Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model

Charli, Adhithiya; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

doi:10.1016/j.neuro.2015.06.007

Cited by 66 publications

(50 citation statements)

References 53 publications

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“…As ETC inhibitors can cause mitochondrial dysfunction leading to mitochondrial depolarization and energy depletion (Plaza Davila et al, 2015; Charli et al, 2016), we next assessed the impact of ROT on mitochondrial membrane potential (MMP, Δψ m ). The outer membrane of mitochondria is highly susceptible to reactive free radicals and increased free radical generation within the cell can damage the structure of the outer membrane, creating pores and making the membrane leaky (Kowaltowski et al, 2001; Chipuk et al, 2006; Tait and Green, 2010).…”

Section: Resultsmentioning

confidence: 99%

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

Lawana

Singh

Sarkar

et al. 2017

J Neuroimmune Pharmacol

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A growing body of evidence suggests that excessive microglial activation and pesticide exposure may be linked to the etiology of PD; however, the mechanisms involved remain elusive. Emerging evidence indicates that intracellular inflammasome complex namely NLRP3 complex is involved in the recognition and execution of host inflammatory response. Thus, in the present study, we investigated the hypothesis that NLRP3 inflammasome activation is linked to rotenone (ROT)-induced microglial activation which is dependent upon a priming stimulus by a pathogen-associated molecular pattern (PAMP) or damage associated molecular pattern (DAMP), respectively. Herein using both BV2 cells and primary microglial cells, we show that LPS priming and subsequent ROT stimulation enhanced NLRP3 inflammasome activation, c-Abl and PKCδ activation, mitochondrial dysfunction, NF-κB activation, and autophagic markers, while TFEB levels were decreased dramatically. Mechanistic studies revealed c-Abl acts as a proximal signal that exacerbated the activation of the afore mentioned markers. Intriguingly, siRNA-mediated depletion or pharmacological inhibition of c-Abl via dasatinib abrogated LPS and ROT-induced microglial activation response via attenuation of NLRP3 inflammasome activation, mitochondrial oxidative stress, and ALS dysfunction. Moreover, mitoTEMPO, a mitochondrial antioxidant, attenuated NLRP3 inflammasome activation effects via blockade of c-Abl and PKCδ activation. In LPS treated mice, dasatinib attenuated NLRP3 inflammasome activation, c-Abl and PKCδ activation; and sickness behavior. Together our findings identify an exaggerated ROS/c-Abl/NLRP3 signaling axis in the heightened microglial activation response evidenced in LPS-primed ROT-stimulated microglial cells and suggest that targeting c-Abl-regulated NLRP3 inflammasome signaling offers a novel therapeutic strategy for PD treatment.

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Section: Resultsmentioning

confidence: 99%

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

Lawana

Singh

Sarkar

et al. 2017

J Neuroimmune Pharmacol

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“…The MitoTraker Red signal was then analyzed, after background subtraction, using ImageJ 1, 46 software (Wayne Rasband, National Institutes of Health, Bethesda, MD, USA) using a semi-manual method based on the delimitation of the cells. We measured mitochondrial morphological characteristics for each cells, as previously described [19]. Average circularity [19] was used as an indicator for mitochondrial morphological changes.…”

Section: Immunoflurescencementioning

confidence: 99%

“…We measured mitochondrial morphological characteristics for each cells, as previously described [19]. Average circularity [19] was used as an indicator for mitochondrial morphological changes.…”

Section: Immunoflurescencementioning

confidence: 99%

Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells

Salani

Ravera

Fabbi

et al. 2017

Cell Physiol Biochem

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Background: Sulfonylureas, such as glibenclamide, are antidiabetic drugs that stimulate beta-cell insulin secretion by binding to the sulfonylureas receptors (SURs) of adenosine triphosphate-sensitive potassium channels (K ATP ). Glibenclamide may be also cardiotoxic, this effect being ascribed to interference with the protective function of cardiac K ATP channels for which glibenclamide has high affinity. Prompted by recent evidence that glibenclamide impairs energy metabolism of renal cells, we investigated whether this drug also affects the metabolism of cardiac cells. Methods: The cardiomyoblast cell line H9c2 was treated for 24 h with glibenclamide or metformin, a known inhibitor of the mitochondrial respiratory chain. Cell viability was evaluated by sulforodhamine B assay. ATP and AMP were measured according to the enzyme coupling method and oxygen consumption by using an amperometric electrode, while Fo-F1 ATP synthase activity assay was evaluated by chemiluminescent method. Protein expression was measured by western blot. Results: Glibenclamide deregulated energy balance of H9c2 cardiomyoblasts in a way similar to that of metformin. It inhibited mitochondrial complexes I, II and III with ensuing impairment of oxygen consumption and ATP synthase activity, ATP depletion and increased AMPK phosphorylation. Furthermore, glibenclamide disrupted mitochondrial subcellular organization. The perturbation of mitochondrial energy balance was associated with enhanced anaerobic glycolysis, with increased activity of phosphofructo kinase, pyruvate kinase and lactic dehydrogenase. Interestingly, some additive effects of glibenclamide and metformin were observed. Conclusions: Glibenclamide deeply alters cell metabolism in cardiac cells by impairing mitochondrial organization and function. This may further explain the risk of cardiovascular events associated with the use of this drug, alone or in combination with metformin.

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“…The Seahorse XF96 Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA, USA) was used to measure oxygen consumption rate (OCR) in N27 dopaminergic neuronal cells as described previously (Charli et al 2016). Briefly, N27 cells were seeded at 10,000 cells/well in a Seahorse Bioscience polystyrene microplate.…”

Section: Measurement Of Mitochondrial Oxygen Consumptionmentioning

confidence: 99%

Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease

Luo

Langley

et al. 2017

Journal of Neurochemistry

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149

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Quercetin, one of the major flavonoids in plants, has been recently reported to have neuroprotective effects against neurodegenerative processes. However, since the molecular signaling mechanisms governing these effects are not well clarified, we evaluated quercetin’s effect on the neuroprotective signaling events in dopaminergic neuronal models and further tested its efficacy in the MitoPark transgenic mouse model of Parkinson’s disease (PD). Western blotting analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 (PKD1) and Akt in MN9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or siRNA knockdown of PKD1 blocked the activation of Akt, suggesting that PKD1 acts as an upstream regulator of Akt in quercetin-mediated neuroprotective signaling. Quercetin also enhanced CREB phosphorylation and expression of the CREB target gene BDNF. Results from qRT-PCR, Western blot analysis, mtDNA content analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protected MN9D cells against 6-OHDA-induced neurotoxicity. To further evaluate the neuroprotective efficacy of quercetin against the mitochondrial dysfunction underlying PD, we used the progressive dopaminergic neurodegenerative MitoPark transgenic mouse model of PD. Oral administration of quercetin significantly reversed behavioral deficits, striatal dopamine depletion, and TH neuronal cell loss in MitoPark mice. Together, our findings demonstrate that quercetin activates PKD1-Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treating PD may offer clinical benefits.

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Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model

Cited by 66 publications

References 53 publications

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells

Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease

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