. Two main pathways leading to caspase activation have been well characterized: the extrinsic route initiated by cell surface receptors leading directly to caspase 8 activation, and the intrinsic path that is regulated by mitochondria. The mitochondrial stage of apoptosis control is upstream of caspase activation and is mediated by the Bcl-2 family of proteins. One well understood role of mitochondria in caspase activation is to regulate the release of proteins from the space between the inner and outer mitochondrial membranes to the cytosol. When cytochrome c is released from mitochondria, it binds to APAF1 in the cytosol, activating the assembly of the apoptosome that activates caspase 9 (Bao and Shi 2007). Other proteins released from mitochondria, such as SMAC/Diablo, have less crucial accessory roles in caspase activation, perhaps most important in long-lived cells (Potts et al. 2005).Bcl-2 family proteins regulate the release of cytochrome c and other proteins through the outer mitochondrial membrane (OMM) (Adams and Cory 2007;Chipuk and Green 2008). Some members of the Bcl-2 family inhibit apoptosis, such as Bcl-2, Bcl-xL, and Mcl-1, whereas others, such as Bax and Bak, activate apoptosis. Bax and Bak actively induce cytochrome c release from mitochondria within cells and in cell-free systems, both of which are inhibited by anti-apoptotic Bcl-2 family members. As the anti-apoptotic Bcl-2 family members closely resemble the proapoptotic members in structure, they may function as dominant negative inhibitors by binding and inhibiting Bax and Bak. Another class of disparate proteins including Puma and Bim, called BH3-only proteins, shares a short motif with Bcl-2 family proteins and regulates their activity. One model posits that upon apoptosis initiation, BH3-only proteins are induced and then bind and inhibit anti-apoptotic Bcl-2 family proteins, allowing pro-apoptotic Bax and Bak to permeabilize the mitochondrial outer membrane releasing cytochrome c and other proteins to activa...

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

Cited by 908 publications

References 26 publications

Mitochondrial network in the heart

Mitochondrial network in the heart

Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation

Mitochondrial Dynamics and Apoptosis

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