A Calcineurin Docking Motif (LXVP) in Dynamin-related Protein 1 Contributes to Mitochondrial Fragmentation and Ischemic Neuronal Injury

Slupe, Andrew M.; Merrill, Ronald A.; Flippo, Kyle H.; Lobas, Mark A.; Houtman, Jon C. D.; Strack, Stefan

doi:10.1074/jbc.m113.459677

Cited by 67 publications

(62 citation statements)

References 68 publications

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“…For example, phosphorylation of DRP1 at Ser637 by PKA inhibits its GTPase activity and thus inactivates fission 81,106 . By contrast, dephosphorylation of DRP1 at Ser637 by calcium and calmodulin-dependent serine/threonine protein phosphatase 2B catalytic subunit α isoform or calcineurin (CaN) activates DRP1 and promotes fission 107,108 . The balance between fission and fusion to maintain a functional population of mitochondria is an intricate process and is still under investigation.…”

Section: Maintaining Mitochondrial Homeostasismentioning

confidence: 99%

Mitochondrial energetics in the kidney

2017

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The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.

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Section: Maintaining Mitochondrial Homeostasismentioning

confidence: 99%

Mitochondrial energetics in the kidney

2017

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“…Calcineurin promotes fission by dephosphorylating Dynamin Related Protein 1 (DRP1), which contains an LxVP calcineurin-docking motif [193], thereby activating it to initiate fission at the OMM [194, 195]. PKA rephosphorylates DRP1, thus, promoting fusion.…”

Section: Calcineurin Substrates Relevant To Cardiovascular Healthmentioning

confidence: 99%

Calcineurin signaling in the heart: The importance of time and place

Parra

Rothermel

2017

Journal of Molecular and Cellular Cardiology

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The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure.

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“…Additionally, PKA at the OMM is known to phosohorylate Dynamin-1-like protein (Drp1), a large GTP-ase involved in regulating mitochondrial fission-fusion balance (figure 2). PKA-mediated phosphorylation of Drp1 at Ser637 blocks its ability to promote fission resulting in elongated mitochondria and enhanced cell survival in a neuronal cell model (Chang and Blackstone, 2007; Cribbs and Strack, 2007; Dagda et al, 2011; Merrill et al, 2011; Slupe et al, 2013; Merrill and Strack, 2014). The pro-survival actions of AKAP121-tethered PKA are also supported by its effects on ROS production.…”

Section: Cyclic Amp Microdomainsmentioning

confidence: 99%

cAMP signaling in subcellular compartments

Lefkimmiatis

Zaccolo

2014

Pharmacology & Therapeutics

170

149

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In the complex microcosm of a cell, information security and its faithful transmission are critical for maintaining internal stability. To achieve a coordinated response of all its parts to any stimulus the cell must protect the information received from potentially confounding signals. Physical segregation of the information transmission chain ensures that only the entities able to perform the encoded task have access to the relevant information. The cAMP intracellular signaling pathway is an important system for signal transmission responsible for the ancestral ‘flight or fight’ response and involved in the control of critical functions including frequency and strength of heart contraction, energy metabolism and gene transcription. It is becoming increasingly apparent that the cAMP signaling pathway uses compartmentalization as a strategy for coordinating the large number of key cellular functions under its control. Spatial confinement allows the formation of cAMP signaling “hot spots” at discrete subcellular domains in response to specific stimuli, bringing the information in proximity to the relevant effectors and their recipients, thus achieving specificity of action. In this report we discuss how the different constituents of the cAMP pathway are targeted and participate in the formation of cAMP compartmentalized signaling events. We illustrate a few examples of localized cAMP signaling, with a particular focus on the nucleus, the sarcoplasmic reticulum and the mitochondria. Finally, we discuss the therapeutic potential of interventions designed to perturb specific cAMP cascades locally.

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A Calcineurin Docking Motif (LXVP) in Dynamin-related Protein 1 Contributes to Mitochondrial Fragmentation and Ischemic Neuronal Injury

Cited by 67 publications

References 68 publications

Mitochondrial energetics in the kidney

Mitochondrial energetics in the kidney

Calcineurin signaling in the heart: The importance of time and place

cAMP signaling in subcellular compartments

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