Dynamin-related protein 1-mediated mitochondrial fission and cerebral ischemia
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Abstract:
Dynamin-related protein 1 (Drp1) is a major protein for regulating mitochondrial fission. Its activity is associated with the post-translational modification, mainly including phosphorylation, ubiquitination, sumoylation, and S-nitrosylation. During the cerebral ischemia, Drp1 is activated and translocates from the cytoplasm to the mitochondrial outer membrane, mediates mitochondrial fission and eliminates damaged mitochondria. Drp1 plays the important roles in the pathological processes of ischemic neuronal apoptosis, necrotic apoptosis, and mitophagy. Excessive mitochondria fission or accumulation of damaged mitochondria will aggravate neuronal injury.
Key words:
Dynamins; Mitochondria; Reactive Oxygen Species; Brain IschemiaKeywords:
DNM1L
Mitochondrial apoptosis-induced channel
The constant physiological flux of mitochondrial fission and fusion is inextricably tied to the maintenance of cellular bioenergetics and the fluidity of mitochondrial networks. Yet, the intricacies of this dynamic duo remain unclear in diseases that encompass mitochondrial dysregulation. Particularly, the role of the GTPase fission protein dynamin-related protein 1 (Drp1) is of profound interest. Studies have identified that Drp1 participates in complex signaling pathways, suggesting that the function of mitochondria in pathophysiology may extend far beyond energetics alone. Research indicates that, in stressed conditions, Drp1 translocation to the mitochondria leads to elevated fragmentation and mitophagy; however, despite this, there is limited knowledge about the mechanistic regulation of Drp1 in disease conditions. This review highlights literature about fission, fusion, and, more importantly, discusses Drp1 in cardiac, neural, carcinogenic, renal, and pulmonary diseases. The therapeutic desirability for further research into its contribution to diseases that involve mitochondrial dysregulation is also discussed.
DNM1L
Bioenergetics
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Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.
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Mitochondrial apoptosis-induced channel
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Phosphorylation of dynamin-related protein 1 (Drp1) represents an important regulatory mechanism for mitochondrial fission. Here, we established the role of Drp1 serine 600 (Drp1S600) phosphorylation in mitochondrial fission in vivo and assessed the functional consequences of targeted elimination of the Drp1S600 phosphorylation site in the progression of diabetic nephropathy (DN). We generated a knockin mouse in which S600 was mutated to alanine (Drp1S600A). We found that diabetic Drp1S600A mice exhibited improved biochemical and histological features of DN along with reduced mitochondrial fission and diminished mitochondrial ROS in vivo. Importantly, we observed that the effect of Drp1S600 phosphorylation on mitochondrial fission in the diabetic milieu was stimulus dependent but not cell type dependent. Mechanistically, we show that mitochondrial fission in high-glucose conditions occurs through concomitant binding of phosphorylated Drp1S600 with mitochondrial fission factor (MFF) and actin-related protein 3 (Arp3), ultimately leading to accumulation of F-actin and Drp1 on the mitochondria. Taken together, these findings establish the idea that a single phosphorylation site in Drp1 can regulate mitochondrial fission and progression of DN in vivo and highlight the stimulus-specific consequences of Drp1S600 phosphorylation in mitochondrial dynamics.
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Current research has demonstrated that mitochondrial morphology, distribution, and function are maintained by the balanced regulation of mitochondrial fission and fusion, and perturbation of the homeostasis between these processes has been related to cell or organ dysfunction and abnormal mitochondrial redistribution. Abnormal mitochondrial fusion induces the fragmentation of mitochondria from a tubular morphology into pieces; in contrast, perturbed mitochondrial fission results in the fusion of adjacent mitochondria. A member of the dynamin family of large GTPases, dynamin-related protein 1 (Drp1), effectively influences cell survival and apoptosis by mediating the mitochondrial fission process in mammals. Drp1-dependent mitochondrial fission is an intricate process regulating both cellular and organ dynamics, including development, apoptosis, acute organ injury, and various diseases. Only after clarification of the regulative mechanisms of this critical protein in vivo and in vitro will it set a milestone for preventing mitochondrial fission related pathological processes and refractory diseases.
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Excessive mitochondrial fission is associated with the pathology of a number of neurodegenerative diseases. Therefore, inhibitors of aberrant mitochondrial fission could provide important research tools as well as potential leads for drug development. Using a rational approach, we designed a novel and selective peptide inhibitor, P110, of excessive mitochondrial fission. P110 inhibits Drp1 enzyme activity and blocks Drp1/Fis1 interaction in vitro and in cultured neurons whereas it has no effect on the interaction between Drp1 and other mitochondrial adaptors, as demonstrated by co-immunoprecipitation. Further, using a model of Parkinson's disease (PD) in culture, we demonstrated that P110 is neuroprotective by inhibiting mitochondrial fragmentation and ROS production and subsequently improving mitochondrial membrane potential and mitochondrial integrity. P110 increased neuronal cell viability by reducing apoptosis and autophagic cell death, and reduced neurite loss of primary dopaminergic neurons in this PD cell culture model. We also found that P110 treatment appears to have minimal effects on mitochondrial fission and cell viability under basal conditions. Finally, P110 required the presence of Drp1 to inhibit mitochondrial fission under oxidative stress conditions. Together, our findings suggest that P110, as a selective peptide inhibitor of Drp1, might be useful for treatment of diseases in which excessive mitochondrial fission and mitochondrial dysfunction occur.
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Mitochondria are dynamic organelles that continually divide and fuse with one another. These processes facilitate the control of mitochondrial morphology and respond to cell metabolic demands, such as ATP production, Ca2+ homeostasis and cell apoptosis. The excessive mitochondrial division is associated with neuronal cell death and neuronal dysfunction. Moreover, abnormal mitochondrial morphology can be found in many neurological disorders. Drp1 (dynamin-related protein 1) is a critical protein that facilitates mitochondrial division. However, the regulatory mechanism remains largely unclear. Cdk5 (cyclin dependent kinase 5) is implicated in neuronal death and survival. Previously, we found that Drp1 phosphorylated by Cdk5 in vitro. The goal of this thesis is to characterize the effects of Cdk5 dependent post-translational modification on Drp1 function. Overexpression of Drp1 S616D phospho-mimetic mutant led mitochondrial dynamic balance toward fusion and promoted Drp1 translocation to mitochondria. Our results suggest that Cdk5 phosphorylation of Drp1 at Ser-616 affects Drp1 protein function and mediates translocation of Drp1 to mitochondria. We consider Cdk5 phosphorylation is one of the mitochondrial division regulatory machineries.
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