Wnt-5a Ligand Modulates Mitochondrial Fission-Fusion in Rat Hippocampal Neurons

Godoy, Juan A.; Arrázola, Macarena S.; Ordenes, Daniela; Silva-Álvarez, Carmen; Braidy, Nady; Inestrosa, Nibaldo C.

doi:10.1074/jbc.m114.557009

Cited by 57 publications

(58 citation statements)

References 68 publications

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“…The Wnt pathway plays an essential role during the development, and Wnt components participate as key players in the development of the central nervous system (61). Previous evidence suggests that Wnt proteins act as a potent modulator of mitochondrial dynamics and initiate the process of mitochondrial fission and fusion in the hippocampal neurons of rodents (59,60). Therefore, increased mitochondrial fission by BPA observed in the present study could also be due to impaired expression and levels of Wnt proteins.…”

Section: Discussionmentioning

confidence: 44%

“…Inhibition of excessive mitochondrial fission reduces aberrant autophagy and prevents neurodegeneration (58). The observed alterations in mitochondrial dynamics by BPA in the present study could also be explained on the basis of alterations in the Wnt/␤-catenin pathway (59,60). In our earlier studies we found that BPA exposure down-regulated the expression and levels of Wnt proteins (2).…”

Section: Discussionmentioning

confidence: 88%

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Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Agarwal

Yadav

Tiwari

et al. 2016

Journal of Biological Chemistry

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The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU-and ␤-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPAmediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus.

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Section: Discussionmentioning

confidence: 44%

Section: Discussionmentioning

confidence: 88%

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Agarwal

Yadav

Tiwari

et al. 2016

Journal of Biological Chemistry

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“…Furthermore, pyruvate can translocate into the mitochondria due to the production of ATP. We observed that treatment with the Wnt3a ligand increased the levels of the major substrate for ATP synthesis, ADP, thereby suggesting that this pathway activates the oxidative metabolism of glucose in neurons (37,63). Meanwhile, we did not observe changes in the regulatory enzyme G6PDH and in the overall PPP.…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 56%

“…The activity of the Wnt signaling pathway is essential for the development and function of central synapses that modulate several process, such as adult hippocampal neurogenesis, the establishment of synapses, neuronal firing activity, neuronal plasticity, nerve transmission, dendritic spine formation, and mitochondrial dynamics (2,(35)(36)(37)(38)(39). The deregulation of Wnt activity by loss or gain of function has been associated with the progression of various diseases, including cancer, diabetes mellitus type II, fibrosis, and AD (6,30,40,41).…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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“…The mitochondrial network was 3-dimensionally reconstructed as previously described [39] from mito-Cherry-transfected neurons. To overexpress mito-Cherry, we used NeuroMag (OZ Bioscience, Marseille, France) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Wnt Signaling Prevents the Aβ Oligomer-Induced Mitochondrial Permeability Transition Pore Opening Preserving Mitochondrial Structure in Hippocampal Neurons

et al. 2017

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Alzheimer’s disease (AD) is a neurodegenerative disorder mainly known for synaptic impairment and neuronal cell loss, affecting memory processes. Beside these damages, mitochondria have been implicated in the pathogenesis of AD through the induction of the mitochondrial permeability transition pore (mPTP). The mPTP is a non-selective pore that is formed under apoptotic conditions, disturbing mitochondrial structure and thus, neuronal viability. In AD, Aβ oligomers (Aβos) favor the opening of the pore, activating mitochondria-dependent neuronal cell death cascades. The Wnt signaling activated through the ligand Wnt3a has been described as a neuroprotective signaling pathway against amyloid-β (Aβ) peptide toxicity in AD. However, the mechanisms by which Wnt signaling prevents Aβos-induced neuronal cell death are unclear. We proposed here to study whether Wnt signaling protects neurons earlier than the late damages in the progression of the disease, through the preservation of the mitochondrial structure by the mPTP inhibition. To study specific events related to mitochondrial permeabilization we performed live-cell imaging from primary rat hippocampal neurons, and electron microscopy to analyze the mitochondrial morphology and structure. We report here that Wnt3a prevents an Aβos-induced cascade of mitochondrial events that leads to neuronal cell death. This cascade involves (a) mPTP opening, (b) mitochondrial swelling, (c) mitochondrial membrane potential loss and (d) cytochrome c release, thus leading to neuronal cell death. Furthermore, our results suggest that the activation of the Wnt signaling prevents mPTP opening by two possible mechanisms, which involve the inhibition of mitochondrial GSK-3β and/or the modulation of mitochondrial hexokinase II levels and activity. This study suggests a possible new approach for the treatment of AD from a mitochondrial perspective, and will also open new lines of study in the field of Wnt signaling in neuroprotection.

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Wnt-5a Ligand Modulates Mitochondrial Fission-Fusion in Rat Hippocampal Neurons

Cited by 57 publications

References 68 publications

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Wnt Signaling Prevents the Aβ Oligomer-Induced Mitochondrial Permeability Transition Pore Opening Preserving Mitochondrial Structure in Hippocampal Neurons

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